Abstract

Chemotherapies are the leading treatment for late-stage cancers. Despite their efficacy, these treatments are known to have harsh side effects caused by poor selectivity for cancerous cells over healthy cells. For this reason, the exploration of molecular targets specific to cancer cells is crucial for improving chemotherapies.
In preliminary studies, thienoisoquinolines have shown selective biological activity against lung cancer cells. Microscopy studies of cells treated with a leading thienoisoquinoline derivative exhibited arrested mitosis and disruptions within the microtubules. Additional experimentation via an in vitro microtubule polymerization assay and competition studies indicate that this lead compound has high binding affinity to microtubules at the colchicine site.
With these results, we aimed to further optimize the lead compound 75 (C75) to generate more drug-like molecules and confirm its mode of action through substrate alteration. In order to facilitate candidate modification, new synthetic approaches have been developed for enhanced modularity. This has generated new derivatives for structure-activity relationship studies, as well as provided access to wider range of derivatives for future pull-down assays, with the aim of identifying the specific biomolecular target of thienoisoquinoline derivatives with anti-cancer activity. Notably, the benzylic position is a major contributor to degradation of these molecules in biological assays. A newly devised synthetic route overcame the challenges in functionalization of this position, allowing for the production of more drug-like derivatives which will hopefully have increased biological activity. This was done in conjunction with kinetic solubility measurements and degradation studies in order to streamline the production of more efficacious compounds.