Synthesis and anticancer evaluation of novel, functionalised bisindolylmaleimides and indolocarbazoles

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Cooney, Louise
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University College Cork
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Bisindolylmaleimides (BIMs) and indolocarbazoles (ICZs) have been reported for their potent anticancer activity. These molecules elicit their antiproliferative effects through one of the molecular mechanisms; protein kinase inhibition or interference of topoisomerase I activity. This project focuses on exploring the gaps in knowledge surrounding the BIM and ICZ scaffolds by exploring the target’s horizontal and vertical binding space through structural modifications. This was achieved through the incorporation of rationally designed and selected aromatic units. One indole-type unit of the indolylmaleimide framework was retained to generate a steric probe through N-functionalisation. The hydrogen bonding maleimide headgroup, characteristic to BIM and ICZ, was significantly developed to investigate its importance in biological activity on a molecular level. The NCI-60 human cancer cell line screen was the primary screening method for this project. This in vitro evaluation allowed us to identify lead compounds from the diverse panel of compounds. Initially, 5,6-substituted benzofuran components were incorporated into the BIM and ICZ frame to generate a panel of 55 novel benzofuranylindolylmaleimides (BfIMs) and benzofuranopyrrolocarbazoles (BPCs). Significant anticancer activity was reported for the BfIM series in the one dose screen, with one candidate advancing to five dose screening and having a reported GI50 value of 0.407 µM. Other collaborative studies with the University of Nantes and Ohio added important dimensions to the project by investigating BfIMs that showed no anticancer effects and screening them against fungal and adipocyte PKC-β. These supplementary studies resulted in the identification of compounds as potent kinase inhibitors. A total of 6 BPC candidates progressed to five dose anticancer screening and demonstrated remarkable inhibition. A further 53 novel derivatives were prepared when naphthalene was incorporated to develop naphthylindolylmaleimides (NIMs) and naphthopyrrolocarbazoles (NPCs). Significant antiproliferative effects were exhibited by the NPC panel of compounds compared to the ring-open NIMs with 8 compounds advancing to five dose anticancer screening. In fact, it was the F-ring modified NPCs which were identified as lead candidates. It was noted that many of the BPC and NPC five dose anticancer candidates had strong correlations with known topoisomerase I inhibitors on the COMPARE analysis database.
Anticancer , Bisindolylmaleimides , Indolocarbazoles
Cooney, L. 2022. Synthesis and anticancer evaluation of novel, functionalised bisindolylmaleimides and indolocarbazoles. PhD Thesis, University College Cork.