Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery

Daniel Gedder Silva,Flavio Da Silva Emery

doi:10.1590/s2175-97902018000001004

Daniel Gedder Silva, Flavio Da Silva Emery

Open Access

https://doi.org/10.1590/s2175-97902018000001004

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Abstract

Natural products (NPs) are an excellent source of biologically active molecules that provide many biologically biased features that enable innovative designing of synthetic compounds. NPs are characterized by high content of sp3 -hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity. To date, several approaches have been implemented for mapping and navigating into the chemical space of NPs to explore the different aspects of chemical space. The approaches providing novel opportunities to synthesize NP-inspired compound libraries involve NP-based fragments and ring distortion strategies. These methodologies allow access to areas of chemical space that are less explored, and consequently help to overcome the limitations in the use of NPs in drug discovery, such as lack of accessibility and synthetic intractability. In this review, we describe how NPs have recently been used as a platform for the development of diverse compounds with high structural and stereochemical complexity. In addition, we show developed strategies aiming to reengineer NPs toward the expansion of NP-based chemical space by fragment-based approaches and chemical degradation to yield novel compounds to enable drug discovery.

Highlights

Natural products (NPs) are considered an excellent source for the discovery and development of new drug molecules (Newman, Cragg, 2012) owing to their diversity in both structural features and molecular targets
B) Natural product-based fragments The fragmentation of high-molecular weight NPs can be performed manually or by in silico approaches, and is characterized by dissecting complex structures to find scaffold patterns that can be obtained from in-house or commercial libraries or even by synthetic campaigns for biology studies (Pascolutti et al, 2015; Prescher et al, 2017; Crane, Gademann, 2016)
The novel approaches shown in this review demonstrate the main characteristics of NPs and provide an opportunity to explore compounds by different approaches

Summary

INTRODUCTION

Natural products (NPs) are considered an excellent source for the discovery and development of new drug molecules (Newman, Cragg, 2012) owing to their diversity in both structural features and molecular targets. B) Natural product-based fragments The fragmentation of high-molecular weight NPs can be performed manually or by in silico approaches, and is characterized by dissecting complex structures to find scaffold patterns that can be obtained from in-house or commercial libraries or even by synthetic campaigns for biology studies (Pascolutti et al, 2015; Prescher et al, 2017; Crane, Gademann, 2016). This approach tends to generate simpler compounds, without escaping from the properties of NP scaffolds, making structural diversity one of the most important features of FBDD. To demonstrate ring-distortion strategy, (Figure 11‐14) four of the most readily available and well-studied NPs were selected, including the alkaloids Yohimbine and quinine, the diterpene gibberellic acid, and the steroid adrenosterone

Diversifying Yohimbine

Diversifying quinine

Diversifying the diterpene gibberellic acid

Diversifying adrenosterone

Findings

Concluding remarks