期刊
MOLECULES
卷 27, 期 21, 页码 -出版社
MDPI
DOI: 10.3390/molecules27217642
关键词
1,2,4-triazolo bis-indolyl conjugates; cytotoxicity; colon cancer; beta-catenin pathway; PI3K; tankyrase inhibitors
资金
- Department of Science and Technology (DST) of the Government of India [DST/IMRCD/BRICS/PilotCall2/CCT/2018-G]
- Russian Foundation for Basic Research [18-515-80028]
- National Research Foundation (NRF) of South Africa [116014]
- BRICS STI cooperation program [BRICS2017-236]
Newly synthesized 1,2,4-triazolo-linked bis-indolyl conjugates exhibit enhanced cytotoxic activity against colon and breast cancer cells. These compounds induce cell cycle arrest, apoptosis, and lower the expression levels of markers involved in the beta-catenin pathway of colorectal cancer.
A series of new 1,2,4-triazolo-linked bis-indolyl conjugates (15a-r) were prepared by multistep synthesis and evaluated for their cytotoxic activity against various human cancer cell lines. It was observed that they were more susceptible to colon and breast cancer cells. Conjugates 15o (IC50 = 2.04 mu M) and 15r (IC50 = 0.85 mu M) illustrated promising cytotoxicity compared to 5-fluorouracil (5-FU, IC50 = 5.31 mu M) against the HT-29 cell line. Interestingly, 15o and 15r induced cell cycle arrest at the G(0)/G(1) phase and disrupted the mitochondrial membrane potential. Moreover, these conjugates led to apoptosis in HT-29 at 2 mu M and 1 mu M, respectively, and also enhanced the total ROS production as well as the mitochondrial-generated ROS. Immunofluorescence and Western blot assays revealed that these conjugates reduced the expression levels of the PI3K-P85, beta-catenin, TAB-182, beta-actin, AXIN-2, and NF-kappa B markers that are involved in the beta-catenin pathway of colorectal cancer. The results of the in silico docking studies of 15r and 15o further support their dual inhibitory behaviour against PI3K and tankyrase. Interestingly, the conjugates have adequate ADME-toxicity parameters based on the calculated results of the molecular dynamic simulations, as we found that these inhibitors (15r) influenced the conformational flexibility of the 4OA7 and 3L54 proteins.
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