Complexity‐to‐Diversity and Pseudo‐Natural Product Strategies as Powerful Platforms for Deciphering Next‐Generation Therapeutics

Abstract

Stereochemical and skeletal complexity are particularly important vis‐à‐vis the cross‐talks between a small molecule and a complementary active site of a biological target. This intricate harmony is known to increase selectivity, reduce toxicity, and increase the success rate in clinical trials. Therefore, the development of novel strategies for establishing underrepresented chemical space that is rich in stereochemical and skeletal diversity is an important milestone in a drug discovery campaign. In this review, we discuss the evolution of interdisciplinary synthetic methodologies utilized in chemical biology and drug discovery that has revolutionized the discovery of first‐in‐class molecules over the last decade with an emphasis on complexity‐to‐diversity and pseudo‐natural product strategies as a remarkable toolbox for deciphering next‐generation therapeutics. We also report how these approaches dramatically revolutionized the discovery of novel chemical probes that target underrepresented biological space. We also highlight selected applications and discuss key opportunities offered by these tools and important synthetic strategies used for the construction of chemical spaces that are rich in skeletal and stereochemical diversity. We also provide insight on how the integration of these protocols has the promise of changing the drug discovery landscape.

A divergent intermediate strategy yields biologically diverse pseudo-natural products

“…Employing methods that are inspired by nature and go beyond current biosynthetic pathways may facilitate the exploration of biologically relevant NP-like chemical space 13 , 14 . The complexity-to-diversity approach is a chemical extension of natural biosynthetic pathways in which suitable NPs or synthetic NP-like compounds are subjected to ring distortion reactions to afford compound collections with diverse scaffolds that are distinct from the starting NP yet retain the biological relevance and complexity of NPs 15 – 17 .…”

Synthesis of the first 4-oxobutane-1,1,2,2-tetracarbonitriles containing a phenol fragment and their transformation into cyano-substituted pyrrol-2-ones showing three-position molecular switching

“…Diversity-oriented synthesis (DOS) is one of the effective approaches for preparation of small molecules with various practically useful properties. [1][2][3][4][5][6][7][8][9][10] Thus, based on DOS processes, various biologically active compounds, [1][2][3][4][5][6] luminescent sensors and probes, 8 AIE-luminogens 9 and inaccessible macrocycles 10 have been synthesized. The substrates used in the DOS strategy are quite diverse.…”