CC BY-ND-NC 4.0 · Synthesis 2019; 51(01): 55-66
DOI: 10.1055/s-0037-1610368
short review
Copyright with the author

Guided by Evolution: Biology-Oriented Synthesis of Bioactive Compound Classes

George Karageorgis
a  Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-str. 11, 44227 Dortmund, Germany   Email: herbert.waldmann@mpi-dortmund.mpg.de
b  Current address: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
,
a  Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-str. 11, 44227 Dortmund, Germany   Email: herbert.waldmann@mpi-dortmund.mpg.de
› Author Affiliations
Further Information

Publication History

Received: 29 August 2018

Accepted: 03 September 2018

Publication Date:
11 October 2018 (eFirst)

  

Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

Biology-oriented-synthesis (BIOS), is a chemocentric approach to identifying structurally novel molecules as tools for chemical biology and medicinal chemistry research. The vast chemical space cannot be exhaustively covered by synthetic chemistry. Thus, methods which reveal biologically relevant portions of chemical space are of high value. Guided by structural conservation in the evolution of both proteins and natural products, BIOS classifies bioactive compound classes in a hierarchical manner based on molecular architecture and bioactivity. Biologically relevant scaffolds inspire and guide the synthesis of BIOS libraries, which calls for the development of suitable synthetic methodologies. These compound collections have enriched biological relevance, leading to the discovery of bioactive small molecules. These potent and selective modulators allow the study of complex biological pathways and may serve as starting points for drug discovery programs. Thus, BIOS can also be regarded as a hypothesis-generating tool, guiding the design and preparation of novel, bioactive molecular scaffolds. This review elaborates the principles of BIOS and highlights selected examples of their application, which have in turn created future opportunities for the expansion of BIOS and its combination with fragment-based compound discovery for the identification of biologically relevant small molecules with unprecedented molecular scaffolds.

1 Introduction

2 Structural Classification of Natural Products

3 Implications and Opportunities for Biology-Oriented Synthesis

4 Applications of Biology-Oriented Synthesis

4.1 Chemical Structure and Bioactivity Guided Approaches

4.2 Natural-Product-Derived Fragment-Based Approaches

5 Conclusions and Outlook

 
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