Design, Synthesis, in silico and in vitro Evaluation of New Combretastatin A-4 Analogs as Antimitotic Antitumor Agents

Author:

Hussein Shaker A. Abdul1,Kubba Ammar2,Balakit Asim A.1,Tahtamouni Lubna H.34,Abbas Ali H.5

Affiliation:

1. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Babylon, Babylon, Iraq

2. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Baghdad, Baghdad, Iraq

3. Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa, Jordan

4. Department of Biochemistry and Molecular Biology, College of Natural Sciences, Colorado State University, Fort Collins, Colorado, CO 80523, USA

5. Department of Pharmaceutical Chemistry, College of Pharmacy, University of Tikrit, Tikrit/Salah-Aldin, Iraq

Abstract

Background: Combretastatin A-4 (CA-4) binds β-tubulin at the colchicine-binding site preventing tubulin from polymerizing into microtubules. CA-4 and cis combretastatin analogs isomerize to the trans form resulting in decreased cytotoxicity and anti-tubulin activity. However, the excellent anti-cancer potential and relatively simple molecular structure of CA-4 provide an encouraging starting point for the development of new, more stable and more potent anti-tubulin compounds. Objective: This study aimed to synthesize a new series of compounds derived from 4-(3,4,5- trimethoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives (compounds 10-12) with substituted phenyl group at C5 of the triazole ring (B-ring) as analogs of CA-4, with different alkyl and aryl side chain substituents at the triazole moiety, resulting in the permanent cis configuration of the two phenyl rings. Moreover, the anti-cancer activities of the new compounds were assessed. Methods: Chemical synthesis was carried out by conventional organic methods. The newly synthesized CA-4 analogs were characterized by FT-IR, 1HNMR, 13CNMR, and HR-MS(ESI) techniques. Molecular docking studies, including docking score (ΔG), ADMET, DFT, and molecular similarities, were performed. The anti-proliferative activity of the new compounds against three human cancer cell lines (A549, Hep G2, and HCT-116) and the normal cell line WI-38 was evaluated using the MTT assay, and their ability to inhibit tubulin polymerization, and consequently, their effects on cell cycle progression and induction of apoptosis were assessed. Results: Molecular docking studies showed that compounds 11b and 11d exhibited the highest docking scores (-13.30 and -14.01 Kcal/mol, respectively) into the colchicine-binding site, scores very close to the reference drug colchicine (-13.50 Kcal/mol), and that hydrogen bonding and hydrophobic interaction are essential for binding. The most active cytotoxic compound, 11b, had potent IC50 values against the three human cancer cell lines (3.83, 10.20, and 10.67 μM against Hep G2, HCT- 116, and A549, respectively) while exhibiting low cytotoxicity against non-cancer-human WI-38, suggesting that compound 11b targets rapidly growing cancer cells. Moreover, compound 11b exhibited potent anti-tubulin activity which was comparable to CA-4. Targeting microtubules caused cell cycle arrest at the G2/M phase resulting in the induction of apoptosis. Conclusion: These findings indicate that compound 11b is a promising β-tubulin-binding compound with antimitotic action that has the potential to treat cancer.

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery

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