Identification of 3D Scaffolds Embedded in Natural Products and Synthesis of Focused Libraries

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Quinn, Ronald

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Campitelli, Marc

Pouwer, Rebecca

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2017
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Abstract

The ever-increasing demand for new drugs drives the need to explore new areas of biologically-relevant chemical space. Drug targets, largely the active sites of proteins, have three-dimensional shape. However, chiefly for reasons of synthetic tractability, the screening libraries that are extensively used for high throughput screening (HTS) drug discovery are mostly composed of flat aromatic and heteroaromatic compounds.1 This has resulted in a trend towards flatness in drug candidates, limiting the possibilities in the navigation of three-dimensional biological space. A variety of approaches, such as diversity-oriented synthesis (DOS),2, 3 target-oriented synthesis (TOS),2, 4 function-oriented synthesis (FOS),5 and biology-oriented synthesis (BIOS)6, 7 have emerged to address this issue. Natural products are a source of therapeutically useful compounds with high success rates in drug discovery.8 They tend to be highly saturated, and therefore non-flat, molecules with chiral centres. These features of natural products arise from interaction with the active sites of proteins involved in biosynthetic pathways. Inspired by natural products, we sought to identify three-dimensional (3D) molecular scaffolds embedded in natural products with the aim of producing focused synthetic libraries that explore new biological profiles.

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Thesis (PhD Doctorate)

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Doctor of Philosophy (PhD)

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School of Natural Sciences

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The author owns the copyright in this thesis, unless stated otherwise.

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Drug discovery

Heteroaromatic compounds

Diversity-oriented synthesis

Target-oriented synthesis (TOS)

Function-oriented synthesis (FOS)

Biology-oriented synthesis (BIOS)

Molecular scaffolds

Natural products

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