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Metal-Based Drugs: Bioinorganic Chemistry and Modes of Action—Dedicated to the Research Activity of Professor Luigi Messori

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 18544

Special Issue Editors

Prof. Dr. Chiara Gabbiani

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Guest Editor
Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi 13, 56124 Pisa, Italy
Interests: medicinal inorganic chemistry; bioinorganic chemistry; organometallic chemistry; biologically active transition metal complexes; metal-based drugs (in particular, gold and platinum); photoactivatable Pt(IV) compounds; drug targeting and delivery
Dr. Alessandro Pratesi

E-Mail Website
Guest Editor
Department of Chemistry and Industrial Chemistry, University of Pisa, Via Giuseppe Moruzzi, 13, 56124 Pisa, Italy
Interests: inorganic chemistry; medicinal chemistry; bioinorganic chemistry; mass spectrometry; metal-based drugs; gold-based compounds, platinum-based compounds; drug targeting and delivery strategies; DNA and protein interactions; anticancer therapies; drug repurposing
Special Issues, Collections and Topics in MDPI journals
Dr. Tiziano Marzo

E-Mail Website1 Website2
Guest Editor
Department of Pharmacy, University of Pisa, Pisa, Italy
Interests: inorganic medicinal chemistry; bioinorganic chemistry; protein metalation; metal-based drugs; metal-based anticancer agents; metal-based antimicrobial agents; gold; platinum; ruthenium; targeting and delivery strategies; DNA interactions; drug repurposing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The study of metal-based drugs represents an important part of modern bioinorganic chemistry. Since the discovery of the antitumor activity of cisplatin, metallodrugs have attracted a growing interest in the treatment of many diseases, including cancer, parasitic and bacterial infections. However, the development of novel metal complexes inherently presents some critical aspects being dependent on several chemical and pharmacological features that must be carefully evaluated. Among these, bioaccumulation of metal ions in the cells, biodistribution, clearance and cytotoxicity of the metal complex as well as its pharmacological specificity are of paramount importance in new metal-based drug design and discovery. Nonetheless, the mechanistic understanding of the multiple pathways involved in the biological effects is crucial for the rational design of new compounds endowed with improved potency, and for their clinical applications. Within this frame, with this Special Issue dedicated to the career of Prof. Luigi Messori, we would like to recognize the pivotal role played by his scientific contributions to the field of metal-based drugs. Accordingly, we are glad to invite our valuable colleagues to submit their manuscripts relating to the range of topics covered during Luigi’s scientific career, as summarized in the following topics:

- Anticancer gold drugs. Synthesis, characterization and biological evaluation;

- NAMI A, KP1339 and related ruthenium compounds;

- Interaction studies between metal-based drugs and biomolecules (e.g., proteins, DNA, oligos);

- Mass spectrometry and X-ray diffraction analysis of metal–protein adducts;

- Mechanistic studies of metal-based drugs through omics technologies, in particular proteomics;

- Metalation of biologically relevant target proteins characterized by advanced mass spectrometry tools.

This Special Issue aims to collect the most recent advances on these topics; however, papers and contributions dealing with similar or strongly related topics, still of interest for the field of metal-based anticancer research, are welcome.

Prof. Dr. Chiara Gabbiani
Dr. Alessandro Pratesi
Dr. Tiziano Marzo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metal-based drugs
  • anticancer agents
  • chemotherapy
  • prodrugs
  • gold complexes
  • bioinorganic chemistry
  • protein
  • ESI MS spectrometry
  • X-ray diffraction
  • drug targeting

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Published Papers (5 papers)

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Research

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16 pages, 1504 KiB  
Article
Synthesis of New Thiourea-Metal Complexes with Promising Anticancer Properties
by Guillermo Canudo-Barreras, Lourdes Ortego, Anabel Izaga, Isabel Marzo, Raquel P. Herrera and M. Concepción Gimeno
Molecules 2021, 26(22), 6891; https://doi.org/10.3390/molecules26226891 - 16 Nov 2021
Cited by 19 | Viewed by 4228
Abstract
In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group (T2) or 3,5-di-CF3 substituted phenyl ring (T1) have been prepared and their coordination to Au and Ag has [...] Read more.
In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group (T2) or 3,5-di-CF3 substituted phenyl ring (T1) have been prepared and their coordination to Au and Ag has been studied. A different behavior is observed for gold complexes, a linear geometry with coordination only to the phosphorus atom or an equilibrium between the linear and three-coordinated species is present, whereas for silver complexes the coordination of the ligand as P^S chelate is found. The thiourea ligands and their complexes were explored against different cancer cell lines (HeLa, A549, and Jurkat). The thiourea ligands do not exhibit relevant cytotoxicity in the tested cell lines and the coordination of a metal triggers excellent cytotoxic values in all cases. In general, data showed that gold complexes are more cytotoxic than the silver compounds with T1, in particular the complexes [AuT1(PPh3)]OTf, the bis(thiourea) [Au(T1)2]OTf and the gold-thiolate species [Au(SR)T1]. In contrast, with T2 better results are obtained with silver species [AgT1(PPh3)]OTf and the [Ag(T1)2]OTf. The role played by the ancillary ligand bound to the metal is important since it strongly affects the cytotoxic activity, being the bis(thiourea) complex the most active species. This study demonstrates that metal complexes derived from thiourea can be biologically active and these compounds are promising leads for further development as potential anticancer agents. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Bioinorganic Chemistry and Modes of Action—Dedicated to the Research Activity of Professor Luigi Messori)
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16 pages, 1904 KiB  
Article
Iodide Analogs of Arsenoplatins—Potential Drug Candidates for Triple Negative Breast Cancers
by Ðenana Miodragović, Wenan Qiang, Zohra Sattar Waxali, Željko Vitnik, Vesna Vitnik, Yi Yang, Annie Farrell, Matthew Martin, Justin Ren and Thomas V. O’Halloran
Molecules 2021, 26(17), 5421; https://doi.org/10.3390/molecules26175421 - 6 Sep 2021
Cited by 4 | Viewed by 3573
Abstract
Patients with triple negative breast cancers (TNBCs)—highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors—have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate [...] Read more.
Patients with triple negative breast cancers (TNBCs)—highly aggressive tumors that do not express estrogen, progesterone, and human epidermal growth factor 2 receptors—have limited treatment options. Fewer than 30% of women with metastatic TNBC survive five years after their diagnosis, with a mortality rate within three months after a recurrence of 75%. Although TNBCs show a higher response to platinum therapy compared to other breast cancers, drug resistance remains a major obstacle; thus, platinum drugs with novel mechanisms are urgently needed. Arsenoplatins (APs) represent a novel class of anticancer agents designed to contain the pharmacophores of the two FDA approved drugs cisplatin and arsenic trioxide (As2O3) as one molecular entity. Here, we present the syntheses, crystal structures, DFT calculations, and antiproliferative activity of iodide analogs of AP-1 and AP-2, i.e., AP-5 and AP-4, respectively. Antiproliferative studies in TNBC cell lines reveal that all AP family members are more potent than cisplatin and As2O3 alone. DFT calculations demonstrate there is a low energy barrier for hydrolysis of the platinum-halide bonds in arsenoplatins, possibly contributing to their higher cytotoxicities compared to cisplatin. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Bioinorganic Chemistry and Modes of Action—Dedicated to the Research Activity of Professor Luigi Messori)
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24 pages, 3818 KiB  
Article
Heteroleptic Oxidovanadium(V) Complexes with Activity against Infective and Non-Infective Stages of Trypanosoma cruzi
by Gonzalo Scalese, Ignacio Machado, Gustavo Salinas, Leticia Pérez-Díaz and Dinorah Gambino
Molecules 2021, 26(17), 5375; https://doi.org/10.3390/molecules26175375 - 3 Sep 2021
Cited by 16 | Viewed by 2561
Abstract
Five heteroleptic compounds, [VVO(IN-2H)(L-H)], where L are 8-hydroxyquinoline derivatives and IN is a Schiff base ligand, were synthesized and characterized in both the solid and solution state. The compounds were evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi as well as [...] Read more.
Five heteroleptic compounds, [VVO(IN-2H)(L-H)], where L are 8-hydroxyquinoline derivatives and IN is a Schiff base ligand, were synthesized and characterized in both the solid and solution state. The compounds were evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi as well as on VERO cells, as a mammalian cell model. Compounds showed activity against trypomastigotes with IC50 values of 0.29–3.02 μM. IN ligand and the new [VVO2(IN-H)] complex showed negligible activity. The most active compound [VVO(IN-2H)(L2-H)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, showed good selectivity towards the parasite and was selected to carry out further biological studies. Stability studies suggested a partial decomposition in solution. [VVO(IN-2H)(L2-H)] affects the infection potential of cell-derived trypomastigotes. Low total vanadium uptake by parasites and preferential accumulation in the soluble proteins fraction were determined. A trypanocide effect was observed when incubating epimastigotes with 10 × IC50 values of [VVO(IN-2H)(L2-H)] and the generation of ROS after treatments was suggested. Fluorescence competition measurements with DNA:ethidium bromide adduct showed a moderate DNA interaction of the complexes. In vivo toxicity study on C. elegans model showed no toxicity up to a 100 μM concentration of [VVO(IN-2H)(L2-H)]. This compound could be considered a prospective anti-T. cruzi agent that deserves further research. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Bioinorganic Chemistry and Modes of Action—Dedicated to the Research Activity of Professor Luigi Messori)
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17 pages, 2344 KiB  
Article
Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells
by Maria Dalla Pozza, Christophe Orvain, Leonardo Brustolin, Nicolò Pettenuzzo, Chiara Nardon, Christian Gaiddon and Dolores Fregona
Molecules 2021, 26(13), 4073; https://doi.org/10.3390/molecules26134073 - 3 Jul 2021
Cited by 8 | Viewed by 3846
Abstract
Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts [...] Read more.
Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Bioinorganic Chemistry and Modes of Action—Dedicated to the Research Activity of Professor Luigi Messori)
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47 pages, 10324 KiB  
Review
Coordination Chemistry of Nucleotides and Antivirally Active Acyclic Nucleoside Phosphonates, including Mechanistic Considerations
by Astrid Sigel, Helmut Sigel and Roland K. O. Sigel
Molecules 2022, 27(9), 2625; https://doi.org/10.3390/molecules27092625 - 19 Apr 2022
Cited by 5 | Viewed by 2592
Abstract
Considering that practically all reactions that involve nucleotides also involve metal ions, it is evident that the coordination chemistry of nucleotides and their derivatives is an essential corner stone of biological inorganic chemistry. Nucleotides are either directly or indirectly involved in all processes [...] Read more.
Considering that practically all reactions that involve nucleotides also involve metal ions, it is evident that the coordination chemistry of nucleotides and their derivatives is an essential corner stone of biological inorganic chemistry. Nucleotides are either directly or indirectly involved in all processes occurring in Nature. It is therefore no surprise that the constituents of nucleotides have been chemically altered—that is, at the nucleobase residue, the sugar moiety, and also at the phosphate group, often with the aim of discovering medically useful compounds. Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon–phosphorus bond to make the compounds less hydrolysis-sensitive. Several of these ANPs show antiviral activity, and some of them are nowadays used as drugs. The antiviral activity results from the incorporation of the ANPs into the growing nucleic acid chain—i.e., polymerases accept the ANPs as substrates, leading to chain termination because of the missing 3′-hydroxyl group. We have tried in this review to describe the coordination chemistry (mainly) of the adenine nucleotides AMP and ATP and whenever possible to compare it with that of the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2− = adenine(N9)-CH2-CH2-O-CH2-PO32) [or its diphosphate (PMEApp4−)] as a representative of the ANPs. Why is PMEApp4− a better substrate for polymerases than ATP4−? There are three reasons: (i) PMEA2− with its anti-like conformation (like AMP2−) fits well into the active site of the enzyme. (ii) The phosphonate group has an enhanced metal ion affinity because of its increased basicity. (iii) The ether oxygen forms a 5-membered chelate with the neighboring phosphonate and favors thus coordination at the Pα group. Research on ANPs containing a purine residue revealed that the kind and position of the substituent at C2 or C6 has a significant influence on the biological activity. For example, the shift of the (C6)NH2 group in PMEA to the C2 position leads to 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer with only a moderate antiviral activity. Removal of (C6)NH2 favors N7 coordination, e.g., of Cu2+, whereas the ether O atom binding of Cu2+ in PMEA facilitates N3 coordination via adjacent 5- and 7-membered chelates, giving rise to a Cu(PMEA)cl/O/N3 isomer. If the metal ions (M2+) are M(α,β)-M(γ)-coordinated at a triphosphate chain, transphosphorylation occurs (kinases, etc.), whereas metal ion binding in a M(α)-M(β,γ)-type fashion is relevant for polymerases. It may be noted that with diphosphorylated PMEA, (PMEApp4−), the M(α)-M(β,γ) binding is favored because of the formation of the 5-membered chelate involving the ether O atom (see above). The self-association tendency of purines leads to the formation of dimeric [M2(ATP)]2(OH)− stacks, which occur in low concentration and where one half of the molecule undergoes the dephosphorylation reaction and the other half stabilizes the structure—i.e., acts as the “enzyme” by bridging the two ATPs. In accord herewith, one may enhance the reaction rate by adding AMP2− to the [Cu2(ATP)]2(OH)− solution, as this leads to the formation of mixed stacked Cu3(ATP)(AMP)(OH)− species, in which AMP2− takes over the structuring role, while the other “half” of the molecule undergoes dephosphorylation. It may be added that Cu3(ATP)(PMEA) or better Cu3(ATP)(PMEA)(OH)− is even a more reactive species than Cu3(ATP)(AMP)(OH)−. – The matrix-assisted self-association and its significance for cell organelles with high ATP concentrations is summarized and discussed, as is, e.g., the effect of tryptophanate (Trp−), which leads to the formation of intramolecular stacks in M(ATP)(Trp)3− complexes (formation degree about 75%). Furthermore, it is well-known that in the active-site cavities of enzymes the dielectric constant, compared with bulk water, is reduced; therefore, we have summarized and discussed the effect of a change in solvent polarity on the stability and structure of binary and ternary complexes: Opposite effects on charged O sites and neutral N sites are observed, and this leads to interesting insights. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Bioinorganic Chemistry and Modes of Action—Dedicated to the Research Activity of Professor Luigi Messori)
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