Triazole-tethered boswellic acid derivatives against breast cancer: Synthesis, in vitro, and in-silico studies

A series of new analogues of 3-O-acetyl-11-keto-fi-boswellic acid (fi-AKBA, 1), 3-O-acetyl-fi-boswellic acid (fi-ABA, 2) (3-8) and 1H-1,2,3-triazole hybrids of fi-AKBA (10a-j) were synthesized by employing highly efficient Click chemistry reaction protocol. All synthesized compounds were characterized by 1 H-, 13C NMR, and HRMS spectroscopy. The structures of compounds 5 and 6 were unambiguously confirmed by the single crystal X-ray analysis diffraction method. The cytotoxic potential of the synthesized com-pounds was scrutinized against the triple-negative breast cancer (MDA-MB-231) and normal (MCF-10A) cell lines. Furthermore, all the synthesized derivatives exhibited highly potent anti-proliferative activity with IC50 values ranging from 4.45 to 14.45 mu M. Among them, compounds 10j, 10f, and 10i exhibited ex-ceptional inhibitory potency and were found several times more potent than the parent compounds 1 and 2. Additionally, the cheminformatics method was used to identify the potential drug target of the most potent compounds (10j, 10f, and 10i) and their binding mechanism with the selected drug target was predicted through molecular docking. The combined 2D-similarity searching, and structure-based bind-ing investigation predict that these compounds can target CHK1 to produce anti-cancer effects in TNBC. This study lays a good foundation for new triterpenic triazole analogues of boswellic acids and could be effective anticancer leads in breast cancer therapeutics. (c) 2023 Published by Elsevier B.V.

Automated summary

A series of new analogues of 3-O-acetyl-11-keto-fi-boswellic acid and 3-O-acetyl-fi-boswellic acid were synthesized using Click chemistry reaction protocol. The synthesized compounds showed potent anti-proliferative activity against triple-negative breast cancer cell lines. Compounds 10j, 10f, and 10i exhibited exceptional inhibitory potency and were more potent than the parent compounds. The cheminformatics method identified CHK1 as the potential drug target for the most potent compounds.