Design, structure-activity relationship study and biological evaluation of the thieno[3,2-c]isoquinoline scaffold as a potential anti-cancer agent

Bioorg Med Chem Lett. 2021 Nov 15:52:128327. doi: 10.1016/j.bmcl.2021.128327.

Jiang Tian Liu ¹, Dilan B Jaunky ², Kevin Larocque ², Fei Chen ¹, Keegan Mckibbon ¹, Mehdi Sirouspour ¹, Sarah Taylor ¹, Alexandre Shafeii ¹, Donald Campbell ¹, Helena Braga ¹, Alisa Piekny ², Pat Forgione ³

Affiliations

1 Department of Chemistry & Biochemistry, Concordia University, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6, Canada.
2 Department of Biology, Concordia University, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6, Canada.
3 Department of Chemistry & Biochemistry, Concordia University, 7141 rue Sherbrooke O., Montréal, QC H4B 1R6, Canada; Center for Green Chemistry and Catalysis, Department of Chemistry, McGill University, 801 rue Sherbrooke O., Montréal, QC H3A 0B8, Canada. Electronic address: [email protected].

PMID: 34416378 DOI: 10.1016/j.bmcl.2021.128327

Abstract

Several derivatives of a series that share a thienoisoquinoline scaffold have demonstrated potent activity against Cancer cell lines A549, HeLa, HCT-116, and MDA-MB-231 in the submicromolar concentration range. Structure-activity relationship (SAR) studies on a range of derivatives aided in identifying key pharmacophores in the lead compound. A series of compounds have been identified as the most promising with submicromolar IC₅₀ values against a lung Cancer cell line (A549). Microscopy studies of Cancer cells treated with the lead compound revealed that it causes mitotic arrest and disrupts microtubules. Further evaluation via an in vitro microtubule polymerization assay and competition studies indicate that the lead compound binds to tubulin via the colchicine site.

Keywords

Anticancer; Colchicine; Microtubules; SAR study; Thienoisoquinoline.

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