Srinivasa Reddy T, Kulhari Hitesh, Ganga Reddy V, Subba Rao A V, Bansal Vipul, Kamal Ahmed, Shukla Ravi
Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India.
Org Biomol Chem. 2015 Oct 28;13(40):10136-49. doi: 10.1039/c5ob00842e. Epub 2015 Sep 8.
A series of pyrazolo-triazole hybrids were designed and synthesized by combining the 1,3-diphenyl pyrazole and triazole scaffolds to obtain (1-benzyl-1H-1,2,3-triazol-4-yl)(1,3-diphenyl-1H-pyrazol-4-yl)methanones. All the synthesized compounds were screened for their anticancer activity against four tumor cell lines, viz. HT-29 (colon), PC-3 (prostate), A549 (lung), and U87MG (glioblastoma) cells. Most of the tested compounds showed moderate to potent cell growth inhibition on different cancer cells, in particular, the compounds 17, 23, and 29 exhibited promising cytotoxicity against these cell lines with the IC50 values in the range of 0.86-3.72 μM. In addition, the potential mechanism of cell growth inhibition and apoptotic induction by these compounds was investigated in U87MG cancer cells using cell-based assays, including wound healing assay, flow cytometry, Hoechst staining, acridine orange/ethidium bromide staining, Annexin V-FITC/propidium Iodide dual staining, Rhodamine 123 staining, and carboxy-DCFDA staining. The results indicate that the compounds induce apoptosis in U87MG cells via mitochondrial pathway through up-regulation of pro-apoptotic (Bax) and down-regulation of anti-apoptotic (Bcl-2) genes. Based on these studies, three compounds 17, 23 and 29 have been identified as promising new molecules that have the potential to be developed as leads.
通过将1,3 - 二苯基吡唑和三唑支架相结合，设计并合成了一系列吡唑并 - 三唑杂化物，以获得(1 - 苄基 - 1H - 1,2,3 - 三唑 - 4 - 基)(1,3 - 二苯基 - 1H - 吡唑 - 4 - 基)甲酮。对所有合成的化合物针对四种肿瘤细胞系，即HT - 29（结肠）、PC - 3（前列腺）、A549（肺）和U87MG（胶质母细胞瘤）细胞进行了抗癌活性筛选。大多数测试化合物对不同癌细胞表现出中度至强效的细胞生长抑制作用，特别是化合物17、23和29对这些细胞系表现出有前景的细胞毒性，IC50值在0.86 - 3.72μM范围内。此外，使用基于细胞的实验，包括伤口愈合实验、流式细胞术、Hoechst染色、吖啶橙/溴化乙锭染色、膜联蛋白V - FITC/碘化丙啶双重染色、罗丹明123染色和羧基 - DCFDA染色，在U87MG癌细胞中研究了这些化合物抑制细胞生长和诱导凋亡的潜在机制。结果表明，这些化合物通过上调促凋亡基因（Bax）和下调抗凋亡基因（Bcl - 2），经由线粒体途径诱导U87MG细胞凋亡。基于这些研究，三种化合物17、23和29已被确定为有前景的新分子，具有作为先导物开发的潜力。
