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Inorganic Compounds in Medicine, Cancer Therapy and Beyond – an Update from Drug Design Perspective

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

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 10065

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Special Issue Editors

Dr. Tiziano Marzo

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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

Dr. Iogann Tolbatov

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Guest Editor

Institute of Chemical Research of Catalonia (ICIQ), Tarragona, Spain
Interests: computational bioinorganic chemistry; inorganic medicinal chemistry; protein metalation; metalloproteins; metal-based drugs; metal-based anticancer agents; metal-based antimicrobial agents; metal ions in biological milieu

Special Issue Information

Dear Colleagues,

Metal complexes have a crucial role in the anticancer therapy nowadays, and even with the emergence of novel chemotherapeutical treatments, the employment of metallodrugs will remain the key instrument in the struggle against the cancer. A plethora of both Pt- and non-Pt-based anticancer metal complexes have been developed. For example, gold complexes display exceptional cytotoxicity, and some ruthenium complexes inhibit metastases of solid invasive tumors. Analogously, arsenic, though well known as potent poison, when administered as oxide (As2O3) is widely used as potent and effective agent to treat promyelocytic leukemia. Additionally, several Gd, Ge, Ti, Ga-based complexes are now at the stage of human clinical trials. Thus, on one hand, various metal complexes possess various modes of action, such as DNA binding, enzyme or protein targeting, redox modulation and targeting oncogenic signaling pathways. On the other hand, this peculiar versatility makes metal -or metalloids- suitable for a wide array of medicinal application in several fields including anticancer, antimicrobial, antiparasitic and antiviral therapy.

On the ground of these considerations, metal complexes present a myriad of unexplored features which make them perfect scaffolds for drug development. Their rational design includes fine-tuning of their structure with the aim to reach the intended biological effects, indeed, various metal centers possess different physicochemical properties, which include redox potentials, binding preferences to biomolecules, and kinetics of ligand exchange.

This Special Issue aims to collect the most recent advances on the topics related to anticancer metal complexes, their synthesis, characterization and biological evaluation, both experimental and computational. Furthermore, contribution dealing with the development of inorganic compounds for medicinal applications beyond the anticancer therapy are also welcome.

Dr. Tiziano Marzo
Dr. Iogann Tolbatov
Guest Editors

Manuscript Submission Information

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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

anticancer metal complexes
antitumor metallodrugs
antimicrobial agents
antiviral metallodrugs
medicinal inorganic chemistry
bioinorganic chemistry
DNA targeting
TrxR targeting
rational metallodrug design
cytotoxic metal complexes

Published Papers (4 papers)

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Research

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15 pages, 4657 KiB

Open AccessArticle

Copper(II) Complex Containing 4-Fluorophenoxyacetic Acid Hydrazide and 1,10-Phenanthroline: A Prostate Cancer Cell-Selective and Low-Toxic Copper(II) Compound

by Nayara Júnia de Souza Bontempo, Drielly Aparecida Paixão, Paula Marynella Alves Pereira Lima, Deysse Carla Tolentino Barros, Dayanne Silva Borges, Priscila Capelari Orsolin, Isabella Castro Martins, Pedro Henrique Alves Machado, Ricardo Campos Lino, Tiago Rodrigues de Souza, Luana Munique Sousa Ramos, Samuel Cota Teixeira, Raoni Pais Siqueira, Luiz Ricardo Goulart Filho, Wendell Guerra, Robson José de Oliveira Júnior and Thaise Gonçalves de Araújo

Molecules 2022, 27(20), 7097; https://doi.org/10.3390/molecules27207097 - 20 Oct 2022

Cited by 2 | Viewed by 1407

Abstract

Prostate Cancer (PCa) is the second leading cause of cancer-related deaths among men worldwide. The treatment of advanced cases is based on chemotherapy, which lacks specificity and efficacy, due to severe side effects and resistance to the traditional drugs. Copper complexes have shown antitumoral efficacy and low toxicity, being considered a promising class of metal-based drugs for the treatment of malignant neoplasms. Thus, the present study aimed to evaluate the cellular effects of a copper(II) complex with 4-fluorophenoxyacetic acid hydrazide and 1,10-phenanthroline (1) on PCa cell lines, as well as the mutagenic/recombinogenic and anticarcinogenic potential of 1 in Drosophila melanogaster. PNT-2 (non-tumorigenic), LNCaP (hormone-responsive PCa) and PC-3 (androgen-independent PCa) cells were cultured, and cytotoxicity was assessed using the MTT assay. The expression levels of the proliferation markers Ki-67 and Cyclin D1 were analyzed by flow cytometry. Furthermore, the Somatic Mutation and Recombination Test (SMART) and the Epithelial Tumor Test (ETT) were performed. Complex 1 was selective to LNCaP cells, significantly reducing Ki-67 and Cyclin D1 expression levels. Sub-toxic concentrations of complex 1 were defined by the toxicity test in D. melanogaster, and no mutagenic/recombinogenic/carcinogenic effects were observed. Anticarcinogenic potential was observed in D. melanogaster, suggesting modulating activity of the complex 1 against Doxorubicin, a drug used as control by its carcinogenic properties. Therefore, complex 1 is a possible starting point for the development of new antitumor agents for the treatment of PCa. Full article

(This article belongs to the Special Issue Inorganic Compounds in Medicine, Cancer Therapy and Beyond – an Update from Drug Design Perspective)

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11 pages, 1395 KiB

Open AccessArticle

Porphyrins and Metalloporphyrins Combined with N-Heterocyclic Carbene (NHC) Gold(I) Complexes for Photodynamic Therapy Application: What Is the Weight of the Heavy Atom Effect?

by Stefano Scoditti, Francesco Chiodo, Gloria Mazzone, Sébastien Richeter and Emilia Sicilia

Molecules 2022, 27(13), 4046; https://doi.org/10.3390/molecules27134046 - 23 Jun 2022

Cited by 8 | Viewed by 2689

Abstract

The photophysical properties of two classes of porphyrins and metalloporphyrins linked to N-heterocyclic carbene (NHC) Au(I) complexes have been investigated by means of density functional theory and its time-dependent extension for their potential application in photodynamic therapy. For this purpose, the absorption spectra, the singlet–triplet energy gaps, and the spin–orbit coupling (SOC) constants have been determined. The obtained results show that all the studied compounds possess the appropriate properties to generate cytotoxic singlet molecular oxygen, and consequently, they can be employed as photosensitizers in photodynamic therapy. Nevertheless, on the basis of the computed SOCs and the analysis of the metal contribution to the involved molecular orbitals, a different influence in terms of the heavy atom effect in promoting the intersystem crossing process has been found as a function of the identity of the metal center and its position in the center of the porphyrin core or linked to the peripheral NHC. Full article

(This article belongs to the Special Issue Inorganic Compounds in Medicine, Cancer Therapy and Beyond – an Update from Drug Design Perspective)

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Graphical abstract

12 pages, 679 KiB

Open AccessArticle

Anti-Staphylococcal Activity of the Auranofin Analogue Bearing Acetylcysteine in Place of the Thiosugar: An Experimental and Theoretical Investigation

by Lorenzo Chiaverini, Alessandro Pratesi, Damiano Cirri, Arianna Nardinocchi, Iogann Tolbatov, Alessandro Marrone, Mariagrazia Di Luca, Tiziano Marzo and Diego La Mendola

Molecules 2022, 27(8), 2578; https://doi.org/10.3390/molecules27082578 - 16 Apr 2022

Cited by 6 | Viewed by 1859

Abstract

Auranofin (AF, hereafter) is an orally administered chrysotherapeutic agent approved for the treatment of rheumatoid arthritis that is being repurposed for various indications including bacterial infections. Its likely mode of action involves the impairment of the TrxR system through the binding of the pharmacophoric cation [AuPEt₃]⁺. Accordingly, a reliable strategy to expand the medicinal profile of AF is the replacement of the thiosugar moiety with different ligands. Herein, we aimed to prepare the AF analogue bearing the acetylcysteine ligand (AF-AcCys, hereafter) and characterize its anti-staphylococcal activity. Biological studies revealed that AF-AcCys retains an antibacterial effect superimposable with that of AF against Staphylococcus aureus, whereas it is about 20 times less effective against Staphylococcus epidermidis. Bioinorganic studies confirmed that upon incubation with human serum albumin, AF-AcCys, similarly to AF, induced protein metalation through the [AuPEt₃]⁺ fragment. Additionally, AF-AcCys appeared capable of binding the dodecapeptide Ac-SGGDILQSGCUG-NH₂, corresponding to the tryptic C-terminal fragment (488–499) of hTrxR. To shed light on the pharmacological differences between AF and AF-AcCys, we carried out a comparative experimental stability study and a theoretical estimation of bond dissociation energies, unveiling the higher strength of the Au–S bond in AF-AcCys. From the results, it emerged that the lower lipophilicity of AF-AcCys with respect to AF could be a key feature for its different antibacterial activity. The differences and similarities between AF and AF-AcCys are discussed, alongside the opportunities and consequences that chemical structure modifications imply. Full article

(This article belongs to the Special Issue Inorganic Compounds in Medicine, Cancer Therapy and Beyond – an Update from Drug Design Perspective)

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Review

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16 pages, 3682 KiB

Open AccessReview

Evidence of Metallic and Polyether Ionophores as Potent Therapeutic Drug Candidate in Cancer Management

by Pratibha Pandey, Fahad Khan, Huda A. Qari, Tarun Kumar Upadhyay, Abdulhameed F. Alkhateeb and Mohammad Oves

Molecules 2022, 27(15), 4708; https://doi.org/10.3390/molecules27154708 - 23 Jul 2022

Cited by 2 | Viewed by 1777

Abstract

Cancer remains one of the most crucial human malignancies with a higher mortality rate globally, and is predicted to escalate soon. Dysregulated ion homeostasis in cancerous cells prompted the researchers to investigate further ion homeostasis impeding agents as potent anticancerous agents. Reutilization of FDA-approved non-cancerous drugs has emerged as a practical approach to developing potent, cost-effective drugs for cancer treatment. Across the globe, most nations are incapable of fulfilling the medical demands of cancer patients due to costlier cancerous drugs. Therefore, we have inclined our review towards emphasizing recent advancements in cancer therapies involving ionophores utilization in exploring potent anticancer drugs. Numerous research reports have established the significant anticancerous potential of ionophores in several pre-clinical reports via modulating aberrant cell signaling pathways and enhancing antitumor immunity in immune cells. This review has mainly summarized the most significant ion homeostasis impeding agents, including copper, zinc, calcium, and polyether, that presented remarkable potential in cancer therapeutics via enhanced antitumor immunity and apoptosis induction. Altogether, this study could provide a robust future perspective for developing cost-effective anticancerous drugs rapidly and cost-effectively, thereby combating the limitations of currently available drugs used in cancer treatment. Full article

(This article belongs to the Special Issue Inorganic Compounds in Medicine, Cancer Therapy and Beyond – an Update from Drug Design Perspective)

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