Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India; Tumor Immunology & Immunotherapy Group, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai 400085, India.
Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India; Department of Humanities and Sciences, Vardhaman College of Engineering (Autonomous), Shamshabad, Hyderabad, Telangana 501218, India.
Bioorg Chem. 2020 Dec;105:104447. doi: 10.1016/j.bioorg.2020.104447. Epub 2020 Nov 1.
A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.
设计并合成了一系列基于苯并菲斯汀的吲哚连接查尔酮的新型化合物库（9a-z 和 9aa-ad）。其中，化合物 9a 在芳环上带有 1-甲基、2-和 3-甲氧基取代基，对人口腔癌细胞系 SCC-29B、球体和口腔癌异种移植模型 AW13516 有效。化合物 9a 通过破坏细胞完整性和影响葡萄糖代谢来发挥抗癌活性，这是癌症的一个标志。细胞结构受到微管蛋白聚合的抑制影响，这可以通过对 9a 处理的 SCC-29B 细胞进行免疫荧光检测观察到。体外微管蛋白聚合动力学测定提供了 9a 与微管蛋白直接相互作用的证据。表面等离子体共振（SPR）分析进一步证实了微管蛋白和化合物 9a 之间的这种物理相互作用。分子对接实验和验证表明，化合物 9a 与微管蛋白的秋水仙碱结合位点以及葡萄糖代谢途径中关键酶的活性位点相互作用和结合。基于计算机建模、生物物理相互作用和临床前观察，由苯并菲斯汀基吲哚查尔酮支架组成的 9a 可被视为开发抗癌治疗药物的有吸引力的微管蛋白聚合抑制剂候选物。
