Synthetic strategies for mining the information-rich content of natural products for biology and medicine

Natural products have driven the field of chemical synthesis forward from the earliest attempts to use chemical methods to elucidate structure. Long a source of education about new reactivity, they later provided an exceptional testing ground for the development of strategic approaches to their synthesis, as well as new chemical methods. In the heyday of the late 20^th century, synthetic chemists showed that virtually any structure that could be made by nature could also be made in the lab. About this time, a serious shift in the focus of many “total synthesis labs” began. It was a transition from simply making the target—sometimes via any means possible and in vanishingly small quantities—to an increased emphasis on efficient synthesis that could support in-depth biological studies of the powerful activities so often associated with natural products. This general trend begat new areas of research at the nexus of complex molecule synthesis, chemical biology, medicinal chemistry, biology, and medicine. The eight articles in this themed collection are premier examples of the critical roles played by chemical synthesis in natural product space and the opportunities that accrue for moving forward allied disciplines.

Broadly speaking, the goal of this collection is to provide an analysis of the impact of new strategies for the chemical synthesis of natural products that seek to address important issues in biology and human health. Natural products might be the starting point, as inspiration, or medicinal chemistry lead compounds, or even starting materials; or the end point, as in the final targets of specific synthetic or biosynthetic campaigns focused on answering biological questions. The unifying threads of this collection are the importance of synthetic strategy and the inspiration provided by natural products to address pressing questions in biology and medicine.

In a review article that traces the arc of Nicolaou’s career in the synthesis of complex, bioactive secondary metabolites and their analogues, he and Rigol discuss an exemplary list of achievements from this laboratory (DOI: 10.1039/D0NP00003E). Starting with early work on prostaglandin synthesis, the article highlights achievements with molecules of both great complexity and important biological activities, and includes discussion of key SAR data for many of the programs in which key analogues were generated. Full of outstanding chemistry, one standout example of the power of synthesis to drive biology and medicine forward is the synthesis of highly complex enediyne natural products with phenomenal cytotoxicity and their application in antibody–drug conjugates.

Boger and Wu describe in detail several exceptional research programs from their laboratory and others that seek to improve on the properties of important biologically active natural products (DOI: 10.1039/D0NP00060D). Their insightful discussion of the “quest for supernatural products” shows how critically important natural products have been subjected to medicinal chemistry endeavors by academics and industrial chemists to improve potency, in vivo efficacy, selectivity and safety, resistance avoidance, stability, and/or synthetic accessibility. The Boger lab’s two-decade long foray into the chemistry and biology of vinblastine is a particularly poignant example of the power of synthetic chemistry and rational design for the improvements of medicinally important natural products.

As a fascinating counterpoint to traditional medicinal chemistry enhancements of bioactive natural products, Motika and Hergenrother highlight the power of using readily available complex secondary metabolites as starting points for the generation of new compounds with new or different biological activities than the original (DOI: 10.1039/D0NP00059K). This “complexity to diversity” strategy seeks to rearrange and thus repurpose the starting material into a range of diverse scaffolds with reasonable drug-like properties. Phenotypic high-throughput screening of the new collection reveals potential hit compounds for development against a priori unconsidered biological targets. As the authors show, this approach is bearing fruit, with a particularly striking example in the re-engineering of pleuromutilin to the antitumor agent ferroptocide.

Cremosnik, Liu, and Waldmann provide an insightful review of approaches to generate novel biologically relevant compounds by careful consideration of potential bioactive natural product fragments or scaffolds (DOI: 10.1039/D0NP00015A). Architectures from complex natural products inspire the development of clever but straightforward pathways for the synthesis of collections of related molecules in “biology-oriented synthesis” (BIOS). Taking advantage of computational methods to theoretically fragment the database of known natural products, and using a deep understanding of strategies for chemical synthesis to physically combine them, leads to “pseudo natural products”. Both of these approaches have proven to be fruitful tools for discovery, yielding completely new lead molecules in multiple disease areas.

In an excellent pedagogical treatise of the evolution of various strategies for natural-product-based drug discovery, Truax and Romo discuss, among others, diversity-oriented synthesis, function-oriented synthesis, diverted total synthesis, and biology-oriented synthesis (DOI: 10.1039/D0NP00048E). Their article ends with an in-depth analysis of their recently reported approach to natural product synthesis that aims to build, stepwise, from a proposed “pharmacophore” to the complete target structure. “Pharmacophore-directed synthesis” looks to shift the early intermediates in the structural direction of motifs that are likely to be responsible for activity. This approach provides SAR data along a complexity/activity continuum that can thus identify simplified analogues that correspond to the minimal pharmacophoric unit, and that can serve as lead compounds for drug discovery.

Williams, Wernke, Tirla, and Herzon explain the concept of biosynthetic “dark matter” in the context of their in-depth studies on colibactin, an unstable genotoxic natural product that had puzzled chemists for over a decade (DOI: 10.1039/D0NP00072H). After an introduction to the concept featuring classical examples of chemical detective work to uncover the structures of unstable yet biologically significant natural products, they delve deeply into their own synthesis-driven investigations of the precolibactins and candidate colibactin structures. Their efforts ultimately uncovered the true structure of the toxic metabolite and gained an understanding of its mechanism of double-stranded DNA cleavage. This story provides a chemist’s point-of-view of what can be gained by attacking challenging problems in biosynthetic dark matter.

Salvinorin, a diterpene with hallucinogenic properties, holds promise as a potential analgesic via interaction with the kappa opioid receptor and, more broadly, as a tool to investigate this poorly understood receptor. Chemical synthesis can play a powerful role in these studies, by providing analogues as tool compounds as well as congeners with increased stability relative to the natural product itself. Hill, Brion, and Shenvi discuss the potential importance of salvinorin-type compounds, provide details on the many syntheses of these targets, and then showcase their lab’s synthesis of analogues in which a key configurational instability problem has been engineered out, leaving a molecule with similar properties but with a greater stability profile and a more straightforward synthesis (DOI: 10.1039/D0NP00028K). They end their review with a fascinating multi-variable analysis of the many salvinorin syntheses with respect to complexity and chemical space similarity, and a brief discussion of “dynamic retrosynthesis”, in which designed changes to the target can both improve properties and simplify synthesis.

Finally, Melander, Basak, and Melander provide their perspective on the successes of harnessing natural product chemical space to generate new agents against bacterial biofilms (DOI: 10.1039/D0NP00022A). After an introduction to the properties of biofilms and difficulties associated with eradicating bacteria in these forms, the authors describe a range of plant-derived, microbial, and marine natural products with antibiofilm properties. Each is discussed with respect to origin, mechanism of biofilm disruption, relevant synthesis work, and analogues with improved properties, where relevant. This article makes clear that the molecular agents of interspecies chemical warfare make exceptional lead molecules for the discovery of this critical component of our antibiotic arsenal.

The enduring potential of natural products to inspire both new chemistry and advances in biology will only be limited by the creativity of synthetic chemists. With continued improvements in synthesis design, we better our ability to fully tap their utility as chemical probes and medicinal agents. We hope this themed collection will inspire the next generation of natural product synthetic chemists to continue harvesting the information-rich content of natural products in new and exciting ways, thereby driving forward the allied disciplines of biology and medicine.

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