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14 pages, 13478 KiB

Open AccessArticle

Hybrids of 1,4-Naphthoquinone with Thymidine Derivatives: Synthesis, Anticancer Activity, and Molecular Docking Study

by Monika Kadela-Tomanek, Kamil Krzykawski, Adrianna Halama and Robert Kubina

Molecules 2023, 28(18), 6644; https://doi.org/10.3390/molecules28186644 - 15 Sep 2023

Cited by 2 | Viewed by 1297

Abstract

One of the most essential health problems is cancer, the first or second cause of death worldwide. Head and neck cancers are hard to detect due to non-specific symptoms. The treatment often relies on a combination of radio and chemotherapy. For this reason, [...] Read more.

One of the most essential health problems is cancer, the first or second cause of death worldwide. Head and neck cancers are hard to detect due to non-specific symptoms. The treatment often relies on a combination of radio and chemotherapy. For this reason, the research of new anticancer compounds is fundamental. The natural and synthetic compounds with 1,4-naphthoquinone scaffold is characterized by high anticancer activity. The study aimed to evaluate the synthesis and anticancer activity of hybrids 1,4-naphthoquinone with thymidine derivatives. The series of compounds allows us to check the influence of the substituent in the C3′ position of the thymidine moiety on the cytotoxicity against squamous cancer cell lines (SCC-9 and SCC-25) and submandibular gland cancer (A-253). An annexin V/propidium iodide (PI) co-staining assay shows that derivatives cause the apoptotic in SCC-25 and A-253 cell lines. The molecular docking study examined the interaction between the active site of the BCL-2 protein and the hybrids. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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19 pages, 1382 KiB

Open AccessArticle

Design and Synthesis of AMPK Activators and GDF15 Inducers

by Meijian Zhang, Andrea Bagán, Donna Martínez, Emma Barroso, Xavier Palomer, Santiago Vázquez, Carmen Escolano and Manuel Vázquez-Carrera

Molecules 2023, 28(14), 5468; https://doi.org/10.3390/molecules28145468 - 17 Jul 2023

Viewed by 1841

Abstract

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were [...] Read more.

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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10 pages, 2111 KiB

Open AccessCommunication

A General Protocol for Synthesizing Thiolated Folate Derivatives

by Jie Li, Yao Wang, Liangang Shan, Lei Qian, Wenchao Wang, Jixian Liu and Jianguo Tang

Molecules 2023, 28(13), 5228; https://doi.org/10.3390/molecules28135228 - 5 Jul 2023

Cited by 1 | Viewed by 1286

Abstract

Folic acid (FA) has shown great potential in the fields of targeted drug delivery and disease diagnosis due to its highly tumor-targeting nature, biocompatibility, and low cost. However, FA is generally introduced in targeted drug delivery systems through macromolecular linkage via complex synthetic [...] Read more.

Folic acid (FA) has shown great potential in the fields of targeted drug delivery and disease diagnosis due to its highly tumor-targeting nature, biocompatibility, and low cost. However, FA is generally introduced in targeted drug delivery systems through macromolecular linkage via complex synthetic processes, resulting in lower yields and high costs. In this work, we report a general protocol for synthesizing thiolated folate derivatives. The small molecule thiolated folate (TFa) was first synthesized with a purity higher than 98.20%. First, S-S-containing diol was synthesized with a purity higher than 99.44 through a newly developed green oxidation protocol, which was carried out in water with no catalyst. Then, folic acid was modified using the diol through esterification, and TFa was finally synthesized by breaking the disulfide bond. Further, the synthesized TFa was utilized to modify silver nanoparticles. The results showed that TFa could be easily bonded to metal particles. The protocol could be extended to the synthesis of a series of thiolated derivatives of folate, such as mercaptohexyl folate, mercaptoundecyl folate, etc., which would greatly benefit the biological applications of FA. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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14 pages, 3268 KiB

Open AccessArticle

Evaluation of Biological Activity of New 1,2,4-Triazole Derivatives Containing Propionic Acid Moiety

by Renata Paprocka, Małgorzata Wiese-Szadkowska, Przemysław Kołodziej, Jolanta Kutkowska, Sara Balcerowska and Anna Bogucka-Kocka

Molecules 2023, 28(9), 3808; https://doi.org/10.3390/molecules28093808 - 29 Apr 2023

Cited by 6 | Viewed by 2143

Abstract

To this day, the quest to find new drugs is still a challenge due to the growing demands of patients suffering from chronic inflammatory diseases and the need for the individualization of therapy. The aim of this research was to synthesize new 1,2,4-triazole [...] Read more.

To this day, the quest to find new drugs is still a challenge due to the growing demands of patients suffering from chronic inflammatory diseases and the need for the individualization of therapy. The aim of this research was to synthesize new 1,2,4-triazole derivatives containing propanoic acid moiety and to investigate their anti-inflammatory, antibacterial and anthelmintic activity. Compounds 3a–3g were obtained in reactions of amidrazones 1a–1g with succinic anhydride. Several analyses of proton and carbon nuclear magnetic resonance (¹H NMR, ¹³C NMR, respectively), as well as high-resolution mass spectra (HRMS), confirmed the structures of 1,2,4-triazole derivatives 3a–3g. Toxicity, antiproliferative activity and influence on cytokine release (TNF-α: Tumor Necrosis Factor-α, IL-6: Interleukin-6, IFN-γ: Interferon-γ, and IL-10: Interleukin-10) of the compounds 3a–3g were evaluated in peripheral blood mononuclear cells culture. Moreover, mitogen-stimulated cell culture was used for biological activity tests. The antimicrobial and anthelmintic activity of derivatives 3a–3g were studied against Gram-positive and Gram-negative bacterial strains and Rhabditis sp. culture. Despite the lack of toxicity, compounds 3a–3g significantly reduced the level of TNF-α. Derivatives 3a, 3c and 3e also decreased the release of IFN-γ. Taking all of the results into consideration, compounds 3a, 3c and 3e show the most beneficial anti-inflammatory effects. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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18 pages, 2713 KiB

Open AccessArticle

Synthesis of Enantiomerically Enriched Protected 2-Amino-, 2,3-Diamino- and 2-Amino-3-Hydroxypropylphosphonates

by Aleksandra Trocha, Dorota G. Piotrowska and Iwona E. Głowacka

Molecules 2023, 28(3), 1466; https://doi.org/10.3390/molecules28031466 - 2 Feb 2023

Viewed by 1471

Abstract

Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N [...] Read more.

Simple and efficient strategies for the syntheses of enantiomerically enriched functionalized diethyl 2-amino-, 2,3-diamino- and 2-amino-3-hydroxypropylphosphonates have been developed starting from, respectively, N-protected (aziridin-2-yl)methylphosphonates, employing a regioselective aziridine ring-opening reaction with corresponding nucleophiles. Diethyl (R)- and (S)-2-(N-Boc-amino)propylphosphonates were obtained via direct regiospecific hydrogenolysis of the respective enantiomer of (R)- and (S)-N-Boc-(aziridin-2-yl)methylphosphonates. N-Boc-protected (R)- and (S)-2,3-diaminopropylphosphonates were synthesized from (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates via a regiospecific ring-opening reaction with neat trimethylsilyl azide and subsequent reduction of (R)- and (S)-2-(N-Boc-amino)-3-azidopropylphosphonates using triphenylphosphine. On the other hand, treatment of the corresponding (R)- and (S)-N-Bn-(aziridin-2-yl)methylphosphonates with glacial acetic acid led regiospecifically to the formation of (R)- and (S)-2-(N-Bn-amino)-3-acetoxypropylphosphonates. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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14 pages, 3976 KiB

Open AccessArticle

Tri- and Pentacyclic Azaphenothiazine as Pro-Apoptotic Agents in Lung Carcinoma with a Protective Potential to Healthy Cell Lines

by Magdalena Skonieczna, Anna Kasprzycka, Małgorzata Jeleń and Beata Morak-Młodawska

Molecules 2022, 27(16), 5255; https://doi.org/10.3390/molecules27165255 - 17 Aug 2022

Cited by 5 | Viewed by 1774

Abstract

The phenothiazine derivatives, tricyclic 10H-3,6-diazaphenothiazine (DPT-1) and pentacyclic 7-(3′-dimethylaminopropyl)diquinothiazine (DPT-2), have recently been shown to exhibit promising anticancer activities in vitro. In this report, we demonstrated that DPT-1 and DPT-2 could be pro-apoptotic agents in lung carcinoma, [...] Read more.

The phenothiazine derivatives, tricyclic 10H-3,6-diazaphenothiazine (DPT-1) and pentacyclic 7-(3′-dimethylaminopropyl)diquinothiazine (DPT-2), have recently been shown to exhibit promising anticancer activities in vitro. In this report, we demonstrated that DPT-1 and DPT-2 could be pro-apoptotic agents in lung carcinoma, the human lung carcinoma A549 and non-small lung carcinoma H1299, in the range of IC₅₀ = 1.52–12.89 µM, with a protective potential to healthy cell lines BEAS-2B and NHDF. The compounds showed higher activity in the range of the tested concentrations and low cytotoxicity in relation to normal healthy cells than doxorubicin, used as the reference drug. The cytostatic potential of DPT-1 and DPT-2 was demonstrated with the use of MTT assay. Cell cycle analysis via flow cytometry using Annexin-V assay showed the pro-apoptotic and pro-necrotic role of the studied diazaphenothiazines in the cell cycle. DPT-1 and DPT-2 initiated a biological response in the investigated cancer models with a different mechanism and at a different rate. Based on these findings, it can be concluded that DPT-1 and DPT-2 have potential as chemotherapeutic agents. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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16 pages, 2892 KiB

Open AccessArticle

Formulation Development of Mirtazapine Liquisolid Compacts: Optimization Using Central Composite Design

by Faiza Naureen, Yasar Shah, Sayyed Ibrahim Shah, Muhammad Abbas, Inayat Ur Rehman, Salar Muhammad, Hamdullah Hamdullah, Khang Wen Goh, Fazli Khuda, Amjad Khan, Siok Yee Chan, Mehwish Mushtaq and Long Chiau Ming

Molecules 2022, 27(13), 4005; https://doi.org/10.3390/molecules27134005 - 22 Jun 2022

Cited by 11 | Viewed by 3125

Abstract

Mirtazapine is a tetracyclic anti-depressant with poor water solubility. The aim of this study was to improve the dissolution rate of mirtazapine by delivering the drug as a liquisolid compact. Central composite design (CCD) was employed for the preparation of mirtazapine liquisolid compacts. [...] Read more.

Mirtazapine is a tetracyclic anti-depressant with poor water solubility. The aim of this study was to improve the dissolution rate of mirtazapine by delivering the drug as a liquisolid compact. Central composite design (CCD) was employed for the preparation of mirtazapine liquisolid compacts. In this, the impacts of two independent factors, i.e., excipient ratio (carrier:coating) and different drug concentration on the response of liquisolid system were optimized. Liquisolid compacts were prepared using propylene glycol as a solvent, microcrystalline cellulose as a carrier, and silicon dioxide (Aerosil) as the coating material. The crystallinity of the formulated drug and the interactions between the excipients were examined using X-ray powder diffraction (XRD) and Fourier-transform infrared spectroscopy (FTIR), respectively. The dissolution study for the liquisolid compact was carried out as per FDA guidelines. The results showed loss of crystallinity of the mirtazapine in the formulation and was completely solubilized in non-volatile solvent and equally dispersed throughout the powder system. Moreover, drug dissolution was found to be higher in liquisolid compacts than the direct compressed conventional tablets (of mirtazapine). The liquisolid technique appears to be a promising approach for improving the dissolution of poorly soluble drugs like mirtazapine. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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14 pages, 1826 KiB

Open AccessArticle

Synthesis of Four Enantiomers of (1-Amino-3-Hydroxypropane-1,3-Diyl)Diphosphonic Acid as Diphosphonate Analogues of 4-Hydroxyglutamic Acid

by Liwia Lebelt, Iwona E. Głowacka and Dorota G. Piotrowska

Molecules 2022, 27(9), 2699; https://doi.org/10.3390/molecules27092699 - 22 Apr 2022

Viewed by 1718

Abstract

All the enantiomers of (1-amino-3-hydroxypropane-1,3-diyl)diphosphonic acid, newly design phosphonate analogues of 4-hydroxyglutamic acids, were obtained. The synthetic strategy involved Abramov reactions of diethyl (R)- and (S)-1-(N-Boc-amino)-3-oxopropylphosphonates with diethyl phosphite, separation of diastereoisomeric [1-(N-Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates as O [...] Read more.

All the enantiomers of (1-amino-3-hydroxypropane-1,3-diyl)diphosphonic acid, newly design phosphonate analogues of 4-hydroxyglutamic acids, were obtained. The synthetic strategy involved Abramov reactions of diethyl (R)- and (S)-1-(N-Boc-amino)-3-oxopropylphosphonates with diethyl phosphite, separation of diastereoisomeric [1-(N-Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates as O-protected esters, followed by their hydrolysis to the enantiomeric phosphonic acids. The absolute configuration of the enantiomeric phosphonates was established by comparing the ³¹P NMR chemical shifts of respective (S)-O-methylmandelic acid esters obtained from respective pairs of syn- and anti-[1-(N-Boc-amino)-3-hydroxypropane-1,3-diyl]diphosphonates according to the Spilling rule. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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Review

Jump to: Research

58 pages, 20404 KiB

Open AccessReview

Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review

by Aqsa Mushtaq, Ameer Fawad Zahoor, Muhammad Bilal, Syed Makhdoom Hussain, Muhammad Irfan, Rabia Akhtar, Ali Irfan, Katarzyna Kotwica-Mojzych and Mariusz Mojzych

Molecules 2023, 28(6), 2722; https://doi.org/10.3390/molecules28062722 - 17 Mar 2023

Cited by 14 | Viewed by 4456

Abstract

Sharpless asymmetric dihydroxylation is an important reaction in the enantioselective synthesis of chiral vicinal diols that involves the treatment of alkene with osmium tetroxide along with optically active quinine ligand. Sharpless introduced this methodology after considering the importance of enantioselectivity in the total [...] Read more.

Sharpless asymmetric dihydroxylation is an important reaction in the enantioselective synthesis of chiral vicinal diols that involves the treatment of alkene with osmium tetroxide along with optically active quinine ligand. Sharpless introduced this methodology after considering the importance of enantioselectivity in the total synthesis of medicinally important compounds. Vicinal diols, produced as a result of this reaction, act as intermediates in the synthesis of different naturally occurring compounds. Hence, Sharpless asymmetric dihydroxylation plays an important role in synthetic organic chemistry due to its undeniable contribution to the synthesis of biologically active organic compounds. This review emphasizes the significance of Sharpless asymmetric dihydroxylation in the total synthesis of various natural products, published since 2020. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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48 pages, 24987 KiB

Open AccessReview

Unveiling the Chemistry and Synthetic Potential of Catalytic Cycloaddition Reaction of Allenes: A Review

by Sana Sikandar, Ameer Fawad Zahoor, Abdul Ghaffar, Muhammad Naveed Anjum, Razia Noreen, Ali Irfan, Bushra Munir, Katarzyna Kotwica-Mojzych and Mariusz Mojzych

Molecules 2023, 28(2), 704; https://doi.org/10.3390/molecules28020704 - 10 Jan 2023

Cited by 6 | Viewed by 3677

Abstract

Allenes with two carbon–carbon double bonds belong to a unique class of unsaturated hydrocarbons. The central carbon atom of allene is sp hybridized and forms two σ-bonds and two π-bonds with two terminal sp² hybridized carbon atoms. The chemistry of allenes has [...] Read more.

Allenes with two carbon–carbon double bonds belong to a unique class of unsaturated hydrocarbons. The central carbon atom of allene is sp hybridized and forms two σ-bonds and two π-bonds with two terminal sp² hybridized carbon atoms. The chemistry of allenes has been well documented over the last decades. They are more reactive than alkenes due to higher strain and exhibit significant axial chirality, thus playing a vital role in asymmetric synthesis. Over a variety of organic transformations, allenes specifically undergo classical metal catalyzed cycloaddition reactions to obtain chemo-, regio- and stereoselective cycloadducts. This review briefly describes different types of annulations including [2+2], [2+2+1], [3+2], [2+2+2], [4+2], [5+2], [6+2] cycloadditions using titanium, cobalt, rhodium, nickel, palladium, platinum, gold and phosphine catalyzed reactions along with a mechanistic study of some highlighted protocols. The synthetic applications of these reactions towards the synthesis of natural products such as aristeromycin, ent-[3]-ladderanol, waihoensene(−)-vindoline and (+)-4-epi-vindoline have also been described. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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67 pages, 20389 KiB

Open AccessReview

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

by Saba Munawar, Ameer Fawad Zahoor, Shafaqat Ali, Sadia Javed, Muhammad Irfan, Ali Irfan, Katarzyna Kotwica-Mojzych and Mariusz Mojzych

Molecules 2022, 27(20), 6953; https://doi.org/10.3390/molecules27206953 - 17 Oct 2022

Cited by 23 | Viewed by 10388

Abstract

The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing [...] Read more.

The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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29 pages, 11658 KiB

Open AccessReview

Anticancer Profile of Rhodanines: Structure–Activity Relationship (SAR) and Molecular Targets—A Review

by Jacek Szczepański, Helena Tuszewska and Nazar Trotsko

Molecules 2022, 27(12), 3750; https://doi.org/10.3390/molecules27123750 - 10 Jun 2022

Cited by 11 | Viewed by 2794

Abstract

The rhodanine core is a well-known privileged heterocycle in medicinal chemistry. The rhodanines, as subtypes of thiazolidin-4-ones, show a broad spectrum of biological activity, including anticancer properties. This review aims to analyze the anticancer features of the rhodanines described over the last decade [...] Read more.

The rhodanine core is a well-known privileged heterocycle in medicinal chemistry. The rhodanines, as subtypes of thiazolidin-4-ones, show a broad spectrum of biological activity, including anticancer properties. This review aims to analyze the anticancer features of the rhodanines described over the last decade in the scientific literature. The structure–activity relationship of rhodanine derivatives, as well as some of the molecular targets, were discussed. The information contained in this review could be of benefit to the design of new, effective small molecules with anticancer potential among rhodanine derivatives or their related heterocycles. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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60 pages, 13715 KiB

Open AccessReview

FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021

by Aleksandra Sochacka-Ćwikła, Marcin Mączyński and Andrzej Regiec

Molecules 2022, 27(7), 2259; https://doi.org/10.3390/molecules27072259 - 31 Mar 2022

Cited by 23 | Viewed by 8717

Abstract

Solid cancers are the most common types of cancers diagnosed globally and comprise a large number of deaths each year. The main challenge currently in drug development for tumors raised from solid organs is to find more selective compounds, which exploit specific molecular [...] Read more.

Solid cancers are the most common types of cancers diagnosed globally and comprise a large number of deaths each year. The main challenge currently in drug development for tumors raised from solid organs is to find more selective compounds, which exploit specific molecular targets. In this work, the small molecule drugs registered by the Food and Drug Administration (FDA) for solid cancers treatment between 2011 and 2022 were identified and analyzed by investigating a type of therapy they are used for, as well as their structures and mechanisms of action. On average, 4 new small molecule agents were introduced each year, with a few exceptions, for a total of 62 new drug approvals. A total of 50 of all FDA-approved drugs have also been authorized for use in the European Union by the European Medicines Agency (EMA). Our analysis indicates that many more anticancer molecules show a selective mode of action, i.e., 49 targeted agents, 5 hormone therapies and 3 radiopharmaceuticals, compared to less specific cytostatic action, i.e., 5 chemotherapeutic agents. It should be emphasized that new medications are indicated for use mainly for monotherapy and less for a combination or adjuvant therapies. The comprehensive data presented in this review can serve for further design and development of more specific targeted agents in clinical usage for solid tumors. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 2nd Edition)

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