Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 October 2023) | Viewed by 9414

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Guest Editor
School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
Interests: metal-based drugs; cancer; chemotherapeutics agents; bioinorganic chemistry; protein metalation; DNA metalation
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Guest Editor
Department of Chemistry and Industrial Chemistry, University of Pisa, Via Moruzzi 13, 56124 Pisa, Italy
Interests: bioinorganic chemistry; inorganic chemistry; NMR; metal-based drugs; chemotherapeutic agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Four decades after cisplatin was approved by the FDA, platinum-based compounds still represent the most valuable tools in the treatment of a wide variety of neoplastic diseases. Nevertheless, despite the undeniable advancements in cancer therapy which have been achieved with these molecules, some relevant drawbacks still encourage the discovery of new chemotherapeutic agents. First, the clinically established platinum drugs (i.e., cisplatin, oxaliplatin and carboplatin) are known to induce significant side effects in treated patients, such as bone marrow suppression, severe nausea and vomiting, ototoxicity, nephrotoxicity and hepatotoxicity. Moreover, their effectiveness is usually highly reduced in the case of relapse. For these reasons, both the life quality and life expectancy of cancer-affected patients are often dramatically reduced. In this context, the discovery of new and safer chemotherapeutic agents still represents a central concern in the field of cancer research. More precisely, bioinorganic chemists should expand their interest towards the whole family of transition metals, with the aim of discovering new classes of active compounds without reverting to the irreplaceable electrophilic features of metal centers. This Special Issue aims to collect contributions reporting on advancements in the field of platinum-free metal-based anticancer drug candidates.

Prof. Dr. Wukun Liu
Dr. Damiano Cirri
Guest Editors

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Keywords

  • metal-based drugs
  • cancer
  • chemotherapeutic agents
  • bioinorganic chemistry
  • protein metalation
  • DNA metalation

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Published Papers (6 papers)

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Research

20 pages, 2138 KiB  
Article
Development of Zeise’s Salt Derivatives Bearing Substituted Acetylsalicylic Acid Substructures as Cytotoxic COX Inhibitors
by Alexander Weninger, Jessica Sagasser, Victoria Obermoser, Josef Egger, Susanna Wisboeck, Qianqian Qiu, Miriam Ladstaetter, Andrea Cucchiaro, Klaus Wurst, Daniel Baecker and Ronald Gust
Pharmaceutics 2023, 15(6), 1573; https://doi.org/10.3390/pharmaceutics15061573 - 23 May 2023
Cited by 3 | Viewed by 1186
Abstract
Zeise’s salt derivatives of the potassium trichlorido[η2-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl3/ASA-But-PtCl3 derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl3 and ASA-But-PtCl3 interfere with the arachidonic acid cascade [...] Read more.
Zeise’s salt derivatives of the potassium trichlorido[η2-((prop-2-en/but-3-en)-1-yl)-2-acetoxybenzoate]platinate(II) type (ASA-Prop-PtCl3/ASA-But-PtCl3 derivatives) were synthesized and characterized regarding their structure, stability, and biological activity. It is proposed that the leads ASA-Prop-PtCl3 and ASA-But-PtCl3 interfere with the arachidonic acid cascade as part of their mode of action to reduce the growth of COX-1/2-expressing tumor cells. With the aim to increase the antiproliferative activity by strengthening the inhibitory potency against COX-2, F, Cl, or CH3 substituents were introduced into the acetylsalicylic acid (ASA) moiety. Each structural modification improved COX-2 inhibition. Especially compounds with F substituents at ASA-But-PtCl3 reached the maximum achievable inhibition of about 70% already at 1 µM. The PGE2 formation in COX-1/2-positive HT-29 cells was suppressed by all F/Cl/CH3 derivatives, indicating COX inhibitory potency in cellular systems. The CH3-bearing complexes showed the highest cytotoxicity in COX-1/2-positive HT-29 cells with IC50 values of 16–27 µM. In COX-negative MCF-7 cells, they were 2–3-fold less active. These data clearly demonstrate that it is possible to increase the cytotoxicity of ASA-Prop-PtCl3 and ASA-But-PtCl3 derivatives by enhancing COX-2 inhibition. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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18 pages, 7144 KiB  
Article
New Organometallic Ru(II) Compounds with Lonidamine Motif as Antitumor Agents
by Ilya A. Shutkov, Yulia N. Okulova, Dmitrii M. Mazur, Nikolai A. Melnichuk, Denis A. Babkov, Elena V. Sokolova, Alexander A. Spasov, Elena R. Milaeva and Alexey A. Nazarov
Pharmaceutics 2023, 15(5), 1366; https://doi.org/10.3390/pharmaceutics15051366 - 29 Apr 2023
Cited by 3 | Viewed by 1349
Abstract
The combination of one molecule of organic and metal-based fragments that exhibit antitumor activity is a modern approach in the search for new promising drugs. In this work, biologically active ligands based on lonidamine (a selective inhibitor of aerobic glycolysis used in clinical [...] Read more.
The combination of one molecule of organic and metal-based fragments that exhibit antitumor activity is a modern approach in the search for new promising drugs. In this work, biologically active ligands based on lonidamine (a selective inhibitor of aerobic glycolysis used in clinical practice) were introduced into the structure of an antitumor organometallic ruthenium scaffold. Resistant to ligand exchange reactions, compounds were prepared by replacing labile ligands with stable ones. Moreover, cationic complexes containing two lonidamine-based ligands were obtained. Antiproliferative activity was studied in vitro by MTT assays. It was shown that the increase in the stability in ligand exchange reactions does not influence cytotoxicity. At the same time, the introduction of the second lonidamine fragment approximately doubles the cytotoxicity of studied complexes. The ability to induce apoptosis and caspase activation in tumour cell MCF7 was studied by employing flow cytometry. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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14 pages, 1396 KiB  
Article
Modulation of Transcription Profile Induced by Antiproliferative Thiosemicarbazone Metal Complexes in U937 Cancer Cells
by Serena Montalbano, Franco Bisceglie, Giorgio Pelosi, Mirca Lazzaretti and Annamaria Buschini
Pharmaceutics 2023, 15(5), 1325; https://doi.org/10.3390/pharmaceutics15051325 - 24 Apr 2023
Viewed by 1318
Abstract
Since the discovery of cisplatin, the search for metal-based compounds with therapeutic potential has been a challenge for the scientific community. In this landscape, thiosemicarbazones and their metal derivatives represent a good starting point for the development of anticancer agents with high selectivity [...] Read more.
Since the discovery of cisplatin, the search for metal-based compounds with therapeutic potential has been a challenge for the scientific community. In this landscape, thiosemicarbazones and their metal derivatives represent a good starting point for the development of anticancer agents with high selectivity and low toxicity. Here, we focused on the action mechanism of three metal thiosemicarbazones [Ni(tcitr)2], [Pt(tcitr)2], and [Cu(tcitr)2], derived from citronellal. The complexes were already synthesized, characterized, and screened for their antiproliferative activity against different cancer cells and for genotoxic/mutagenic potential. In this work, we deepened the understanding of their molecular action mechanism using an in vitro model of a leukemia cell line (U937) and an approach of transcriptional expression profile analysis. U937 cells showed a significant sensitivity to the tested molecules. To better understand DNA damage induced by our complexes, the modulation of a panel of genes involved in the DNA damage response pathway was evaluated. We analyzed whether our compounds affected cell cycle progression to determine a possible correlation between proliferation inhibition and cell cycle arrest. Our results demonstrate that metal complexes target different cellular processes and could be promising candidates in the design of antiproliferative thiosemicarbazones, although their overall molecular mechanism is still to be understood. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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12 pages, 4047 KiB  
Article
In Situ Synthesis of a Tumor-Microenvironment-Responsive Chemotherapy Drug
by Xiupeng Wang, Ayako Oyane, Tomoya Inose and Maki Nakamura
Pharmaceutics 2023, 15(4), 1316; https://doi.org/10.3390/pharmaceutics15041316 - 21 Apr 2023
Cited by 2 | Viewed by 1440
Abstract
Current chemotherapy still suffers from unsatisfactory therapeutic efficacy, multi-drug resistance, and severe adverse effects, thus necessitating the development of techniques to confine chemotherapy drugs in the tumor microenvironment. Herein, we fabricated nanospheres of mesoporous silica (MS) doped with Cu (MS-Cu) and polyethylene glycol [...] Read more.
Current chemotherapy still suffers from unsatisfactory therapeutic efficacy, multi-drug resistance, and severe adverse effects, thus necessitating the development of techniques to confine chemotherapy drugs in the tumor microenvironment. Herein, we fabricated nanospheres of mesoporous silica (MS) doped with Cu (MS-Cu) and polyethylene glycol (PEG)-coated MS-Cu (PEG-MS-Cu) as exogenous copper supply systems to tumors. The synthesized MS-Cu nanospheres showed diameters of 30–150 nm with Cu/Si molar ratios of 0.041–0.069. Only disulfiram (DSF) and only MS-Cu nanospheres showed little cytotoxicity in vitro, whereas the combination of DSF and MS-Cu nanospheres showed significant cytotoxicity against MOC1 and MOC2 cells at concentrations of 0.2–1 μg/mL. Oral DSF administration in combination with MS-Cu nanospheres intratumoral or PEG-MS-Cu nanospheres intravenous administration showed significant antitumor efficacy against MOC2 cells in vivo. In contrast to traditional drug delivery systems, we herein propose a system for the in situ synthesis of chemotherapy drugs by converting nontoxic substances into antitumor chemotherapy drugs in a specific tumor microenvironment. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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15 pages, 4624 KiB  
Article
Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and -Resistant to Cisplatin
by Martin Vojtek, Clara B. Martins, Raquel Ramos, Sara Gomes Duarte, Isabel M. P. L. V. O. Ferreira, Ana L. M. Batista de Carvalho, M. Paula M. Marques and Carmen Diniz
Pharmaceutics 2023, 15(4), 1205; https://doi.org/10.3390/pharmaceutics15041205 - 10 Apr 2023
Cited by 3 | Viewed by 1709
Abstract
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10–20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug [...] Read more.
Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10–20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd3Spd2 and Pt3Spd2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDA-MB-231/R), (ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes’ ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd3Spd2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC50 values 4.65–8.99 µM and 9.24–13.34 µM, respectively), with a resistance index lower than 2.3. Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB-231/R cells. Altogether, the data presently gathered reveal Pd3Spd2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatin-resistant forms. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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20 pages, 3855 KiB  
Article
Modulation of the Cytotoxic Properties of Pd(II) Complexes Based on Functionalized Carboxamides Featuring Labile Phosphoryl Coordination Sites
by Diana V. Aleksanyan, Aleksandr V. Konovalov, Svetlana G. Churusova, Ekaterina Yu. Rybalkina, Alexander S. Peregudov, Svetlana A. Aksenova, Evgenii I. Gutsul, Zinaida S. Klemenkova and Vladimir A. Kozlov
Pharmaceutics 2023, 15(4), 1088; https://doi.org/10.3390/pharmaceutics15041088 - 28 Mar 2023
Cited by 4 | Viewed by 1704
Abstract
Platinum-based drugs are commonly recognized as a keystone in modern cancer chemotherapy. However, intrinsic and acquired resistance as well as serious side effects often caused by the traditional Pt(II) anticancer agents prompt a continuous search for more selective and efficient alternatives. Today, significant [...] Read more.
Platinum-based drugs are commonly recognized as a keystone in modern cancer chemotherapy. However, intrinsic and acquired resistance as well as serious side effects often caused by the traditional Pt(II) anticancer agents prompt a continuous search for more selective and efficient alternatives. Today, significant attention is paid to the compounds of other transition metals, in particular those of palladium. Recently, our research group has suggested functionalized carboxamides as a useful platform for the creation of cytotoxic Pd(II) pincer complexes. In this work, a robust picolinyl- or quinoline-carboxamide core was combined with a phosphoryl ancillary donor group to achieve hemilabile coordination capable of providing the required level of thermodynamic stability and kinetic lability of the ensuing Pd(II) complexes. Several cyclopalladated derivatives featuring either a bi- or tridentate pincer-type coordination mode of the deprotonated phosphoryl-functionalized amides were selectively synthesized and fully characterized using IR and NMR spectroscopy as well as X-ray crystallography. The preliminary evaluation of the anticancer potential of the resulting palladocycles revealed a strong dependence of their cytotoxic properties on the binding mode of the deprotonated amide ligands and demonstrated certain advantages of the pincer-type ligation. Full article
(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy, 2nd Edition)
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