Synthesis and biological evaluation of cis -restricted triazole/tetrazole mimics of combretastatin-benzothiazole hybrids as tubulin polymerization inhibitors and apoptosis inducers

Chitti

Journal of Heterocyclic Chem

et al. 2018

A series of 28 novel 2‐(4‐aminophenyl)benzothiazole analogues have been synthesized and characterized using various analytical techniques like 1H NMR, 13C NMR, electrospray ionization mass spectrometry, and IR and bioevaluated for their antiproliferative activity over a group of three human cancer cell lines, namely, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MDA‐MB‐231), using sulforhodamine B assay method. Few synthesized molecules (5a, 5c, 5d, 5f, 7b, and 7j) displayed effective growth inhibition (GI50) activity against the tested human cancer cell lines at lower micromolar concentration (GI50) values in the range 0.2–1.7 μM. Noticeably, compound 7b exhibited reasonable activity in all three cancer cell lines in the GI50 range 0.55–1.2 μM. Further, when 7b was screened for tubulin polymerization inhibition, it exhibited more than 55% inhibition at concentration of 5.0 μM. The molecular docking simulations supported the molecular interactions of the derivatives with the targeted receptor. These derivatives may serve as lead structures for development of potential anticancer drug candidates, and 7b might act as a potential microtubule polymerization inhibitor.

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 2‐(4‐Aminophenyl)benzothiazole Analogues as Antiproliferative Agents

Chitti

Journal of Heterocyclic Chem

et al. 2018

“…Thus, an extensive focus of research was directed towards the rational modifications of the unstable olefinic bond as the main pursued strategy. Various olefinic linkers including silicon [14], butadiene [15], cyclopropane [16], cyclopropyl [17], chiral-lactam [18], furan [19], furazan [20], imidazole [21], 2,3-diarylthiophene [22], isoxazole and terphenyl [23], triazoles [24,25], thiazole [26,27] and 1,2,4-triazolo-4,3-b-pyridazines [28] has unveiled novel agents endowed with cytotoxic activity. The structure-activity relationships (SARs) have made clearly important features of maintaining the tubulin interaction for CA-4.…”

Section: Introductionmentioning

confidence: 99%

Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

Song

Wang

et al. 2020

IJMS

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

“…Colchicine (Figure ) is an alkaloid isolated from Colchicum autumnale and Gloriosa superba and the first drug known to bind tubulin at a particular site called the colchicine domain . A number of small molecules have been discovered which bind tubulins at the colchicine site, and therefore lead into cell death by inhibiting microtubule polymerization and consequent cell‐cycle arrest . Combretastatins separated from the South African tree Combretum caffrum are also a group of antimitotic compounds among which is combretastatin A‐4 (CA‐4; Figure ) as one of the famous natural antitubulin molecule that exerts its antimitotic effect by binding to colchicine's binding site of tubulin.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of novel benzo[c]acridine‐diones as potential anticancer agents and tubulin polymerization inhibitors

Behbahani

Tabeshpour

Mirzaei

et al. 2019

Archiv der Pharmazie

A new series of novel benzo[c]acridine-diones possessing pharmacophoric elements of antitubulins with central dihydropyridine bridge were designed and synthesized as potential anticancer agents and tubulin polymerization inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against eight cancer cell lines including MCF-7, A2780, HeLa, HepG2, DU145, A549, PC3, and LNCAP cancer cells and normal cells (HUVEC) through 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, wherein β-lapachone and combretastatin A-4 were used as positive controls. Some of our compounds (4c and 4g) showed significant cytotoxic activity on cancer cells with IC 50 values in the range of 5.23-24.32 μM. None of the synthesized compounds showed significant cytotoxicity on normal HUVEC cells. Among all investigated derivatives, compound 4g showed promising greater antiproliferative activity against all tested cancer cells with the highest sensitivity observed for the PC3 cell line. Results from the flow cytometry analysis of PC3 and MCF-7 cancer cells treated with 4g showed an induced cell-cycle arrest at G2/M, and therefore induced apoptosis which occurred at low concentration of test compound, whereas annexin V-FITC/propidium iodide staining assay in the aforementioned cancer cell lines treated with 4g showed that 4g can cause necrosis in PC3 and MCF-7 cancer cells at higher concentration. Compound 4g proved to be an inhibitor of tubulin polymerization in a mode similar to that of colchicine and in a dose-dependent manner. Molecular docking studies of 4g into the colchicine-binding site of tubulin exhibited a possible mode of interaction between this compound and tubulin.