SciCombinator

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Concept: Natural product

5

An asymmetric approach to the synthesis of neurotrophic seco-prezizaane sesquiterpenes is described that is based on strategic application of a hydroxyl-directed metallacycle-mediated [2+2+2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1R,10S)-2-oxo-3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin and (-)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindane-forming annulation reaction in natural product synthesis and the first total synthesis of (2S)-hydroxy-3,4-dehydroneomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the C5 quaternary center common to the natural product class.

Concepts: Chemical reaction, Total synthesis, Paclitaxel total synthesis, Chemical synthesis, Real number, Integer, Natural product, Multiplication

5

High-throughput biology has contributed a wealth of data on chemicals, including natural products (NPs). Recently, attention was drawn to certain, predominantly synthetic, compounds that are responsible for disproportionate percentages of hits but are false actives. Spurious bioassay interference led to their designation as pan-assay interference compounds (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining of 80+ years of the phytochemistry and biology literature, using the NAPRALERT database, revealed that only 39 compounds represent the NPs most reported by occurrence, activity, and distinct activity. Over 50% are not explained by phenomena known for synthetic libraries, and all had manifold ascribed bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative distributions of ∼200,000 NPs uncovered that NP research follows power-law characteristics typical for behavioral phenomena. Projection into occurrence-bioactivity-effort space produces the hyperbolic black hole of NPs, where IMPs populate the high-effort base.

Concepts: Pharmacology, Biology, Chemistry, Drug discovery, Activity, Topological space, Natural product, High-throughput screening

5

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Concepts: Protein, Chemical reaction, Chemistry, Chemical substance, Chemical synthesis, Drug discovery, Synthesis, Natural product

4

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

Concepts: Pharmacology, Gene, Bioinformatics, Drug discovery, Proteomics, Functional genomics, Natural product, Natural products

3

Ring expansion provides a powerful way of introducing a heteroatom substituent into a carbocyclic framework. However, such reactions are often limited by the tendency of a given substrate to afford only one of the two rearrangement products or fail to achieve high selectivity at all. These limitations are particularly acute when seeking to carry out late-stage functionalization of natural products as starting points in drug discovery. In this work, we present a stereoelectronically controlled ring expansion sequence towards selective and flexible access to complementary ring systems derived from common steroidal substrates. Chemical diversification of the reaction intermediate affords over 100 isomerically pure analogs with spatial and functional diversity. This regiodivergent rearrangement, and the concept of using chiral reagents to affect regiocontrol in chiral natural products, should be broadly applicable to late-stage natural product diversification programs.

Concepts: Enzyme substrate, Product, Chemical reaction, Drug discovery, Medicinal chemistry, Metaphysics, Natural product, Natural products

3

The dormant phenotype acquired by Mycobacterium tuberculosis (Mtb) during infection poses a major challenge in disease treatment since these bacilli are tolerant to front-line drugs. Therefore, it is imperative to find novel compounds that effectively kill dormant bacteria. By screening 4,400 marine natural product samples against dual-fluorescent Mtb under both replicating and non-replicating conditions we have identified compounds that are selectively active against dormant Mtb This validates our strategy of screening all compounds in both assays as opposed to using the dormancy model as a secondary screen. Bioassay guided deconvolution enabled the identification of unique pharmacophores active in each screening model. To confirm the activity of samples against dormant Mtb we used a luciferase reporter assay and CFU enumeration. The structures of five purified active compounds were defined by NMR and mass spectrometry. We identified two lipid compounds with potent activity towards dormant and actively growing Mtb One of these was commercially obtained and showed similar activity against Mtb in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant Mtb. In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target Mtb pathways conditionally essential for dormancy survival.

Concepts: Natural selection, Tuberculosis, Assay, Mycobacterium, Mycobacterium tuberculosis, Natural product, Marine biology, Killing vector field

3

At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic “toolkit” cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.

Concepts: Oxygen, Chemical reaction, Chemistry, Experiment, Solvent, Drug discovery, Natural product, Dimethyl sulfoxide

3

The pseudopterosins are a family of diterpene marine natural products, which, by virtue of their interesting anti-inflammatory and analgesic properties, have attracted the attentions of many synthetic chemists. The most efficient syntheses reported to date are 14 and 20 steps in the longest linear sequence for chiral pool and enantioselective approaches, respectively, and all start with precursors that are easily mapped onto the natural product structure. Here, we describe an unconventional approach in which a chiral cross-conjugated hydrocarbon is used as the starting material for a series of three cycloadditions. Our approach has led to a significant reduction in the step count required to access these interesting natural products (10 steps chiral pool and 11 steps enantioselective). Furthermore it demonstrates that cross-conjugated hydrocarbons, erroneously considered by many to be too unstable and difficult to handle, are viable precursors for natural product synthesis.

Concepts: Attention, Hydrogen, Sequence, Organic chemistry, Hydrocarbon, Analgesic, Natural product, Start

2

Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high sp³ character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in sp³ features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.

Concepts: Pharmacology, Chemistry, Drug discovery, Chemical compound, Medicinal chemistry, Pharmacy, Natural product, Cheminformatics

2

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties.

Concepts: Mathematics, Chemical substance, Drug discovery, Chemical compound, Nature, Natural product, Natural products, Planet Earth