Principle and design of pseudo-natural products

Abstract

Natural products (NPs) are a significant source of inspiration towards the discovery of new bioactive compounds based on novel molecular scaffolds. However, there are currently only a small number of guiding synthetic strategies available to generate novel NP-inspired scaffolds, limiting both the number and types of compounds accessible. In this Perspective, we discuss a design approach for the preparation of biologically relevant small molecule libraries, harnessing the unprecedented combination of NP-derived fragments as an overarching strategy for the synthesis of new bioactive compounds. These novel 'pseudo-natural product' classes retain the biological relevance of NPs, yet exhibit structures and bioactivities not accessible to nature or through the use of existing design strategies. We also analyse selected pseudo-NP libraries using chemoinformatic tools, to assess their molecular shape diversity and properties. To facilitate the exploration of biologically relevant chemical space, we have identified design principles and connectivity patterns that would provide access to unprecedented pseudo-NP classes, offering new opportunities for bioactive small molecule discovery. Main textThe search for small molecules with novel molecular scaffolds that display unprecedented or unexpected biological activity greatly benefits from insights gained from compound classes that are biologically relevant by definition, such as natural products (NPs). NPs have served as an inspiration and resource in drug discovery and chemical biology 1 and constitute chemical matter pre-validated by evolution. 2 Libraries based on natural product structure or more relaxed chemical and structural considerations have been developed through different approaches. At one end of the spectrum NP-derived compound collections may be synthesised directly from readily available NPs, e.g. by derivatisations at pre-existing reactive sites, and by ringdistortion and/or -modification approaches ("complexity to diversity"; CtD) as first demonstrated by Hergenrother. 3,4 For instance, abietic acid was converted into a chemically diverse collection of complex compounds by means of 3-6 transformations, including ring opening-, expansion-and contraction sequences 4 (Figure 1a), whilst ring-distortion of the alkaloid quinidine yielded novel inhibitors of autophagy. 5 In an alternative approach complex polycyclic scaffolds that exhibit NP characteristics and properties are directly synthesised and distorted. For instance, tropane-containing compounds delivered multiple new scaffolds not found within NPs, several of which were found to be novel bromodomain binders. 6

Sprouts and Microgreens: Trends, Opportunities, and Horizons for Novel Research

“…Secondly; sprouts, such as plants, stand out for chemical diversity, which may arise as a result of (1) the influence that genetic and environmental factors, and agronomic setups, may have on metabolic homeostasis [276]; (2) chemical sensitivity to elicitation techniques that may be established through a wide array of combinations between germination conditions and abiotic and/or biotic stimuli [4]; and (3) the occurrence of alternative biosynthetic routes in relation to changes in gene expression profiles [277]. Together with the vast number of structural modifications exhibited by plant metabolites [278], such metabolic adaptability can potentially contribute to the expansion of natural product chemistry into the uncharted regions of druggable space, namely, the realm of chemicals that specifically interact with, and modulate, disease-relevant targets [279][280][281][282][283].…”

Library Design Strategies To Accelerate Fragment‐Based Drug Discovery

“…Along the same lines of breaking down bioactive molecules to access privileged fragments, the synthesis of natural-product-like fragments hasa lso attracted attention in FBDD. [87] Natural productsa re, owing to evolution, predisposedt ob iological activity and have served as am ajor source of inspiration for drug discovery. [88,89] As such, it is worth considering the inclusion of natural-product-like structures in fragment collections to enhance the biological relevance of as creening library.…”

Phenotyping Reveals Targets of a Pseudo‐Natural‐Product Autophagy Inhibitor

“…[3,4] Recently developed design strategies include complexity-to-diversity (CtD) approaches, in which alternative NPs [4] or complex synthetic intermediates [5] are modified or distorted;a nd biology-oriented synthesis (BIOS), [3] in which the NP structure is simplified to arrive at synthetically tractable NP-derived scaffolds.Wevery recently introduced pseudo-natural products as novel compounds with NP-like structures and properties. [6][7][8][9][10][11] Pseudo-NPs are obtained through the unprecedented combination of NP-derived fragments and occupy areas of biologically relevant chemical space inaccessible to nature through biosynthesis. [12] There is an urgent requirement for unbiased biological profiling of these new compounds since their possible biological activities are unknown.…”