Diversity-oriented synthetic strategies applied to cancer chemical biology and drug discovery.

Ian Collins,Alan Jones

doi:10.3390/molecules191117221

Abstract

How can diversity-oriented strategies for chemical synthesis provide chemical tools to help shape our understanding of complex cancer pathways and progress anti-cancer drug discovery efforts? This review (surveying the literature from 2003 to the present) considers the applications of diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS) and associated strategies to cancer biology and drug discovery, summarising the syntheses of novel and often highly complex scaffolds from pluripotent or synthetically versatile building blocks. We highlight the role of diversity-oriented synthetic strategies in producing new chemical tools to interrogate cancer biology pathways through the assembly of relevant libraries and their application to phenotypic and biochemical screens. The use of diversity-oriented strategies to explore structure-activity relationships in more advanced drug discovery projects is discussed. We show how considering appropriate and variable focus in library design has provided a spectrum of DOS approaches relevant at all stages in anti-cancer drug discovery.

Highlights

Diversity-oriented synthetic (DOS) approaches can provide new chemical tools to help shape our understanding of complex cancer biology, and a platform for the identification and progression of anti-cancer drug leads
The examples collected above clearly show that diversity-oriented approaches can deliver useful new chemical tools for cancer biology, and can be productively applied to early drug discovery
While the importance of skeletal, stereochemical and substituent diversity remains fundamental, the field has evolved as diversity-oriented synthesis (DOS) strategies have been used in the context of drug discovery

Summary

Introduction

Diversity-oriented synthetic (DOS) approaches can provide new chemical tools to help shape our understanding of complex cancer biology, and a platform for the identification and progression of anti-cancer drug leads. On the other hand it is possible to consider constraints to the diversity during the forward synthesis design stage to provide a varying level of focus to the DOS libraries, with the aim of tailoring them to increase the likelihood of hits in specific screening settings or against selected molecular targets. The techniques of DOS may be applied to expand scaffold diversity from single starting points within medicinal chemistry projects This could be of particular importance when an initial hit lacks novelty or target specificity, or in structure-based drug discovery when the first scaffold discovered lacks synthetically tractable vectors to explore regions of interest in the binding site. We will discuss more tightly targeted drug discovery, where a single start point with specific activity is expanded and explored through DOS

DOS as a Source of New Chemical Tools for Cancer Biology

DOS Applied to Cancer Drug Discovery Screening Strategies

DOS Applied to Specific Molecular Starting Points in Cancer Drug Discovery

Findings

Conclusions