Bora Darshana, Samir Khan Mehtab, Sharma Anamika, Chilvery Shrilekha, Bansod Sapana, John Stephy Elza, Ali Khan Mursalim, Godugu Chandraiah, Shankaraiah Nagula
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad - 500 037 India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad - 500 037 India.
RSC Med Chem. 2023 Feb 6;14(3):482-490. doi: 10.1039/d2md00400c. eCollection 2023 Mar 22.
To scrutinize -stilbene based molecules with potential anticancer and tubulin polymerization inhibition activity, a new series of -stilbene-1,2,3-triazole congeners was designed and synthesized a click chemistry protocol. The cytotoxicity of these compounds 9a-j and 10a-j was screened against lung, breast, skin and colorectal cancer cell lines. Based on the results of MTT assay, we further evaluated the selectivity index of the most active compound 9j (IC 3.25 ± 1.04 μM on HCT-116) by comparing its IC value (72.24 ± 1.20 μM) to that of the normal human cell line. Further, to confirm apoptotic cell death, cell morphology and staining studies (AO/EB, DAPI and Annexin V/PI) were carried out. The outcomes of studies showed apoptotic features like change in cell shape, cornering of nuclei, micronuclei formation, fragmented, bright, horseshoe-shaped nuclei, Moreover, active compound 9j displayed G2/M phase cell cycle arrest with significant tubulin polymerization inhibition activity with an IC value of 4.51 μM. Additionally, ADMET, molecular docking and molecular dynamic studies of 9j with 3E22 protein proved the binding of the compound at the colchicine binding site of tubulin.
为了研究具有潜在抗癌和微管蛋白聚合抑制活性的芪基分子，我们设计并合成了一系列新的芪-1,2,3-三唑类似物，采用点击化学方法。对这些化合物9a-j和10a-j针对肺癌、乳腺癌、皮肤癌和结肠癌细胞系进行了细胞毒性筛选。基于MTT试验结果，我们通过比较其IC值（在HCT-116上为3.25±1.04μM）与正常人细胞系的IC值（72.24±1.20μM），进一步评估了最具活性的化合物9j的选择性指数。此外，为了确认凋亡细胞死亡，进行了细胞形态和染色研究（AO/EB、DAPI和Annexin V/PI）。研究结果显示出凋亡特征，如细胞形状改变、细胞核边角化、微核形成、细胞核碎片化、明亮、马蹄形等。此外，活性化合物9j显示出G2/M期细胞周期阻滞，具有显著的微管蛋白聚合抑制活性，IC值为4.51μM。此外，对9j与3E22蛋白的ADMET、分子对接和分子动力学研究证明了该化合物在微管蛋白的秋水仙碱结合位点处的结合。
