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Synthesis and evaluation of novel, functionalised indoles as potential kinase inhibitors
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Date
2019
Authors
O'Shea, Kevin D.
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Publisher
University College Cork
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Abstract
This thesis details the implementation of chemical routes towards the synthesis of novel indolocarbazole and bisindolylmaleimide type derivatives, and subsequent evaluation of their biological potential.
Exploration of novel kinase binding characteristics associated with the underexploited hydroxymaleimide pharmacophore formed a central tennet of these synthetic endeavors. Through oxygen insertion into the maleimide N-H bond, this particular pharmacophore serves as a viable replacement to the maleimide/lactam pharmacophores that are prevalent in the literature. Assimilation of novel 7- azaindolyl, 5-bromoindolyl, 7-fluoroindolyl and aryl fragments within the indolocarbazole/bisindolylmaleimide frame also constituted novel A/E-ring substitution. Application of Perkin-type methodology made way for access to critical maleic anhydride intermediates, which could be formed via the coupling of functionalised indole and aryl precursors. Further modification of these intermediates, as required, was realised through either direct reaction with substituted amines or through an initial photo-mediated dehydrogenation followed by F-ring modification. Expansion towards novel six-membered F-rings was also undertaken on a panel of trimethoxyphenylcarbazole derivatives and represents the first time this expansion has been undertaken on such a template.
Following the synthesis of 57 novel compounds, biological screemng was undertaken in collaboration with the NCI (NCI 60-cell screen) in Maryland US and KISSf (Kinase screen) in France. This lead to the identification of two novel compounds, which showed excellent potency and selectivity against GSK-s isoforms that were in the low nanomolar range (lC50 = 11 - 50 nM). Furthermore, certain carbazole derivatives were found to be selective towards A 498, SNB-7 5 and MOL T-4 cancer cell lines. Work undertaken on the incorporation of a bromine within the carbazole frame also resulted in the most cytotoxic indolocarbazole derivative synthesised within our group to date with almost complete cytotoxicity seen towards melanoma cell lines (Gl50= 38 nM vs. LOX IMVI) and boasting a mean Gl50 value of 132 nM.
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Keywords
Synthesis of novel indolocarbazole , Bisindolylmaleimide type derivatives , Novel kinase binding characteristics
Citation
O'Shea, K. D. 2019. Synthesis and evaluation of novel, functionalised indoles as potential kinase inhibitors. PhD Thesis, University College Cork.