Molecules

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2595 KiB

Open AccessArticle

Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?

by Iwona Dams, Anna Ostaszewska, Maria Puchalska, Justyna Chmiel, Piotr Cmoch, Iwona Bujak, Agata Białońska and Wojciech J. Szczepek

Molecules 2015, 20(12), 21346-21363; https://doi.org/10.3390/molecules201219762 - 1 Dec 2015

Cited by 12 | Viewed by 10484

Abstract

During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which [...] Read more.

During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their ¹H, ¹³C and ¹⁵N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers. Full article

(This article belongs to the Special Issue Prodrugs)

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3664 KiB

Open AccessArticle

Evaluation of Novel Antibacterial N-Halamine Nanoparticles Prodrugs towards Susceptibility of Escherichia coli Induced by DksA Protein

by Qigeqi Dong, Alideertu Dong and Morigen

Molecules 2015, 20(4), 7292-7308; https://doi.org/10.3390/molecules20047292 - 21 Apr 2015

Cited by 17 | Viewed by 7872

Abstract

Novel N-halamine nanoparticles potentially useful for killing pathogenic bacteria, i.e., SiO₂@PS/N-halamine NPs, were successfully synthesized via the immobilization of N-halamines onto the polystyrene-coated silica nanoparticles (SiO₂@PS NPs). The effect of reaction conditions, i.e., [...] Read more.

Novel N-halamine nanoparticles potentially useful for killing pathogenic bacteria, i.e., SiO₂@PS/N-halamine NPs, were successfully synthesized via the immobilization of N-halamines onto the polystyrene-coated silica nanoparticles (SiO₂@PS NPs). The effect of reaction conditions, i.e., chlorination temperature, bleaching concentration, chlorination time, on the oxidative chlorine content in the products was systematically investigated. The antibacterial activity of the products was tested via the modified plate counting methd using Escherichia coli (E. coli) as a model bacterium. The possible mechanism of the antibacterial action of the products was also studied using scanning electron microscopy combined with a inhibition zone study. The antimicrobial capability of the products was well controlled by tuning the oxidative chlorine content in the products. More importantly, the role of DksA protein in the susceptibility of E. coli against the products was proven using a time-kill assay. This in-depth investigation of the sensitivity of E. coli towards N-halamine NPs provides a systematic understanding of the utility of N-halamines for deactivating bacteria or even disease control. Full article

(This article belongs to the Special Issue Prodrugs)

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607 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs

by Mo Zhou, Meixia Liu, Xinhua He, Hong Yu, Di Wu, Yishan Yao, Shiyong Fan, Ping Zhang, Weiguo Shi and Bohua Zhong

Molecules 2014, 19(12), 19718-19731; https://doi.org/10.3390/molecules191219718 - 27 Nov 2014

Cited by 13 | Viewed by 8351

Abstract

In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. [...] Read more.

In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC₅₀ values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC₅₀ values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo. Full article

(This article belongs to the Special Issue Prodrugs)

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494 KiB

Open AccessCommunication

Polylactide Conjugates of Camptothecin with Different Drug Release Abilities

by Ewa Oledzka, Paweł Horeglad, Zuzanna Gruszczyńska, Andrzej Plichta, Grzegorz Nałęcz-Jawecki and Marcin Sobczak

Molecules 2014, 19(12), 19460-19470; https://doi.org/10.3390/molecules191219460 - 25 Nov 2014

Cited by 16 | Viewed by 7500

Abstract

Camptothecin-polylactide conjugates (CMPT-PLA) were synthesized by covalent incorporation of CMPT into PLA of different microstructure, i.e., atactic PLA and atactic-block-isotactically enriched PLA (P_m = 0.79) via urethane bonds. The kinetic release of CPMT from CMPT-PLA conjugates, tested in [...] Read more.

Camptothecin-polylactide conjugates (CMPT-PLA) were synthesized by covalent incorporation of CMPT into PLA of different microstructure, i.e., atactic PLA and atactic-block-isotactically enriched PLA (P_m = 0.79) via urethane bonds. The kinetic release of CPMT from CMPT-PLA conjugates, tested in vitro under different conditions, is possible in both cases and notably, strongly dependent on PLA microstructure. It shows that release properties of drug-PLA conjugates can be tailored by controlled design of the PLA microstructure, and allow in the case of CMPT-PLA conjugates for the development of highly controlled biodegradable CMPT systems—important delivery systems for anti-cancer agents. Full article

(This article belongs to the Special Issue Prodrugs)

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302 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Liguzinediol Mono- and Dual Ester Prodrugs as Promising Inotropic Agents

by Jing Zhang, Wei Li, Hong-Mei Wen, Hao-Hao Zhu, Tian-Lin Wang, Dong Cheng, Kun-Di Yang and Yu-Qing Chen

Molecules 2014, 19(11), 18057-18072; https://doi.org/10.3390/molecules191118057 - 5 Nov 2014

Cited by 9 | Viewed by 6461

Abstract

The potent positive inotropic effect, together with the relatively low safety risk of liguzinediol (LZDO), relative to currently available inotropic drugs, has prompted us to intensively research and develop LZDO as a potent positive inotropic agent. In this study, to obtain [...] Read more.

The potent positive inotropic effect, together with the relatively low safety risk of liguzinediol (LZDO), relative to currently available inotropic drugs, has prompted us to intensively research and develop LZDO as a potent positive inotropic agent. In this study, to obtain LZDO alternatives for oral chronic administration, a series of long-chain fatty carboxylic mono- and dual-esters of LZDO were synthesized, and preliminarily evaluated for physicochemical properties and bioconversion. Enhanced lipophilic properties and decreased solubility of the prodrugs were observed as the side chain length increased. All esters showed conspicuous chemical stability in phosphate buffer (pH 7.4). Moreover, the enzymatic hydrolysis of esters in human plasma and human liver microsomes confirmed that the majority of esters were converted to LZDO, with release profiles that varied due to the size and structure of the side chain. In vivo pharmacokinetic studies following oral administration of monopivaloyl (M5), monodecyl (M10) and monododecyl (M12) esters demonstrated the evidently extended half-lives relative to LZDO dosed alone. In particular the monopivaloyl ester M5 exhibited an optimal pharmacokinetic profile with appropriate physiochemical characteristics. Full article

(This article belongs to the Special Issue Prodrugs)

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574 KiB

Open AccessArticle

Anti-Obesity Effects of Hispidin and Alpinia zerumbet Bioactives in 3T3-L1 Adipocytes

by Pham Thi Be Tu and Shinkichi Tawata

Molecules 2014, 19(10), 16656-16671; https://doi.org/10.3390/molecules191016656 - 15 Oct 2014

Cited by 44 | Viewed by 10024

Abstract

Obesity and its related disorders have become leading metabolic diseases. In the present study, we used 3T3-L1 adipocytes to investigate the anti-obesity activity of hispidin and two related compounds that were isolated from Alpinia zerumbet (alpinia) rhizomes. The results showed that hispidin, dihydro-5,6-dehydrokawain [...] Read more.

Obesity and its related disorders have become leading metabolic diseases. In the present study, we used 3T3-L1 adipocytes to investigate the anti-obesity activity of hispidin and two related compounds that were isolated from Alpinia zerumbet (alpinia) rhizomes. The results showed that hispidin, dihydro-5,6-dehydrokawain (DDK), and 5,6-dehydrokawain (DK) have promising anti-obesity properties. In particular, all three compounds significantly increased intracellular cyclic adenosine monophosphate (cAMP) concentrations by 81.2% ± 0.06%, 67.0% ± 1.62%, and 56.9% ± 0.19%, respectively. Hispidin also stimulated glycerol release by 276.4% ± 0.8% and inhibited lipid accumulation by 47.8% ± 0.16%. Hispidin and DDK decreased intracellular triglyceride content by 79.5% ± 1.37% and 70.2% ± 1.4%, respectively, and all three compounds inhibited glycerol-3-phosphate dehydrogenase (GPDH) and pancreatic lipase, with hispidin and DDK being the most potent inhibitors. Finally, none of the three compounds reduced 3T3-L1 adipocyte viability. These results highlight the potential for developing hispidin and its derivatives as anti-obesity compounds. Full article

(This article belongs to the Special Issue Prodrugs)

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1074 KiB

Open AccessArticle

Exploration of Piperidinols as Potential Antitubercular Agents

by Areej Abuhammad, Elizabeth Fullam, Sanjib Bhakta, Angela J. Russell, Garrett M. Morris, Paul W. Finn and Edith Sim

Molecules 2014, 19(10), 16274-16290; https://doi.org/10.3390/molecules191016274 - 10 Oct 2014

Cited by 16 | Viewed by 7970

Abstract

Novel drugs to treat tuberculosis are required and the identification of potential targets is important. Piperidinols have been identified as potential antimycobacterial agents (MIC < 5 μg/mL), which also inhibit mycobacterial arylamine N-acetyltransferase (NAT), an enzyme essential for mycobacterial survival inside macrophages. [...] Read more.

Novel drugs to treat tuberculosis are required and the identification of potential targets is important. Piperidinols have been identified as potential antimycobacterial agents (MIC < 5 μg/mL), which also inhibit mycobacterial arylamine N-acetyltransferase (NAT), an enzyme essential for mycobacterial survival inside macrophages. The NAT inhibition involves a prodrug-like mechanism in which activation leads to the formation of bioactive phenyl vinyl ketone (PVK). The PVK fragment selectively forms an adduct with the cysteine residue in the active site. Time dependent inhibition of the NAT enzyme from Mycobacterium marinum (M. marinum) demonstrates a covalent binding mechanism for all inhibitory piperidinol analogues. The structure activity relationship highlights the importance of halide substitution on the piperidinol benzene ring. The structures of the NAT enzymes from M. marinum and M. tuberculosis, although 74% identical, have different residues in their active site clefts and allow the effects of amino acid substitutions to be assessed in understanding inhibitory potency. In addition, we have used the piperidinol 3-dimensional shape and electrostatic properties to identify two additional distinct chemical scaffolds as inhibitors of NAT. While one of the scaffolds has anti-tubercular activity, both inhibit NAT but through a non-covalent mechanism. Full article

(This article belongs to the Special Issue Prodrugs)

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826 KiB

Open AccessArticle

Synthesis, Leishmanicidal and Cytotoxic Activity of Triclosan-Chalcone, Triclosan-Chromone and Triclosan-Coumarin Hybrids

by Elver Otero, Sebastián Vergara, Sara M. Robledo, Wilson Cardona, Miguel Carda, Ivan D. Vélez, Carlos Rojas and Felipe Otálvaro

Molecules 2014, 19(9), 13251-13266; https://doi.org/10.3390/molecules190913251 - 28 Aug 2014

Cited by 40 | Viewed by 9459

Abstract

Twelve hybrids derived from triclosan were obtained via Williamson etherification of O-triclosan alkyl bromide plus chalcone and O-coumarin or O-chromone alkyl bromide plus triclosan, respectively. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against [...] Read more.

Twelve hybrids derived from triclosan were obtained via Williamson etherification of O-triclosan alkyl bromide plus chalcone and O-coumarin or O-chromone alkyl bromide plus triclosan, respectively. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes. Cytotoxic activity was also evaluated against mammalian U-937 cells. Compounds 7–9 and 17, were active against Leishmania parasites (EC₅₀ = 9.4; 10.2; 13.5 and 27.5 µg/mL, respectively) and showed no toxicity toward mammalian cells (>200 µg/mL). They are potential candidates for antileishmanial drug development. Compounds 25–27, were active and cytotoxic. Further studies using other cell types are needed in order to discriminate whether the toxicity shown by these compounds is against tumor or non-tumor cells. The results indicate that compounds containing small alkyl chains show better selectivity indices. Moreover, Michael acceptor moieties may modify both the leishmanicidal activity and cytotoxicity. Further studies are required to evaluate if the in vitro activity against Leishmania panamensis demonstrated here is also observed in vivo. Full article

(This article belongs to the Special Issue Prodrugs)

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1202 KiB

Open AccessArticle

Effects of Ursolic Acid Derivatives on Caco-2 Cells and Their Alleviating Role in Streptozocin-Induced Type 2 Diabetic Rats

by Panpan Wu, Ping He, Suqing Zhao, Tianming Huang, Yujing Lu and Kun Zhang

Molecules 2014, 19(8), 12559-12576; https://doi.org/10.3390/molecules190812559 - 19 Aug 2014

Cited by 23 | Viewed by 9216

Abstract

In this study, the effect and mechanism of a series of ursolic acid (UA) derivatives on glucose uptake were investigated in a Caco-2 cells model. Their effect on hyperglycemia, hyperlipidemia and oxidative stress were also demonstrated in streptozocin (STZ)-induced diabetic rats. 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-glucose (2-NBDG) [...] Read more.

In this study, the effect and mechanism of a series of ursolic acid (UA) derivatives on glucose uptake were investigated in a Caco-2 cells model. Their effect on hyperglycemia, hyperlipidemia and oxidative stress were also demonstrated in streptozocin (STZ)-induced diabetic rats. 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-glucose (2-NBDG) was used as a fluorescein in Caco-2 cells model to screen UA derivatives by glucose uptake and expression of glucose transporter protein (SGLT-1, GLUT-2). Moreover, STZ-induced diabetic rats were administered with these derivatives for 4 weeks of treatment. The fasting blood glucose (FBG), insulin levels, biochemical parameters, lipid levels, and oxidative stress markers were finally evaluated. The results of this study indicated that compounds 10 and 11 significantly inhibited 2-NBDG uptake under both Na⁺-dependent and Na⁺-independent conditions by decreasing SGLT-1 and GLUT-2 expression in the Caco-2 cells model. Further in vivo studies revealed that compound 10 significantly reduced hyperglycemia by increasing levels of serum insulin, total protein, and albumin, while the fasting blood glucose, body weight and food intake were restored much closer to those of normal rats. Compounds 10 and 11 showed hypolipidemic activity by decreasing the total amounts of cholesterol (TC) and triglycerides (TG). Furthermore, compound 10 showed antioxidant potential which was confirmed by elevation of glutathione (GSH) and superoxide dismutase (SOD) and reduction of malondialdehyde (MDA) levels in the liver and kidney of diabetic rats. It was concluded that compound 10 caused an apparent inhibition of intestinal glucose uptake in Caco-2 cells and hypoglycemia, hypolipidemia and augmented oxidative stress in STZ-induced diabetic rats. Thus, compound 10 could be developed as a potentially complementary therapeutic or prophylactic agent for diabetics mellitus and its complications. Full article

(This article belongs to the Special Issue Prodrugs)

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175 KiB

Open AccessArticle

Synthesis and Antifungal Evaluation of 1-Aryl-2-dimethyl-aminomethyl-2-propen-1-one Hydrochlorides

by Ebru Mete, Halise Inci Gul, Sinan Bilginer, Oztekin Algul, Mehmet Emin Topaloglu, Medine Gulluce and Cavit Kazaz

Molecules 2011, 16(6), 4660-4671; https://doi.org/10.3390/molecules16064660 - 3 Jun 2011

Cited by 15 | Viewed by 7826

Abstract

The development of resistance to current antifungal therapeutics drives the search for new effective agents. The fact that several acetophenone-derived Mannich bases had shown remarkable antifungal activities in our previous studies led us to design and synthesize some acetophenone-derived Mannich bases, 1-8 and [...] Read more.

The development of resistance to current antifungal therapeutics drives the search for new effective agents. The fact that several acetophenone-derived Mannich bases had shown remarkable antifungal activities in our previous studies led us to design and synthesize some acetophenone-derived Mannich bases, 1-8 and 2-acetylthiophene-derived Mannich base 9, 1-aryl-2-dimethylaminomethyl-2-propen-1-one hydrochloride, to evaluate their antifungal activities. The designed chemical structures have α,β-unsaturated ketone moieties, which are responsible for the bioactivities of the Mannich bases. The aryl part was C₆H₅(1); 4-CH₃C₆H₄(2); 4-CH₃OC₆H₄(3); 4-ClC₆H₄(4); 4-FC₆H₄(5); 4-BrC₆H₄(6); 4-HOC₆H₄(7); 4-NO₂C₆H₄(8); and C₄H₃S(2-yl) (9). In this study the designed compounds were synthesized by the conventional heating method and also by the microwave irradiation method to compare these methods in terms of reaction times and yields to find an optimum synthetic method, which can be applied for the synthesis of Mannich bases in further studies. Since there are limited number of studies reporting the synthesis of Mannich bases by microwave irradiation, this study may also contribute to the general literature on Mannich bases. Compound 7 was reported for the first time. Antifungal activities of all compounds and synthesis of the compounds by microwave irradiation were also reported for the first time by this study. Fungi (15 species) were used for antifungal activity test. Amphotericin B was tested as an antifungal reference compound. In conclusion, compounds 1-6, and 9, which had more potent (2–16 times) antifungal activity than the reference compound amphotericin B against some fungi, can be model compounds for further studies to develop new antifungal agents. In addition, microwave irradiation can be considered to reduce reaction period, while the conventional method can still be considered to obtain compounds with higher reaction yields in the synthesis of new Mannich bases. Full article

(This article belongs to the Special Issue Prodrugs)

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370 KiB

Open AccessArticle

Investigation of Solvolysis Kinetics of New Synthesized Fluocinolone Acetonide C-21 Esters—An In Vitro Model for Prodrug Activation

by Bojan D. Markovic, Vladimir D. Dobricic, Sote M. Vladimirov, Olivera A. Cudina, Vladimir M. Savic and Katarina D. Karljikovic-Rajic

Molecules 2011, 16(3), 2658-2671; https://doi.org/10.3390/molecules16032658 - 23 Mar 2011

Cited by 11 | Viewed by 10249

Abstract

In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO₃. The solvolytic [...] Read more.

In this study the solvolysis of newly synthesized fluocinolone acetonide C-21 esters was analysed in comparison with fluocinonide during a 24-hour period of time. The solvolysis was performed in an ethanol-water (90:10 v/v) mixture using the excess of NaHCO₃. The solvolytic mixtures of each investigated ester have been assayed by a RP-HPLC method using isocratic elution with methanol-water (75:25 v/v); flow rate 1 mL/min; detection at 238 nm; temperature 25 °C. Solvolytic rate constants were calculated from the obtained data. Geometry optimizations and charges calculations were carried out by Gaussian W03 software. A good correlation (R = 0.9924) was obtained between solvolytic rate constants and the polarity of the C-O2 bond of those esters. The established relation between solvolytic rate constant (K) and lipophilicity (cLogP) with experimental anti-inflammatory activity could be indicative for topical corticosteroid prodrug activation. Full article

(This article belongs to the Special Issue Prodrugs)

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197 KiB

Open AccessArticle

Synthesis, Characterization and Biological Evaluation of Succinate Prodrugs of Curcuminoids for Colon Cancer Treatment

by Wisut Wichitnithad, Ubonthip Nimmannit, Sumrit Wacharasindhu and Pornchai Rojsitthisak

Molecules 2011, 16(2), 1888-1900; https://doi.org/10.3390/molecules16021888 - 22 Feb 2011

Cited by 104 | Viewed by 13435

Abstract

A novel series of succinyl derivatives of three curcuminoids were synthesized as potential prodrugs. Symmetrical (curcumin and bisdesmethoxycurcumin) and unsymmetrical (desmethoxycurcumin) curcuminoids were prepared through aldol condensation of 2,4-pentanedione with different benzaldehydes. Esterification of these compounds with a methyl or ethyl ester of [...] Read more.

A novel series of succinyl derivatives of three curcuminoids were synthesized as potential prodrugs. Symmetrical (curcumin and bisdesmethoxycurcumin) and unsymmetrical (desmethoxycurcumin) curcuminoids were prepared through aldol condensation of 2,4-pentanedione with different benzaldehydes. Esterification of these compounds with a methyl or ethyl ester of succinyl chloride gave the corresponding succinate prodrugs in excellent yields. Anticolon cancer activity of the compounds was evaluated using Caco-2 cells. The succinate prodrugs had IC₅₀ values in the 1.8–9.6 μM range, compared to IC₅₀ values of 3.3–4.9 μM for the parent compounds. Curcumin diethyl disuccinate exhibited the highest potency and was chosen for stability studies. Hydrolysis of this compound in phosphate buffer at pH 7.4 and in human plasma followed pseudo first-order kinetics. In phosphate buffer, the k_obs and t_1/2 for hydrolysis indicated that the compound was much more stable than curcumin. In human plasma, this compound was able to release curcumin, therefore our results suggest that succinate prodrugs of curcuminoids are stable in phosphate buffer, release the parent curcumin derivatives readily in human plasma, and show anti-colon cancer activity. Full article

(This article belongs to the Special Issue Prodrugs)

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533 KiB

Open AccessArticle

3-Acetyloxy-2-cyano-2-(alkylaminocarbamoyl)propyl Groups as Biodegradable Protecting Groups of Nucleoside 5´-mono-Phosphates

by Mikko Ora, Anne Mäntyvaara and Harri Lönnberg

Molecules 2011, 16(1), 552-566; https://doi.org/10.3390/molecules16010552 - 14 Jan 2011

Cited by 3 | Viewed by 7897

Abstract

Thymidine 5´-bis[3-acetyloxy-2-cyano-2-(2-phenylethylcarbamoyl)propyl]phosphate (1) has been prepared and the removal of phosphate protecting groups by hog liver carboxyesterase (HLE) at pH 7.5 and 37 °C has been followed by HPLC. The first detectable intermediates are the (R_P)- and ( [...] Read more.

Thymidine 5´-bis[3-acetyloxy-2-cyano-2-(2-phenylethylcarbamoyl)propyl]phosphate (1) has been prepared and the removal of phosphate protecting groups by hog liver carboxyesterase (HLE) at pH 7.5 and 37 °C has been followed by HPLC. The first detectable intermediates are the (R_P)- and (S_P)-diastereomers of the monodeacetylated triester 14, which subsequently undergo concurrent retro-aldol condensation to diester 4 and enzyme-catalyzed hydrolysis to the fully deacetylated triester 15. The former pathway predominates, representing 90% of the overall breakdown of 14. The diester 4 undergoes the enzymatic deacetylation 700 times less readily than the triester, but gives finally thymidine 5´-monophosphate as the desired main product. To elucidate the potential toxicity of the electrophilic 2-cyano-N-(2-phenylethyl)acrylamideby-product 17 released upon the deprotection, the hydrolysis of 1 has also been studied in the presence of glutathione (GSH). Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Design and Synthesis of Anti-MRSA Benzimidazolylbenzene-sulfonamides. QSAR Studies for Prediction of Antibacterial Activity

by Marco Martín González-Chávez, Francisco Méndez, Roberto Martínez, Cuaúhtemoc Pérez-González and Fidel Martínez-Gutiérrez

Molecules 2011, 16(1), 175-189; https://doi.org/10.3390/molecules16010175 - 29 Dec 2010

Cited by 13 | Viewed by 10642

Abstract

A series of benzimidazolylbenzenesulfonamide compounds containing electron-releasing and electron-withdrawing substituents were synthesized and tested for their in vitro antibacterial activity. Two BZS compounds showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Bacillus subtilis. Quantitative studies of their structure-activity relationship using a [...] Read more.

A series of benzimidazolylbenzenesulfonamide compounds containing electron-releasing and electron-withdrawing substituents were synthesized and tested for their in vitro antibacterial activity. Two BZS compounds showed strong antibacterial activity against methicillin-resistant Staphylococcus aureus and Bacillus subtilis. Quantitative studies of their structure-activity relationship using a simple linear regression analysis were applied to explore the correlation between the biological activity and the charges on acidic hydrogen atoms in the synthesized compounds. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

The Influence of α-, β-, and γ-Melanocyte Stimulating Hormone on Acetaminophen Induced Liver Lesions in Male CBA Mice

by Vladimir Blagaić, Karlo Houra, Petra Turčić, Nikola Štambuk, Paško Konjevoda, Alenka Boban-Blagaić, Tomislav Kelava, Marina Kos, Gorana Aralica and Filip Čulo

Molecules 2010, 15(3), 1232-1241; https://doi.org/10.3390/molecules15031232 - 3 Mar 2010

Cited by 6 | Viewed by 7888

Abstract

Research over the past decade has indicated that melanocortin peptides are potent inhibitors of inflammation and a promising source of new anti-inflammatory and cytoprotective therapies. The purpose of the present paper is to compare protective effects of α-, β-, and γ-melanocyte stimulating hormone [...] Read more.

Research over the past decade has indicated that melanocortin peptides are potent inhibitors of inflammation and a promising source of new anti-inflammatory and cytoprotective therapies. The purpose of the present paper is to compare protective effects of α-, β-, and γ-melanocyte stimulating hormone on acetaminophen induced liver lesions in male CBA mice. Acetaminophen was applied intragastrically in a dose of 150 mg/kg, and tested substances were applied intraperitoneally 1 hour before acetaminophen. Mice were sacrificed after 24 hours and intensity of liver injury was estimated by measurement of plasma transaminase activity (AST and ALT) and histopathological grading of lesions. It was found that α-, β-, and γ-MSH decrease intensity of lesions by both criteria in a dose-dependent manner. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Seeking Polymeric Prodrugs of Norfloxacin. Part 2. Synthesis and Structural Analysis of Polyurethane Conjugates

by Marcin Sobczak, Katarzyna Nurzyńska and Waclaw Kolodziejski

Molecules 2010, 15(2), 842-856; https://doi.org/10.3390/molecules15020842 - 5 Feb 2010

Cited by 18 | Viewed by 8114

Abstract

Oligo(ε-caprolactone) and oligolactide were synthesized via ring-opening polymerization of cyclic esters in the presence of creatinine as initiators. Thus obtained oligomers were successfully used in the synthesis of novel polyurethane conjugates of norfloxacin. The structures of the polymers and conjugates were elucidated by [...] Read more.

Oligo(ε-caprolactone) and oligolactide were synthesized via ring-opening polymerization of cyclic esters in the presence of creatinine as initiators. Thus obtained oligomers were successfully used in the synthesis of novel polyurethane conjugates of norfloxacin. The structures of the polymers and conjugates were elucidated by means of MALDI-TOF MS, NMR and IR studies. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

1-Arylsulfonyl-2-(Pyridylmethylsulfinyl) Benzimidazoles as New Proton Pump Inhibitor Prodrugs

by Jai Moo Shin, George Sachs, Young-moon Cho and Michael Garst

Molecules 2009, 14(12), 5247-5280; https://doi.org/10.3390/molecules14125247 - 15 Dec 2009

Cited by 13 | Viewed by 10168

Abstract

New arylsulfonyl proton pump inhibitor (PPI) prodrug forms were synthesized. These prodrugs provided longer residence time of an effective PPI plasma concentration, resulting in better gastric acid inhibition. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Effects of α-Melanocortin Enantiomers on Acetaminophen-Induced Hepatotoxicity in CBA Mice

by Petra Turčić, Mirna Bradamante, Karlo Houra, Nikola Štambuk, Tomislav Kelava, Paško Konjevoda, Saša Kazazić, Dražen Vikić-Topić and Biserka Pokrić

Molecules 2009, 14(12), 5017-5026; https://doi.org/10.3390/molecules14125017 - 2 Dec 2009

Cited by 10 | Viewed by 11257

Abstract

Proteins and peptides in mammals are based exclusively on L-amino acids. Recent investigations show that D-amino acids exhibit physiological effects in vivo, despite of their very small quantities. We have investigated the hepatoprotective effects of the Land D-enantiomers of α-melanocortin peptide (α-MSH). [...] Read more.

Proteins and peptides in mammals are based exclusively on L-amino acids. Recent investigations show that D-amino acids exhibit physiological effects in vivo, despite of their very small quantities. We have investigated the hepatoprotective effects of the Land D-enantiomers of α-melanocortin peptide (α-MSH). The results showed that peptideenantiomerism is related to the protective effects of melanocortin peptides in vivo. L-α-MSH exhibited potent hepatoprotective effect in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice, while its D-mirror image was inefficient. Furthermore, the antibody to the L-peptide did not recognize the D-structure. The results indicate that the opposite peptide configuration may be used to modulate its function and metabolism in vivo and in vitro. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Soft Alkyl Ether Prodrugs of a Model Phenolic Drug: The Effect of Incorporation of Ethyleneoxy Groups on Transdermal Delivery

by Joshua Denver Thomas, Susruta Majumdar and Kenneth Berry Sloan

Molecules 2009, 14(10), 4231-4245; https://doi.org/10.3390/molecules14104231 - 22 Oct 2009

Cited by 15 | Viewed by 15763

Abstract

Two different types of soft alkyl ether prodrugs incorporating ethyleneoxy groups into the promoiety have been synthesized for a model phenol (acetaminophen, APAP): alkyloxycarbonyloxymethyl type (AOCOM) and N-alkyl-N-alkyloxycarbonyl-aminomethyl type (NANAOCAM). The solubilities in isopropyl myristate, S_IPM, and water, [...] Read more.

Two different types of soft alkyl ether prodrugs incorporating ethyleneoxy groups into the promoiety have been synthesized for a model phenol (acetaminophen, APAP): alkyloxycarbonyloxymethyl type (AOCOM) and N-alkyl-N-alkyloxycarbonyl-aminomethyl type (NANAOCAM). The solubilities in isopropyl myristate, S_IPM, and water, S_AQ, partition coefficients between IPM and pH 4.0 buffer, K_IPM:4.0, and the delivery of total species containing APAP through hairless mouse skin from IPM, J_MMIPM, have been measured for the prodrugs. The J_MMIPM values were accurately predicted by the Roberts-Sloan (RS) equation. Only modest increases in JMMIPM were realized (about 1.4 times) by each type. The only prodrug that was more water soluble and more lipid soluble than APAP did not improve J_MMIPM of APAP. This result may be due to the strong association of water molecules with the ethyleneoxy groups, and especially the triethyleneoxy derivative, which dramatically increases the molecular weight and depresses J_MMIPM. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Polyanionic Drugs and Viral Oncogenesis: a Novel Approach to Control Infection, Tumor-associated Inflammation and Angiogenesis

by Chiara Urbinati, Paola Chiodelli and Marco Rusnati

Molecules 2008, 13(11), 2758-2785; https://doi.org/10.3390/molecules13112758 - 6 Nov 2008

Cited by 46 | Viewed by 14489

Abstract

Polyanionic macromolecules are extremely abundant both in the extracellular environment and inside the cell, where they are readily accessible to many proteins for interactions that play a variety of biological roles. Among polyanions, heparin, heparan sulfate proteoglycans (HSPGs) and glycosphingolipids (GSLs) are widely [...] Read more.

Polyanionic macromolecules are extremely abundant both in the extracellular environment and inside the cell, where they are readily accessible to many proteins for interactions that play a variety of biological roles. Among polyanions, heparin, heparan sulfate proteoglycans (HSPGs) and glycosphingolipids (GSLs) are widely distributed in biological fluids, at the cell membrane and inside the cell, where they are implicated in several physiological and/or pathological processes such as infectious diseases, angiogenesis and tumor growth. At a molecular level, these processes are mainly mediated by microbial proteins, cytokines and receptors that exert their functions by binding to HSPGs and/or GSLs, suggesting the possibility to use polyanionic antagonists as efficient drugs for the treatment of infectious diseases and cancer. Polysulfated (PS) or polysulfonated (PSN) compounds are a heterogeneous group of natural, semi-synthetic or synthetic molecules whose prototypes are heparin and suramin. Different structural features confer to PS/PSN compounds the capacity to bind and inhibit the biological activities of those same heparin-binding proteins implicated in infectious diseases and cancer. In this review we will discuss the state of the art and the possible future development of polyanionic drugs in the treatment of infectious diseases and cancer. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Cytoprotective Efficacy of Amifostine Against Radiation- Induced Rectal Toxicity: Objective and Subjective Grading Scales for Radiomucositis

by Vassilis E. Kouloulias and John R. Kouvaris

Molecules 2008, 13(4), 892-903; https://doi.org/10.3390/molecules13040892 - 18 Apr 2008

Cited by 9 | Viewed by 10501

Abstract

Curative radiation therapy of pelvic malignancies, frequently results in doselimitingtoxicities such as serous, mucoid, or more rarely, bloody diarrhea. Several studieshave evaluated the cytoprotective effects of amifostine in preventing rectal mucositisassociated with radiation treatment. We searched Medline for published comparativestudies that evaluated the [...] Read more.

Curative radiation therapy of pelvic malignancies, frequently results in doselimitingtoxicities such as serous, mucoid, or more rarely, bloody diarrhea. Several studieshave evaluated the cytoprotective effects of amifostine in preventing rectal mucositisassociated with radiation treatment. We searched Medline for published comparativestudies that evaluated the use of amifostine to reduce radiation-induced toxicity associatedwith pelvic irradiation. In ten studies there was an evidence-based cytoprotection (P less than 0.05)by amifostine. Although results are variable, current evidence suggests that amifostine mayhave a radioprotective effect in the rectal mucosa, particularly when administeredintrarectally. Significant improvements were seen in both symptomatic and objective(rectosigmoidoscopy) end points. There is a need to conduct well-designed clinical trialswith sufficient numbers of participants to confirm these findings together with a costbenefitstudy. Objective measurements using rectosigmoidoscopy are superior tosubjective measures such as WHO or RTOG/EORTC toxicity grading scales. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Synthesis and Total ¹H- and ¹³C-NMR Assignment of Cephem Derivatives for Use in ADEPT Approaches

by Lorena Blau, Renato Farina Menegon, Elizabeth Igne Ferreira, Antonio Gilberto Ferreira, Elisangela Fabiana Boffo, Leila Aley Tavares, Vladimir Constantino Gomes Heleno and Man-Chin Chung

Molecules 2008, 13(4), 841-854; https://doi.org/10.3390/molecules13040841 - 10 Apr 2008

Cited by 6 | Viewed by 10563

Abstract

We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4’’-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporinderivative. This compound can be used as the carrier of a wide range of drugs containingan amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide [...] Read more.

We report the synthesis and total NMR characterization of 5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid-3-[[[(4’’-nitrophenoxy)carbonyl]oxy]-methyl]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (5), a new cephalosporinderivative. This compound can be used as the carrier of a wide range of drugs containingan amino group. The preparation of the intermediate product, 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]-diphenylmethyl ester-5-dioxide (6), as well as the synthesis of the antimalarial primaquine prodrug 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid-3-[methyl 4-(6-methoxyquinolin-8-ylamino)pentylcarbamate]-8-oxo-7-[(2-thienyloxoacetyl)amino]- 5-dioxide (7) are alsodescribed, together with their total ¹H- and ¹³C-NMR assignments. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Synthesis and Properties of a New Water-Soluble Prodrug of the Adenosine A_2A Receptor Antagonist MSX-2

by Karl Vollmann, Ramatullah Qurishi, Jörg Hockemeyer and Christa E. Müller

Molecules 2008, 13(2), 348-359; https://doi.org/10.3390/molecules13020348 - 12 Feb 2008

Cited by 42 | Viewed by 12003

Abstract

The compound L-valine-3-{8-[(E)-2-[3-methoxyphenyl)ethenyl]-7-methyl-1-propargylxanthine-3-yl}propyl ester hydrochloride (MSX-4) was synthesized as an aminoacid ester prodrug of the adenosine A2A receptor antagonist MSX-2. It was found to bestable in artificial gastric acid, but readily cleaved by pig liver esterase. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Trimethyl Lock: A Stable Chromogenic Substrate for Esterases

by Michael N. Levine, Luke D. Lavis and Ronald T. Raines

Molecules 2008, 13(2), 204-211; https://doi.org/10.3390/molecules13020204 - 31 Jan 2008

Cited by 21 | Viewed by 13684

Abstract

p-Nitrophenyl acetate is the most commonly used substrate for detecting thecatalytic activity of esterases, including those that activate prodrugs in human cells. Thissubstrate is unstable in aqueous solution, limiting its utility. Here, a stable chromogenicsubstrate for esterases is produced by the structural isolation [...] Read more.

p-Nitrophenyl acetate is the most commonly used substrate for detecting thecatalytic activity of esterases, including those that activate prodrugs in human cells. Thissubstrate is unstable in aqueous solution, limiting its utility. Here, a stable chromogenicsubstrate for esterases is produced by the structural isolation of an acetyl ester andp-nitroaniline group using a trimethyl lock moiety. Upon ester hydrolysis, unfavorablesteric interactions between the three methyl groups of this o-hydroxycinnamic acidderivative encourage rapid lactonization to form a hydrocoumarin and releasep-nitroaniline. This “prochromophore” could find use in a variety of assays. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Synthesis of 1-Aryl-3-phenethylamino-1-propanone Hydrochlorides as Possible Potent Cytotoxic Agents

by Ebru Mete, Halise Inci Gul and Cavit Kazaz

Molecules 2007, 12(12), 2579-2588; https://doi.org/10.3390/12122579 - 12 Dec 2007

Cited by 10 | Viewed by 11721

Abstract

1-Aryl-3-phenethylamino-1-propanone hydrochlorides 1-10, which are potentialpotent cytotoxic agents, were synthesized via Mannich reactions using paraformaldehyde,phenethylamine hydrochloride as the amine component and acetophenone, 4’-methyl-, 4’-methoxy-, 4’-chloro-, 4’-fluoro-, 4’-bromo-, 2’,4’-dichloro-, 4’-nitro-, 4’-hydroxyacetophenone or 2-acetylthiophene as the ketone component. Yields were in the87-98 % range. Of [...] Read more.

1-Aryl-3-phenethylamino-1-propanone hydrochlorides 1-10, which are potentialpotent cytotoxic agents, were synthesized via Mannich reactions using paraformaldehyde,phenethylamine hydrochloride as the amine component and acetophenone, 4’-methyl-, 4’-methoxy-, 4’-chloro-, 4’-fluoro-, 4’-bromo-, 2’,4’-dichloro-, 4’-nitro-, 4’-hydroxyacetophenone or 2-acetylthiophene as the ketone component. Yields were in the87-98 % range. Of the compounds synthesized, compounds 2, 6-8 and 10 were new. Theoptimum reaction conditions were investigated by changing the mol ratios of the reactants,the solvents and the acidity levels using 1 and 10 as representative targets. It was observedthat the best mol ratio of the ketone, paraformaldehyde and phenethylamine hydrochloridewas 1:1.2:1 (compared with a 2:2.1 ratio), and the most suitable reaction medium wasethanol containing concentrated hydrochloric acid (compared with only ethanol or nosolvent). This study may serve as a guide for the conditions of the reactions to synthesizecompounds having similar chemical structures. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

The Drug Release Profile from Calcium-induced Alginate Gel Beads Coated with an Alginate Hydrolysate

by Yoshifumi Murata, Daisaku Jinno, Dongchun Liu, Takshi Isobe, Kyouko Kofuji and Susumu Kawashima

Molecules 2007, 12(11), 2559-2566; https://doi.org/10.3390/12112559 - 29 Nov 2007

Cited by 41 | Viewed by 13785

Abstract

Calcium-induced alginate gel bead (Alg-Ca) coated with an alginate hydrolysate(Alg), e.g. the guluronic acid block (GB) was prepared and the model drug, hydrocortisonerelease profiles were investigated under simulated gastrointestinal conditions. Theirmolecular weights were one sixth or one tenth that of Alg and the [...] Read more.

Calcium-induced alginate gel bead (Alg-Ca) coated with an alginate hydrolysate(Alg), e.g. the guluronic acid block (GB) was prepared and the model drug, hydrocortisonerelease profiles were investigated under simulated gastrointestinal conditions. Theirmolecular weights were one sixth or one tenth that of Alg and the diffraction patterns of thehydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GBapparently lowered than that of Alg-Ca (coating-free) in the gastric juice (pH1.2). And thecoating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8) and thegel erosion accelerated the drug release. On the other hand, for the coated Alg-Cacontaining chitosan, the drug release showed zero-order kinetics without rapid erosion ofAlg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating andmodifying the composition of the gel matrix. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Bioreversible Derivatives of Phenol. 2. Reactivity of Carbonate Esters with Fatty Acid-like Structures Towards Hydrolysis in Aqueous Solutions

by Jesper Ostergaard and Claus Larsen

Molecules 2007, 12(10), 2396-2412; https://doi.org/10.3390/12102396 - 30 Oct 2007

Cited by 25 | Viewed by 19350

Abstract

A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37°C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, [...] Read more.

A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 – 12.5) at 37°C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from ω-hydroxy carboxylic acids with longer alkyl chains. The carbonate esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Bioreversible Derivatives of Phenol. 1. The Role of Human Serum Albumin as Related to the Stability and Binding Properties of Carbonate Esters with Fatty Acid-like Structures in Aqueous Solution and Biological Media

by Jesper Ostergaard and Claus Larsen

Molecules 2007, 12(10), 2380-2395; https://doi.org/10.3390/12102380 - 30 Oct 2007

Cited by 12 | Viewed by 11930

Abstract

With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were [...] Read more.

With the overall objective of assessing the potential of utilizing plasma protein binding interactions in combination with the prodrug approach for improving the pharmacokinetics of drug substances, a series of model carbonate ester prodrugs of phenol, encompassing derivatives with fatty acid-like structures, were characterized in vitro. Stability of the derivatives was studied in aqueous solution, human serum albumin solution, human plasma, and rat liver homogenate at 37°C. Stability of the derivatives in aqueous solution varied widely, with half-lives ranging from 31 to 1.7 × 10⁴ min at pH 7.4 and 37°C. The carbonate esters were subject to catalysis by plasma esterases except for the t-butyl and acetic acid derivatives, which were stabilized in both human plasma and human serum albumin solutions relative to buffer. In most cases, however, hydrolysis was accelerated in the presence of human serum albumin indicating that the derivatives interacted with the protein, a finding which was confirmed using the p-nitrophenyl acetate kinetic assay. Different human serum albumin binding properties of the phenol model prodrugs with fatty acid-like structure and neutral carbonate esters were observed. In the context of utilizing plasma protein binding in combination with the prodrug approach for optimizing drug pharmacokinetics, the esterase-like properties of human serum albumin towards the carbonate esters potentially allowing the protein to act as a catalyst of parent compound regenerations is interesting. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessArticle

Phase I and Phase II Ocular Metabolic Activities and the Role of Metabolism in Ophthalmic Prodrug and Codrug Design and Delivery

by Abeer M Al-Ghananeem and Peter A Crooks

Molecules 2007, 12(3), 373-388; https://doi.org/10.3390/12030373 - 8 Mar 2007

Cited by 34 | Viewed by 14901

Abstract

While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic capabilities of the eye are minuscule; however, phase I and phase II metabolic activities have been detected in various [...] Read more.

While the mammalian eye is seldom considered an organ of drug metabolism, the capacity for biotransformation is present. Compared to the liver, the metabolic capabilities of the eye are minuscule; however, phase I and phase II metabolic activities have been detected in various ocular structures. The careful consideration of ocular tissue metabolic processes within the eye has important implications for controlling the detoxification of therapeutic agents and for providing the potential for site-specific bio-activation of certain drug molecules, thus enabling significant improvements in drug efficacy and the minimization of side-effect from either local or systemic drug delivery to the eye. Knowledge of these processes is important to prodrug and codrug development and to researchers involved in the design, delivery and metabolism of ophthalmic drugs. This present article reviews the progress in ocular prodrug and codrug design and delivery in light of ocular metabolic activities. Full article

(This article belongs to the Special Issue Prodrugs)

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Review

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Open AccessReview

Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids

by Vasu Nair and Maurice Okello

Molecules 2015, 20(7), 12623-12651; https://doi.org/10.3390/molecules200712623 - 13 Jul 2015

Cited by 24 | Viewed by 10012

Abstract

HIV integrase, encoded at the 3′-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of “no-return” in HIV infection. Integrase is a significant target in anti-HIV [...] Read more.

HIV integrase, encoded at the 3′-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of “no-return” in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are β-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC₅₀) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC₅₀ and IC₉₀ ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC₅₀ and EC₉₀ anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Pro-Moieties of Antimicrobial Peptide Prodrugs

by Eanna Forde and Marc Devocelle

Molecules 2015, 20(1), 1210-1227; https://doi.org/10.3390/molecules20011210 - 13 Jan 2015

Cited by 38 | Viewed by 9092

Abstract

Antimicrobial peptides (AMPs) are a promising class of antimicrobial agents that have been garnering increasing attention as resistance renders many conventional antibiotics ineffective. Extensive research has resulted in a large library of highly-active AMPs. However, several issues serve as an impediment to their [...] Read more.

Antimicrobial peptides (AMPs) are a promising class of antimicrobial agents that have been garnering increasing attention as resistance renders many conventional antibiotics ineffective. Extensive research has resulted in a large library of highly-active AMPs. However, several issues serve as an impediment to their clinical development, not least the issue of host toxicity. An approach that may allow otherwise cytotoxic AMPs to be used is to deliver them as a prodrug, targeting antimicrobial activity and limiting toxic effects on the host. The varied library of AMPs is complemented by a selection of different possible pro-moieties, each with their own characteristics. This review deals with the different pro-moieties that have been used with AMPs and discusses the merits of each. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Prodrug Strategies for Enhancing the Percutaneous Absorption of Drugs

by David D. N'Da

Molecules 2014, 19(12), 20780-20807; https://doi.org/10.3390/molecules191220780 - 12 Dec 2014

Cited by 116 | Viewed by 21032

Abstract

The transdermal application of drugs has attracted increasing interest over the last decade or so, due to the advantages it offers, compared to other delivery methods. The development of an efficient means of transdermal delivery can increase drug concentrations, while reducing their systemic [...] Read more.

The transdermal application of drugs has attracted increasing interest over the last decade or so, due to the advantages it offers, compared to other delivery methods. The development of an efficient means of transdermal delivery can increase drug concentrations, while reducing their systemic distribution, thereby avoiding certain limitations of oral administration. The efficient barrier function of the skin, however, limits the use of most drugs as transdermal agents. This limitation has led to the development of various strategies to enhance drug-skin permeation, including the use of penetration enhancers. This method unfortunately has certain proven disadvantages, such as the increased absorption of unwanted components, besides the drug, which may induce skin damage and irritancy. The prodrug approach to increase the skin’s permeability to drugs represents a very promising alternative to penetration enhancers. The concept involves the chemical modification of a drug into a bioreversible entity that changes both its pharmaceutical and pharmacokinetic characteristics to enhance its delivery through the skin. In this review; we report on the in vitro attempts and successes over the last decade by using the prodrug strategy for the percutaneous delivery of pharmacological molecules. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Aminolevulinic Acid (ALA) as a Prodrug in Photodynamic Therapy of Cancer

by Małgorzata Wachowska, Angelika Muchowicz, Małgorzata Firczuk, Magdalena Gabrysiak, Magdalena Winiarska, Małgorzata Wańczyk, Kamil Bojarczuk and Jakub Golab

Molecules 2011, 16(5), 4140-4164; https://doi.org/10.3390/molecules16054140 - 19 May 2011

Cited by 210 | Viewed by 21813

Abstract

Aminolevulinic acid (ALA) is an endogenous metabolite normally formed in the mitochondria from succinyl-CoA and glycine. Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme. Conversion of PpIX to its downstream substrates requires the activity of [...] Read more.

Aminolevulinic acid (ALA) is an endogenous metabolite normally formed in the mitochondria from succinyl-CoA and glycine. Conjugation of eight ALA molecules yields protoporphyrin IX (PpIX) and finally leads to formation of heme. Conversion of PpIX to its downstream substrates requires the activity of a rate-limiting enzyme ferrochelatase. When ALA is administered externally the abundantly produced PpIX cannot be quickly converted to its final product - heme by ferrochelatase and therefore accumulates within cells. Since PpIX is a potent photosensitizer this metabolic pathway can be exploited in photodynamic therapy (PDT). This is an already approved therapeutic strategy making ALA one of the most successful prodrugs used in cancer treatment. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Prodrug Approach for Increasing Cellular Glutathione Levels

by Ivana Cacciatore, Catia Cornacchia, Francesco Pinnen, Adriano Mollica and Antonio Di Stefano

Molecules 2010, 15(3), 1242-1264; https://doi.org/10.3390/molecules15031242 - 3 Mar 2010

Cited by 98 | Viewed by 16698

Abstract

Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. It plays an important role in many cellular processes, such as cell differentiation, proliferation and apoptosis. GSH deficiency [...] Read more.

Reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. It plays an important role in many cellular processes, such as cell differentiation, proliferation and apoptosis. GSH deficiency has been observed in aging and in a wide range of pathologies, including neurodegenerative disorders and cystic fibrosis (CF), as well as in several viral infections. Use of GSH as a therapeutic agent is limited because of its unfavorable biochemical and pharmacokinetic properties. Several reports have provided evidence for the use of GSH prodrugs able to replenish intracellular GSH levels. This review discusses different strategies for increasing GSH levels by supplying reversible bioconjugates able to cross the cellular membrane more easily than GSH and to provide a source of thiols for GSH synthesis. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Bystander or No Bystander for Gene Directed Enzyme Prodrug Therapy

by Gabi U. Dachs, Michelle A. Hunt, Sophie Syddall, Dean C. Singleton and Adam V. Patterson

Molecules 2009, 14(11), 4517-4545; https://doi.org/10.3390/molecules14114517 - 10 Nov 2009

Cited by 99 | Viewed by 16595

Abstract

Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, [...] Read more.

Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives. Full article

(This article belongs to the Special Issue Prodrugs)

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A New Look at the Most Successful Prodrugs for Active Vitamin D (D Hormone): Alfacalcidol and Doxercalciferol

by Noboru Kubodera

Molecules 2009, 14(10), 3869-3880; https://doi.org/10.3390/molecules14103869 - 29 Sep 2009

Cited by 38 | Viewed by 16860

Abstract

Alfacalcidol (1α-hydroxyvitamin D₃) has been widely used since 1981 as a prodrug for calcitriol (1α,25-dihydroxyvitamin D₃) in the treatment of hypocalcemia, chronic renal failure, hypoparathyroidism and osteoporosis. More recently, doxercalciferol (1α-hydroxyvitamin D₂) has been used since 1999 [...] Read more.

Alfacalcidol (1α-hydroxyvitamin D₃) has been widely used since 1981 as a prodrug for calcitriol (1α,25-dihydroxyvitamin D₃) in the treatment of hypocalcemia, chronic renal failure, hypoparathyroidism and osteoporosis. More recently, doxercalciferol (1α-hydroxyvitamin D₂) has been used since 1999 as a prodrug for 1α,25-dihydroxyvitamin D₂ for the treatment of secondary hyperparathyroidism. Currently, six forms of vitamin D are known. They range from vitamin D₂ to vitamin D₇and are distinguished by their differing side chains. Only vitamin D₂ and vitamin D₃ have been found to be biologically active based on the elucidation of activation pathways. Alfacalcidol and osteoporosis/doxercalciferol and secondary hyperparathyroidism are discussed, with a new look at old compounds including their practical syntheses. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Prodrugs of Thyrotropin-Releasing Hormone and Related Peptides as Central Nervous System Agents

by Katalin Prokai-Tatrai and Laszlo Prokai

Molecules 2009, 14(2), 633-654; https://doi.org/10.3390/molecules14020633 - 6 Feb 2009

Cited by 18 | Viewed by 13021

Abstract

Prodrug design for brain delivery of small- and medium-sized neuropeptides was reviewed, focusing on thyrotropin-releasing hormone and structurally related peptides as examples. We have summarized our most important advances in methodology, as well as assessed the benefits and limitations of bioreversible chemical manipulation [...] Read more.

Prodrug design for brain delivery of small- and medium-sized neuropeptides was reviewed, focusing on thyrotropin-releasing hormone and structurally related peptides as examples. We have summarized our most important advances in methodology, as well as assessed the benefits and limitations of bioreversible chemical manipulation techniques to achieve targeting of the parent molecules into the central nervous system. The value of prodrug-amenable analogues as potential drug-like central nervous systems agents was highlighted. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Prodrugs in Cardiovascular Therapy

by Marinella G. Sandros, Chady B. Sarraf and Maryam Tabrizian

Molecules 2008, 13(5), 1156-1178; https://doi.org/10.3390/molecules13051156 - 14 May 2008

Cited by 8 | Viewed by 13078

Abstract

Prodrugs are biologically inactive derivatives of an active drug intended to solve certain problems of the parent drug such as toxicity, instability, minimal solubility and non-targeting capabilities. The majority of drugs for cardiovascular diseases undergo firstpass metabolism, resulting in drug inactivation and generation [...] Read more.

Prodrugs are biologically inactive derivatives of an active drug intended to solve certain problems of the parent drug such as toxicity, instability, minimal solubility and non-targeting capabilities. The majority of drugs for cardiovascular diseases undergo firstpass metabolism, resulting in drug inactivation and generation of toxic metabolites, which makes them appealing targets for prodrug design. Since prodrugs undergo a chemical reaction to form the parent drug once inside the body, this makes them very effective in controlling the release of a variety of compounds to the targeted site. This review will provide the reader with an insight on the latest developments of prodrugs that are available for treating a variety of cardiovascular diseases. In addition, we will focus on several drug delivery methodologies that have merged with the prodrug approach to provide enhanced target specificity and controlled drug release with minimal side effects. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Progress in Drug Delivery to the Central Nervous System by the Prodrug Approach

by Barbara Pavan, Alessandro Dalpiaz, Nunzia Ciliberti, Carla Biondi, Stefano Manfredini and Silvia Vertuani

Molecules 2008, 13(5), 1035-1065; https://doi.org/10.3390/molecules13051035 - 1 May 2008

Cited by 140 | Viewed by 24175

Abstract

This review describes specific strategies for targeting to the central nervoussystem (CNS). Systemically administered drugs can reach the brain by crossing one of twophysiological barriers resistant to free diffusion of most molecules from blood to CNS: theendothelial blood-brain barrier or the epithelial blood-cerebrospinal [...] Read more.

This review describes specific strategies for targeting to the central nervoussystem (CNS). Systemically administered drugs can reach the brain by crossing one of twophysiological barriers resistant to free diffusion of most molecules from blood to CNS: theendothelial blood-brain barrier or the epithelial blood-cerebrospinal fluid barrier. Thesetissues constitute both transport and enzymatic barriers. The most common strategy fordesigning effective prodrugs relies on the increase of parent drug lipophilicity. However,increasing lipophilicity without a concomitant increase in rate and selectivity of prodrugbioconversion in the brain will result in failure. In these regards, consideration of theenzymes present in brain tissue and in the barriers is essential for a successful approach.Nasal administration of lipophilic prodrugs can be a promising alternative non-invasiveroute to improve brain targeting of the parent drugs due to fast absorption and rapid onsetof drug action. The carrier-mediated absorption of drugs and prodrugs across epithelial andendothelial barriers is emerging as another novel trend in biotherapeutics. Several specifictransporters have been identified in boundary tissues between blood and CNScompartments. Some of them are involved in the active supply of nutrients and have been used to explore prodrug approaches with improved brain delivery. The feasibility of CNSuptake of appropriately designed prodrugs via these transporters is described in detail. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Prodrugs for the Treatment of Neglected Diseases

by Man Chin Chung, Elizabeth Igne Ferreira, Jean Leandro Santos, Jeanine Giarolla, Daniela Gonçales Rando, Adélia Emília Almeida, Priscila Longhin Bosquesi, Renato Farina Menegon and Lorena Blau

Molecules 2008, 13(3), 616-677; https://doi.org/10.3390/molecules13030616 - 19 Mar 2008

Cited by 70 | Viewed by 22902

Abstract

Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical [...] Read more.

Recently, World Health Organization (WHO) and Medicins San Frontieres (MSF) proposed a classification of diseases as global, neglected and extremely neglected. Global diseases, such as cancer, cardiovascular and mental (CNS) diseases represent the targets of the majority of the R&D efforts of pharmaceutical companies. Neglected diseases affect millions of people in the world yet existing drug therapy is limited and often inappropriate. Furthermore, extremely neglected diseases affect people living under miserable conditions who barely have access to the bare necessities for survival. Most of these diseases are excluded from the goals of the R&D programs in the pharmaceutical industry and therefore fall outside the pharmaceutical market. About 14 million people, mainly in developing countries, die each year from infectious diseases. From 1975 to 1999, 1393 new drugs were approved yet only 1% were for the treatment of neglected diseases [3]. These numbers have not changed until now, so in those countries there is an urgent need for the design and synthesis of new drugs and in this area the prodrug approach is a very interesting field. It provides, among other effects, activity improvements and toxicity decreases for current and new drugs, improving market availability. It is worth noting that it is essential in drug design to save time and money, and prodrug approaches can be considered of high interest in this respect. The present review covers 20 years of research on the design of prodrugs for the treatment of neglected and extremely neglected diseases such as Chagas’ disease (American trypanosomiasis), sleeping sickness (African trypanosomiasis), malaria, sickle cell disease, tuberculosis, leishmaniasis and schistosomiasis. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Prodrugs for Amines

by Ana L. Simplício, John M. Clancy and John F. Gilmer

Molecules 2008, 13(3), 519-547; https://doi.org/10.3390/molecules13030519 - 3 Mar 2008

Cited by 115 | Viewed by 25353

Abstract

The purpose of this work is to review the published strategies for the productionof prodrugs of amines. The review is divided in two main groups of approaches: those thatrely on enzymatic activation and those that take advantage of physiological chemicalconditions for release of [...] Read more.

The purpose of this work is to review the published strategies for the productionof prodrugs of amines. The review is divided in two main groups of approaches: those thatrely on enzymatic activation and those that take advantage of physiological chemicalconditions for release of the drugs. A compilation of the most important approaches ispresented in the form of a table, where the main advantages and disadvantages of eachstrategy are also referred. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Structure and Catalytic Properties of Carboxylesterase Isozymes Involved in Metabolic Activation of Prodrugs

by Masakiyo Hosokawa

Molecules 2008, 13(2), 412-431; https://doi.org/10.3390/molecules13020412 - 18 Feb 2008

Cited by 336 | Viewed by 22451

Abstract

Mammalian carboxylesterases (CESs) comprise a multigene family whose geneproducts play important roles in biotransformation of ester- or amide-type prodrugs. Theyare members of an α,β-hydrolase-fold family and are found in various mammals. It has beensuggested that CESs can be classified into five major groups [...] Read more.

Mammalian carboxylesterases (CESs) comprise a multigene family whose geneproducts play important roles in biotransformation of ester- or amide-type prodrugs. Theyare members of an α,β-hydrolase-fold family and are found in various mammals. It has beensuggested that CESs can be classified into five major groups denominated CES1-CES5,according to the homology of the amino acid sequence, and the majority of CESs that havebeen identified belong to the CES1 or CES2 family. The substrate specificities of CES1 andCES2 are significantly different. The CES1 isozyme mainly hydrolyzes a substrate with asmall alcohol group and large acyl group, but its wide active pocket sometimes allows it toact on structurally distinct compounds of either a large or small alcohol moiety. In contrast,the CES2 isozyme recognizes a substrate with a large alcohol group and small acyl group,and its substrate specificity may be restricted by the capability of acyl-enzyme conjugateformation due to the presence of conformational interference in the active pocket. Sincepharmacokinetic and pharmacological data for prodrugs obtained from preclinicalexperiments using various animals are generally used as references for human studies, it isimportant to clarify the biochemical properties of CES isozymes. Further experimentationfor an understanding of detailed substrate specificity of prodrugs for CES isozymes and itshydrolysates will help us to design the ideal prodrugs. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Novel Prodrugs for Targeting Diagnostic and Therapeutic Radionuclides to Solid Tumors

by Amin I. Kassis, Houari Korideck, Ketai Wang, Pavel Pospisil and S. James Adelstein

Molecules 2008, 13(2), 391-404; https://doi.org/10.3390/molecules13020391 - 18 Feb 2008

Cited by 12 | Viewed by 11206

Abstract

Most cancer therapeutics (chemo, radiation, antibody-based, anti-angiogenic)are at best partially and/or temporarily effective. In general, the causes for failure can besummarized as: (i) poor diffusion and/or nonuniform distribution of drug/prodrugmolecules in solid tumors; (ii) high drug concentration and retention in normal tissues(leading to [...] Read more.

Most cancer therapeutics (chemo, radiation, antibody-based, anti-angiogenic)are at best partially and/or temporarily effective. In general, the causes for failure can besummarized as: (i) poor diffusion and/or nonuniform distribution of drug/prodrugmolecules in solid tumors; (ii) high drug concentration and retention in normal tissues(leading to side effects); (iii) requirement for plasma-membrane permeability and/orinternalization of drug/prodrug molecules; (iv) low uptake of drug by tumor; (v) lack ofretention of drug within tumor (most have gradient-driven reversible binding); and (vi)multidrug resistance. We are developing an innovative technology that aims to surmountthese problems by actively concentrating and permanently entrapping radioimaging andradiotherapeutic prodrugs specifically within solid tumors. The approach will enablenoninvasive sensing (imaging) and effective therapy of solid tumors, allowing tumordetection, diagnosis, and treatment to be closely coupled (personalized medicine). Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Design, Synthesis and Applications of Hyaluronic Acid-Paclitaxel Bioconjugates†

by Francesca Leonelli, Angela La Bella, Luisa Maria Migneco and Rinaldo Marini Bettolo

Molecules 2008, 13(2), 360-378; https://doi.org/10.3390/molecules13020360 - 12 Feb 2008

Cited by 39 | Viewed by 19216

Abstract

Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatmentof breast and ovarian cancer, suffers from significant disadvantages such as low solubility,certain toxicity and specific drug-resistance of some tumor cells. To overcome theseproblems extensive research has been carried out. Among the [...] Read more.

Paclitaxel (1a), a well known antitumor agent adopted mainly for the treatmentof breast and ovarian cancer, suffers from significant disadvantages such as low solubility,certain toxicity and specific drug-resistance of some tumor cells. To overcome theseproblems extensive research has been carried out. Among the various proposed strategies,the conjugation of paclitaxel (1a) to a biocompatible polymer, such as hyaluronic acid(HA, 2), has also been considered. Coupling a bioactive compound to a biocompatiblepolymer offers, in general, many advantages such as better drug solubilization, betterstabilization, specific localization and controlled release. Hereafter the design, synthesisand applications of hyaluronic acid-paclitaxel bioconjugates are reviewed. An overview ofHA-paclitaxel combinations is also given. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Cholesterylbutyrate Solid Lipid Nanoparticles as a Butyric Acid Prodrug

by Andrea Brioschi, Gian Paolo Zara, Sara Calderoni, Maria Rosa Gasco and Alessandro Mauro

Molecules 2008, 13(2), 230-254; https://doi.org/10.3390/molecules13020230 - 1 Feb 2008

Cited by 44 | Viewed by 14117

Abstract

Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid.Butyrate is not often used in vivo because its half-life is very short and therefore too largeamounts of the drug would be necessary for its efficacy. In the last few years butyric acid'santi-inflammatory properties [...] Read more.

Cholesterylbutyrate (Chol-but) was chosen as a prodrug of butyric acid.Butyrate is not often used in vivo because its half-life is very short and therefore too largeamounts of the drug would be necessary for its efficacy. In the last few years butyric acid'santi-inflammatory properties and its inhibitory activity towards histone deacetylases havebeen widely studied, mainly in vitro. Solid Lipid Nanoparticles (SLNs), whose lipid matrixis Chol-but, were prepared to evaluate the delivery system of Chol-but as a prodrug and totest its efficacy in vitro and in vivo. Chol-but SLNs were prepared using the microemulsionmethod; their average diameter is on the order of 100-150 nm and their shape is spherical.The antineoplastic effects of Chol-but SLNs were assessed in vitro on different cancer celllines and in vivo on a rat intracerebral glioma model. The anti-inflammatory activity wasevaluated on adhesion of polymorphonuclear cells to vascular endothelial cells. In thereview we will present data on Chol-but SLNs in vitro and in vivo experiments, discussingthe possible utilisation of nanoparticles for the delivery of prodrugs for neoplastic andchronic inflammatory diseases. Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessReview

Cyclization-activated Prodrugs

by Paula Gomes, Nuno Vale and Rui Moreira

Molecules 2007, 12(11), 2484-2506; https://doi.org/10.3390/12112484 - 12 Nov 2007

Cited by 52 | Viewed by 18412

Abstract

Many drugs suffer from an extensive first-pass metabolism leading to druginactivation and/or production of toxic metabolites, which makes them attractive targets forprodrug design. The classical prodrug approach, which involves enzyme-sensitive covalentlinkage between the parent drug and a carrier moiety, is a well established [...] Read more.

Many drugs suffer from an extensive first-pass metabolism leading to druginactivation and/or production of toxic metabolites, which makes them attractive targets forprodrug design. The classical prodrug approach, which involves enzyme-sensitive covalentlinkage between the parent drug and a carrier moiety, is a well established strategy toovercome bioavailability/toxicity issues. However, the development of prodrugs that canregenerate the parent drug through non-enzymatic pathways has emerged as an alternativeapproach in which prodrug activation is not influenced by inter- and intraindividualvariability that affects enzymatic activity. Cyclization-activated prodrugs have beencapturing the attention of medicinal chemists since the middle-1980s, and reached maturityin prodrug design in the late 1990s. Many different strategies have been exploited in recentyears concerning the development of intramoleculary-activated prodrugs spanning fromanalgesics to anti-HIV therapeutic agents. Intramolecular pathways have also a key role intwo-step prodrug activation, where an initial enzymatic cleavage step is followed by acyclization-elimination reaction that releases the active drug. This wor Full article

(This article belongs to the Special Issue Prodrugs)

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Open AccessConcept Paper

Modern Prodrug Design for Targeted Oral Drug Delivery

by Arik Dahan, Ellen M. Zimmermann and Shimon Ben-Shabat

Molecules 2014, 19(10), 16489-16505; https://doi.org/10.3390/molecules191016489 - 14 Oct 2014

Cited by 58 | Viewed by 12585

Abstract

The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and [...] Read more.

The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options. Full article

(This article belongs to the Special Issue Prodrugs)

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