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Molecules
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Design, Synthesis and Biological Activity of Novel Antitumor Drugs
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Design, Synthesis and Biological Activity of Novel Antitumor Drugs

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

Deadline for manuscript submissions: 31 March 2025 | Viewed by 3974

Special Issue Editors

Dr. Alessia Bertamino

E-Mail Website
Guest Editor
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy
Interests: design, synthesis and biological characterization of pharmacologically actives small molecules, peptidomimetics e peptides (antitumoral agents, antiviral compounds and ionic channel modulators); study of new reaction mechanisms and synthetic strategy optimization
Dr. Tania Ciaglia

E-Mail Website
Guest Editor
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano, SA, Italy
Interests: novel target; anticancer; small molecules; biological evaluation; synthesis; activity assay; molecular modeling

Special Issue Information

Dear Colleagues,

Anticancer therapy represents an open challenge in the research field, mainly due to off-target toxicity and the development of chemoresistance phenomena. The recent advances in molecular biology have opened the way for the recognition of novel molecular targets that previously have not been explored and analyzed for cancer treatment. In this context, a design that is supported by molecular modeling methodologies, synthesis, and pharmacological characterization of small molecules active against these new targets plays a key role in the medicinal chemistry field, representing a focal point for the future development of more effective treatments.

Dr. Alessia Bertamino
Dr. Tania Ciaglia
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

  • novel target
  • anticancer
  • small molecules
  • biological evaluation
  • synthesis
  • activity assay
  • molecular modeling

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Published Papers (2 papers)

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Research

15 pages, 5847 KiB  
Article
Thiazole Functionalization of Thiosemicarbazone for Cu(II) Complexation: Moving toward Highly Efficient Anticancer Drugs with Promising Oral Bioavailability
by Song-Yu Luo, Chun-Mei Zeng, Ping Xu, Ye Ning, Meng-Lin Dong, Wen-Hua Zhang and Guangliang Yu
Molecules 2024, 29(16), 3832; https://doi.org/10.3390/molecules29163832 - 13 Aug 2024
Viewed by 1018
Abstract
In this work, we report the synthesis of a new thiosemicarbazone-based drug of N′-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 ( [...] Read more.
In this work, we report the synthesis of a new thiosemicarbazone-based drug of N′-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10−5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)
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17 pages, 3856 KiB  
Article
Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties
by Romain Regnault, Frédérique Klupsch, Hassiba El-Bouazzati, Romain Magnez, Raphaël Le Biannic, Natascha Leleu-Chavain, Hania Ahouari, Hervé Vezin, Régis Millet, Jean-François Goossens, Xavier Thuru and Christian Bailly
Molecules 2023, 28(8), 3491; https://doi.org/10.3390/molecules28083491 - 15 Apr 2023
Cited by 1 | Viewed by 2318
Abstract
Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism [...] Read more.
Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties. Full article
(This article belongs to the Special Issue Design, Synthesis and Biological Activity of Novel Antitumor Drugs)
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