The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery

Abstract

A diverse range of strategies leading to natural product derived or inspired screening libraries aims to increase the number of new chemical entities emerging per year. However, the use of isolated natural products as scaffolds for the semi-synthesis of larger biological screening libraries remains rare. This particular method avoids the time-consuming and resource intensive de novo synthetic strategy for scaffold production, and has become more feasible through improvements to synthetic and isolation methodologies. This Highlight examines the increasing popularity of small- to large-sized screening libraries generated directly from isolated natural products. Several of the examples detailed herein show how this strategy can lead to improvements in not only potency but also other important (and often forgotten) drug discovery parameters such as toxicity, selectivity, lipophilicity and bioavailability. However, there are still improvements to be made to this method, particularly in the choice of the natural product scaffold and the derivatising reagents used. Avoidance of known nuisance compounds or structural alert motifs (e.g. PAINS) that interfere with bioactivity screens, and impact downstream drug development will play a significant role in the future success of this methodology. Incorporation of rational design strategies that take into account the physicochemical parameters (e.g. log P, MW, HBA, HBD) of the final semi-synthetic library analogues will also facilitate the discovery and development of leads and drugs. A multi-pronged approach to drug discovery that incorporates the use of isolated natural product scaffolds for library generation will surely be beneficial.

Underexplored Opportunities for Natural Products in Drug Discovery

“…85 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 In recent years, several research groups have expanded on this theme, demonstrating that diverse sets of complex natural product-based libraries can be accessed via the architectural remodeling of natural product cores. 102 Hergenrother and coworkers have reported on the application of ring cleavage, expansion, fusion and rearrangement reactions of gibberellic acid, andrenosterone, quinine, abietic acid and pleuromutilin, a strategy they coined complexity-to-diversity (CtD). [103][104][105] A similar strategy has been applied to lanosterol and bryonolic acid by Tochtrop and coworkers.…”

Induction of the mitochondria-mediated apoptosis in human esophageal cancer cells by DS2, a newly synthetic diterpenoid analog, is regulated by Bax and caused by generation of reactive oxygen species

“…Natural products tend to be a source of inspiration for synthetic chemists attempting to acquire new molecular entities with distinct pharmacological activity [4, 5]. Isodon rubescens (“Donglingcao” in Chinese) is a significant source of a traditional Chinese herbal medicine that has been widely used for esophageal and cardia cancer's treatment for many years in China [6, 7].…”

Semi‐synthesis and NMR spectral assignments of flavonoid and chalcone derivatives

“…The synthesis of analogues based on a bioactive NP lead is essential to drug development because this process generates important structure–activity relationship (SAR) data. Rather than pursuing the total synthesis of a bioactive NP followed by classic medicinal chemistry for analogue generation, many research groups are now utilizing isolated NPs as scaffolds for the creation of semi‐synthetic analogue libraries . This later approach reduces timelines and resource allocation that is typically associated with de novo multi‐step synthesis of a bioactive NP, and can generate rapid SAR data for faster evaluation of a lead molecule.…”