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Design, Synthesis and Applications of New Anti-cancer Agents II

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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 (30 September 2022) | Viewed by 24707

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Special Issue Editor

Prof. Dr. Nicola Micale

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Dipartimento di Scienze del Farmaco e dei Prodotti per la Salute, Università degli Studi di Messina, 98168 Messina, Italy
Interests: conformationally constrained peptidomimetics; neglected diseases; target-based identification of anti-cancer agents; hyaluronic acid-based bioconjugates; study of metal complexes in biological systems
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The increasing incidence of malignancies worldwide coupled with the current global health emergency calls the scientific community to make new, effective, and immediate drug discovery efforts in the field. After the successful first edition of the Special Issue “Design, Synthesis and Applications of New Anti-Cancer Agents”, we determined to produce a second edition aiming to disclose brand new findings and advances in the design and synthesis of target-based anti-cancer agents, as well as information on new approaches, methods, and delivery systems for the improvement of the pharmacological profile of the drugs currently available on the market.

Prof. Dr. Nicola Micale
Guest Editor

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Keywords

Anti-Cancer Agents
Small-Molecules Drug Design
Metal Complexes
Enzyme Inhibitors
Active/Passive Targeting
Docking Studies

Published Papers (10 papers)

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Research

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13 pages, 2318 KiB

Open AccessArticle

Antileukemia Activity and Mechanism of Platinum(II)-Based Metal Complexes

by Maria Letizia Di Pietro, Claudio Stagno, Thomas Efferth, Ejlal A. Omer, Valeria D’Angelo, Maria Paola Germanò, Anna Cacciola, Federica De Gaetano, Nunzio Iraci and Nicola Micale

Molecules 2022, 27(24), 9000; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27249000 - 17 Dec 2022

Cited by 5 | Viewed by 1273

Abstract

Transition metal complexes have continued to constitute an appealing class of medicinal compounds since the exceptional discovery of cisplatin in the late 1960s. Pt(II)-based complexes are endowed with a broad range of biological properties, which are mainly exerted by targeting DNA. In this study, we report a significant biological investigation into and computation analyses of four Pt(II)-complexes, namely, LDP-1–4, synthesized and characterized according to previously reported procedures. Molecular-modelling studies highlighted that the top two LDP compounds (i.e., LDP-1 and LDP-4) might bind to both matched and mismatched base pair sites of the oligonucleotide 5′-(dCGGAAATTACCG)₂-3′, supporting their anticancer potential. These two complexes displayed noteworthy cytotoxicity in vitro (sub-micromolar–micromolar range) against two leukaemia cell lines, i.e., CCRF-CEM and its multi-drug-resistant counterpart CEM/ADR5000, and remarkable anti-angiogenic properties (in the sub-micromolar range) evaluated in an in vivo model, i.e., a chick embryo chorioallantoic membrane (CAM) assay. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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36 pages, 7726 KiB

Open AccessArticle

Bioactive Platinum(IV) Complexes Incorporating Halogenated Phenylacetates

by Angelico D. Aputen, Maria George Elias, Jayne Gilbert, Jennette A. Sakoff, Christopher P. Gordon, Kieran F. Scott and Janice R. Aldrich-Wright

Molecules 2022, 27(20), 7120; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27207120 - 21 Oct 2022

Cited by 6 | Viewed by 2231

Abstract

A new series of cytotoxic platinum(IV) complexes (1–8) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes 1–8 were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely 4 and 6, eliciting an average GI₅₀ value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, 4 exhibited the highest degree of potency amongst the derivatives, displaying a GI₅₀ value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, 56MESS (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, 4 (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes’ solubility, stability, lipophilicity, and reactive oxygen species production. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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22 pages, 15849 KiB

Open AccessArticle

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

by Eslam B. Elkaeed, Reda G. Yousef, Hazem Elkady, Ibraheem M. M. Gobaara, Bshra A. Alsfouk, Dalal Z. Husein, Ibrahim M. Ibrahim, Ahmed M. Metwaly and Ibrahim H. Eissa

Molecules 2022, 27(14), 4606; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144606 - 19 Jul 2022

Cited by 74 | Viewed by 2957

Abstract

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC₅₀ value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC₅₀ values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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19 pages, 4792 KiB

Open AccessArticle

Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

by Sergei Boichuk, Kirill Syuzov, Firuza Bikinieva, Aigul Galembikova, Svetlana Zykova, Ksenia Gankova, Sergei Igidov and Nazim Igidov

Molecules 2022, 27(9), 2873; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092873 - 30 Apr 2022

Cited by 4 | Viewed by 2012

Abstract

Despite the tubulin-binding agents (TBAs) that are widely used in the clinic for cancer therapy, tumor resistance to TBAs (both inherited and acquired) significantly impairs their effectiveness, thereby decreasing overall survival (OS) and progression-free survival (PFS) rates, especially for the patients with metastatic, recurrent, and unresectable forms of the disease. Therefore, the development of novel effective drugs interfering with the microtubules’ dynamic state remains a big challenge in current oncology. We report here about the novel ethyl 2-amino-1-(furan-2-carboxamido)-5-(2-aryl/tert-butyl-2-oxoethylidene)-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates (EAPCs) exhibiting potent anti-cancer activities against the breast and lung cancer cell lines in vitro. This was due to their ability to inhibit tubulin polymerization and induce cell cycle arrest in M-phase. As an outcome, the EAPC-treated cancer cells exhibited a significant increase in apoptosis, which was evidenced by the expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin-V-positive cells. By using the in silico molecular modeling methods (e.g., induced-fit docking, binding metadynamics, and unbiased molecular dynamics), we found that EAPC-67 and -70 preferentially bind to the colchicine-binding site of tubulin. Lastly, we have shown that the EAPCs indicated above and colchicine utilizes a similar molecular mechanism to inhibit tubulin polymerization via targeting the T7 loop in the β-chain of tubulin, thereby preventing the conformational changes in the tubulin dimers required for their polymerization. Collectively, we identified the novel and potent TBAs that bind to the colchicine-binding site and disrupt the microtubule network. As a result of these events, the compounds induced a robust cell cycle arrest in M-phase and exhibited potent pro-apoptotic activities against the epithelial cancer cell lines in vitro. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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18 pages, 4616 KiB

Open AccessArticle

Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of c-myc G-Quadruplex DNA

by Liang Zeng, Chanling Yuan, Jing Shu, Jiayi Qian, Qiong Wu, Yanhua Chen, Ruzhen Wu, Xiaoming Ouyang, Yuan Li and Wenjie Mei

Molecules 2022, 27(6), 1897; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27061897 - 15 Mar 2022

Cited by 4 | Viewed by 1988

Abstract

Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(η⁶-arene)(L)Cl] (L₁ = 2-(2,3-difluorophenyl)imidazole[4,5f][1,10]-phenanthroline; L₂ = 2-(2,4-difluorophenyl)imidazole[4,5f][1,10]-phenanthroline; arene = benzene, toluene, and p-cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to c-myc G-quadruplex DNA through either groove binding or π–π stacking, and the relative difluorinated site in the main ligand plays a role in regulating the binding mode. The binding behavior of these complexes with c-myc G-quadruplex DNA was evaluated using ultraviolet–visible spectroscopy, fluorescence intercalator displacement assay, fluorescence resonance energy transfer melting assay, and polymerase chain reaction. The comprehensive analysis indicated that complex 1 exhibited a better affinity and stability in relation to c-myc G-quadruplex DNA with a DC₅₀ of 6.6 μM and ΔT_m values of 13.09 °C, than other molecules. Further activity evaluation results displayed that this class of complexes can also inhibit the growth of various tumor cells, especially complexes 3 and 6, which exhibited a better inhibitory effect against human U87 glioblastoma cells (51.61 and 23.75 μM) than other complexes, even superior to cisplatin (32.59 μM). Owing to a befitting lipophilicity associated with the high intake of drugs by tumor cells, complexes 3 and 6 had favorable lipid-water partition coefficients of −0.6615 and −0.8077, respectively. Moreover, it was found that complex 6 suppressed the proliferation of U87 cells mainly through an induced obvious S phase arrest and slight apoptosis, which may have resulted from the stabilization of c-myc G-quadruplex DNA to block the transcription and expression of c-myc. In brief, these types of arene Ru(II) complexes with difluorinated ligands can be developed as potential inducers of S-phase arrest and apoptosis through the binding and stabilization of c-myc G-quadruplex DNA, and could be used in clinical applications in the future. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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21 pages, 4291 KiB

Open AccessArticle

Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents

by Farhana Islam, Arpit Doshi, Andrew J. Robles, Tasdique M. Quadery, Xin Zhang, Xilin Zhou, Ernest Hamel, Susan L. Mooberry and Aleem Gangjee

Molecules 2022, 27(1), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27010321 - 05 Jan 2022

Cited by 4 | Viewed by 3077

Abstract

A series of eleven 4-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines were designed and synthesized and their biological activities were evaluated. Synthesis involved the Gewald reaction to synthesize ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate ring, and S_NAr reactions. Compound 4 was 1.6- and ~7-fold more potent than the lead compound 1 in cell proliferation and microtubule depolymerization assays, respectively. Compounds 4, 5 and 7 showed the most potent antiproliferative effects (IC₅₀ values < 40 nM), while compounds 6, 8, 10, 12 and 13 had lower antiproliferative potencies (IC₅₀ values of 53–125 nM). Additionally, compounds 4–8, 10 and 12–13 circumvented Pgp and βIII-tubulin mediated drug resistance, mechanisms that diminish the clinical efficacy of paclitaxel (PTX). In the NCI-60 cell line panel, compound 4 exhibited an average GI₅₀ of ~10 nM in the 40 most sensitive cell lines. Compound 4 demonstrated statistically significant antitumor effects in a murine MDA-MB-435 xenograft model. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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12 pages, 1537 KiB

Open AccessArticle

Cyclodextrin Polymers as Delivery Systems for Targeted Anti-Cancer Chemotherapy

by Noemi Bognanni, Maurizio Viale, Alessia Distefano, Rita Tosto, Nadia Bertola, Fabrizio Loiacono, Marco Ponassi, Domenico Spinelli, Giuseppe Pappalardo and Graziella Vecchio

Molecules 2021, 26(19), 6046; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26196046 - 06 Oct 2021

Cited by 14 | Viewed by 2374

Abstract

In the few last years, nanosystems have emerged as a potential therapeutic approach to improve the efficacy and selectivity of many drugs. Cyclodextrins (CyDs) and their nanoparticles have been widely investigated as drug delivery systems. The covalent functionalization of CyD polymer nanoparticles with targeting molecules can improve the therapeutic potential of this family of nanosystems. In this study, we investigated cross-linked γ- and β-cyclodextrin polymers as carriers for doxorubicin (ox) and oxaliplatin (Oxa). We also functionalized γ-CyD polymer bearing COOH functionalities with arginine-glycine-aspartic or arginine moieties for targeting the integrin receptors of cancer cells. We tested the Dox and Oxa anti-proliferative activity in the presence of the precursor polymer with COOH functionalities and its derivatives in A549 (lung, carcinoma) and HepG2 (liver, carcinoma) cell lines. We found that CyD polymers can significantly improve the antiproliferative activity of Dox in HepG2 cell lines only, whereas the cytotoxic activity of Oxa resulted as enhanced in both cell lines. The peptide or amino acid functionalized CyD polymers, loaded with Dox, did not show any additional effect compared to the precursor polymer. Finally, studies of Dox uptake showed that the higher antiproliferative activity of complexes correlates with the higher accumulation of Dox inside the cells. The results show that CyD polymers could be used as carriers for repositioning classical anticancer drugs such as Dox or Oxa to increase their antitumor activity. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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Review

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16 pages, 3414 KiB

Open AccessReview

A Structure-Based View on ABC-Transporter Linked to Multidrug Resistance

by Jiahui Huang and Gerhard F. Ecker

Molecules 2023, 28(2), 495; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28020495 - 04 Jan 2023

Cited by 13 | Viewed by 2591

Abstract

The discovery of the first ATP-binding cassette (ABC) transporter, whose overexpression in cancer cells is responsible for exporting anticancer drugs out of tumor cells, initiated enormous efforts to overcome tumor cell multidrug resistance (MDR) by inhibition of ABC-transporter. Because of its many physiological functions, diverse studies have been conducted on the mechanism, function and regulation of this important group of transmembrane transport proteins. In this review, we will focus on the structural aspects of this transporter superfamily. Since the resolution revolution of electron microscope, experimentally solved structures increased rapidly. A summary of the structures available and an overview of recent structure-based studies are provided. More specifically, the artificial intelligence (AI)-based predictions from AlphaFold-2 will be discussed. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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15 pages, 1831 KiB

Open AccessReview

Emerging Direct Targeting β-Catenin Agents

by Marianna Nalli, Domiziana Masci, Andrea Urbani, Giuseppe La Regina and Romano Silvestri

Molecules 2022, 27(22), 7735; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227735 - 10 Nov 2022

Cited by 3 | Viewed by 1800

Abstract

Aberrant accumulation of β-catenin in the cell nucleus as a result of deregulation of the Wnt/β-catenin pathway is found in various types of cancer. Direct β-catenin targeting agents are being researched despite obstacles; however, specific β-catenin drugs for clinical treatments have not been approved so far. We focused on direct β-catenin targeting of potential therapeutic value as anticancer agents. This review provides recent advances on small molecule β-catenin agents. Structure-activity relationships and biological activities of reported inhibitors are discussed. This work provides useful knowledge in the discovery of β-catenin agents. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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31 pages, 7984 KiB

Open AccessReview

Recent Advances in the Use of the Dimerization Strategy as a Means to Increase the Biological Potential of Natural or Synthetic Molecules

by Alexis Paquin, Carlos Reyes-Moreno and Gervais Bérubé

Molecules 2021, 26(8), 2340; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26082340 - 17 Apr 2021

Cited by 24 | Viewed by 3439

Abstract

The design of C₂-symmetric biologically active molecules is a subject of interest to the scientific community. It provides the possibility of discovering medicine with higher biological potential than the parent drugs. Such molecules are generally produced by classic chemistry, considering the shortness of reaction sequence and the efficacy for each step. This review describes and analyzes recent advances in the field and emphasizes selected C₂-symmetric molecules (or axial symmetric molecules) made during the last 10 years. However, the description of the dimers is contextualized by prior work allowing its development, and they are categorized by their structure and/or by their properties. Hence, this review presents dimers composed of steroids, sugars, and nucleosides; known and synthetic anticancer agents; polyphenol compounds; terpenes, known and synthetic antibacterial agents; and natural products. A special focus on the anticancer potential of the dimers transpires throughout the review, notwithstanding their structure and/or primary biological properties. Full article

(This article belongs to the Special Issue Design, Synthesis and Applications of New Anti-cancer Agents II)

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