Biological evaluation of 2-pyrazolinyl-1-carbothioamide derivatives against HCT116 human colorectal cancer cell lines and elucidation on QSAR and molecular binding modes

Publication date: Available online 4 August 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Beom Soo Kim, Soon Young Shin, Seunghyun Ahn, Dongsoo Koh, Young Han Lee, Yoongho Lim
In the search of compounds exhibiting anticancer activity, 37 derivatives of 2-pyrazolinyl-1-carbothioamide were designed and synthesized. Clonogenic cell survival assays were adapted to measure the cytotoxicities of the synthetic derivatives against HCT116 human colon cancer cell lines. Half-maximal cell growth inhibitory concentrations (GI50) ranged from 0.49 to 41.22 µM. The compound with the lowest GI50 value, 3-(2-hydroxy-4,5-dimethoxyphenyl)-5-(naphthalen-1-yl)-N-(3,4,5-trimethoxyphenyl)-pyrazolinyl-1-carbothioamide, was subjected to further biological studies, including cell viability and apoptosis assays to examine levels of annexin-V in the outer plasma membrane layer and poly ADP-ribose polymerase cleavage. Additionally, in vitro kinase assays were performed, and Abelson murine leukemia viral oncogene homolog 1 (Abl 1) tyrosine kinase demonstrated good inhibitory activity. The binding mode between the compound of interest and Abl 1 was elucidated using in silico docking. The pharmacophores derived for 2-pyrazolinyl-1-carbothioamides based on their quantitative structure–activity relationships will help us design novel chemotherapeutic agents.

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