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UBC Theses and Dissertations

Benzoisoxazolone-based scaffolds for development of diversity driven small molecule libraries : an effective tool to identify novel molecules targeting key therapeutic applications Gong, Ying


The screening of compound libraries has repeatedly demonstrated its effectiveness as a research tool in drug discovery. Parallel synthesis is a powerful approach for the assembly of compound libraries possessing a wide range of structural and functional group diversity for evaluation against both new and established biological targets. This thesis project was focused on the development of four amino and/or carboxy-substituted benzoisoxazolone (B to E) as privileged scaffolds for the parallel synthesis of diversity driven libraries to identify isoform selective inhibitors of Rho-kinase (ROCK) for the treatment of diabetic cardiovascular disease and different cancers, as well as potential anti-HIV agents that block HIV pre-mRNA alternative splicing, and inhibitors of protein arginine methyltransferase 4 (PRMT4) for the treatment of cancer. In the context of developing a synthesis to the C5-amino substituted benzoisoxazolone scaffold B, the general methodology to construct the benzoisoxazolone ring system found in all four scaffolds is described. This involved reaction of a requisite salicylic acid derivative with hydroxylamine followed by dehydrative cyclization to assemble the isoxazolone ring. Also described in Chapter 2 was the synthesis of the C4-amino substituted scaffold C. The crucial issue encountered was control of chemoselectivity during dehydrative ring closure. The intent was that scaffold B and C-based libraries would contain type 2 ROCK inhibitors. The concept described in Chapter 3 was the “formal” use of the C5-carboxy substituted benzoisoxazolone scaffold D to generate novel molecules that mimic the tetracyclic indole anti-HIV agent IDC16, through conservation of the central (B and C-rings) in its structure. Based on the results of virtual screening/docking experiments on PRMT4, chapter 4 describes the synthesis of the 5-carboxy-7-amino substituted benzoisoxazolone scaffold E and its functionalization such that the benzyl substituents introduced at N-2 and the 5-benzamide motif interact with hydrophobic residues along the PRMT4 substrate binding site, and that the appending side chain at position 7, incorporating a urea sub-element, binds strongly in the arginine binding region in PRMT4. Overall, the synthesis of scaffolds B to E on a multigram scale has been achieved, opening the way for diversity driven parallel synthesis of novel compound libraries.

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