Natural products and their derivatives have long been a significant source of pharmaceuticals. A collection of articles in this Focus highlights efforts to mimic some aspects of the way in which these compounds are made in nature with the aim of improving the processes by which synthetic drug leads are identified.
doi:10.1038/nchem.2081
A collection of articles in this issue focuses on attempts to mimic aspects of natural-product biosynthesis for the identification of new drugs.
Full Text - Inspiration comes naturally | PDF (535 KB) - Inspiration comes naturally
See also: Interview with Jeffrey Bode | Interview with Adam Nelson and Stuart Warriner | News and Views by Lowe | Article by Karageorgis et al. | Article by Huang & Bode
Interview with Adam Nelson and Stuart Warriner
doi:10.1038/nchem.2076
Adam Nelson and Stuart Warriner, from the University of Leeds, talk with Nature Chemistry about their work to develop viable synthetic strategies for preparing new chemical structures in parallel with the identification of desirable biological activity.
Full Text - Parallels with nature | PDF (895 KB) - Parallels with nature
See also: Editorial | Interview with Jeffrey Bode | News and Views by Lowe | Article by Karageorgis et al. | Article by Huang & Bode
Interview with Jeffrey Bode
doi:10.1038/nchem.2070
Jeffrey Bode from ETH Zürich talks with Nature Chemistry about his group's work on synthetic fermentation, and how he hopes it could bring the power of chemical synthesis into the hands of citizen scientists.
Full Text - Public libraries | PDF (630 KB) - Public libraries
See also: Editorial | Interview with Adam Nelson and Stuart Warriner | News and Views by Lowe | Article by Karageorgis et al. | Article by Huang & Bode
Derek B. Lowe
doi:10.1038/nchem.2074
The generation of chemical libraries for screening is a key part of the drug discovery process. Now, two studies describe attempts to combine features of natural product biosynthesis into the creation of libraries with the aim of mimicking nature's success at the production of bioactive molecules.
Full Text - Drug discoveryCombichem all over again | PDF (926 KB) - Drug discoveryCombichem all over again
See also: Editorial | Interview with Adam Nelson and Stuart Warriner | Interview with Jeffrey Bode | Article by Karageorgis et al. | Article by Huang & Bode
George Karageorgis, Stuart Warriner & Adam Nelson
doi:10.1038/nchem.2034
A discovery approach termed activity-directed synthesis is described; it exploits arrays of reactions whose outcome is critically dependent on the conditions used, and prioritizes reactions that yield bioactive product mixtures. The discovery of both bioactive small molecules and associated synthetic routes thus occurs in parallel.
Abstract - Efficient discovery of bioactive scaffolds by activity-directed synthesis | Full Text - Efficient discovery of bioactive scaffolds by activity-directed synthesis | PDF (2,202 KB) - Efficient discovery of bioactive scaffolds by activity-directed synthesis | Supplementary information | Chemical compounds
See also: Editorial | Interview with Adam Nelson and Stuart Warriner | Interview with Jeffrey Bode | News and Views by Lowe | Article by Huang & Bode
Yi-Lin Huang & Jeffrey W. Bode
doi:10.1038/nchem.2048
The production of biologically active compounds by microbial fermentation has proved highly successful in drug discovery. Now, a method that mimics this process has been used to prepare unnatural peptides from small building blocks without the need for additional reagents, and in a fashion that is immediately compatible with biological screening.
Abstract - Synthetic fermentation of bioactive non-ribosomal peptides without organisms, enzymes or reagents | Full Text - Synthetic fermentation of bioactive non-ribosomal peptides without organisms, enzymes or reagents | PDF (2,700 KB) - Synthetic fermentation of bioactive non-ribosomal peptides without organisms, enzymes or reagents | Supplementary information | Chemical compounds
See also: Editorial | Interview with Adam Nelson and Stuart Warriner | Interview with Jeffrey Bode | News and Views by Lowe | Article by Karageorgis et al.
Andrey P. Antonchick, Claas Gerding-Reimers, Mario Catarinella, Markus Schürmann, Hans Preut, Slava Ziegler, Daniel Rauh & Herbert Waldmann
doi:10.1038/nchem.730
A Lewis-acid-catalysed 1,3-dipolar cycloaddition provides rapid access to a variety of substituted spirooxindoles. Initial cellular evaluations supports the view that compound collections based on natural-product-inspired scaffolds constructed with complex stereochemistry, and decorated with assorted substituents, will be a rich source of compounds with diverse bioactivity.
Abstract - Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products | Full Text - Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products | PDF (2,727 KB) - Highly enantioselective synthesis and cellular evaluation of spirooxindoles inspired by natural products | Supplementary information | Chemical compounds
Subject terms: Medicinal chemistry | Chemical biology | Synthesis
Bradley R. Balthaser, Meghan C. Maloney, Aaron B. Beeler, John A. Porco, Jr & John K. Snyder
doi:10.1038/nchem.1178
The natural product fumagillol has been exploited as a stereochemically rich scaffold for the synthesis of a structurally unique, chemically diverse library with chemotypes distinctly different from the parent structure. Thus, fumagillol has been remodelled into a diverse array of isoindoles, isoquinolines, furans, mopholinones and benzoxazepines.
Abstract - Remodelling of the natural product fumagillol employing a reaction discovery approach | Full Text - Remodelling of the natural product fumagillol employing a reaction discovery approach | PDF (695 KB) - Remodelling of the natural product fumagillol employing a reaction discovery approach | Supplementary information | Chemical compounds
Subject terms: Organic chemistry | Synthesis
Claudio Aquino, Mohosin Sarkar, Michael J. Chalmers, Kimberly Mendes, Thomas Kodadek & Glenn C. Micalizio
doi:10.1038/nchem.1200
The design and synthesis of a family of chiral and conformationally constrained oligomers is described. Asymmetric synthesis of the monomers is presented and the preparation of a 160,000-member library of diverse tetramers via split-and-pool methods is discussed. From this library, a non-covalent ligand to the DNA-binding domain of p53 was discovered.
Abstract - A biomimetic polyketide-inspired approach to small-molecule ligand discovery | Full Text - A biomimetic polyketide-inspired approach to small-molecule ligand discovery | PDF (1,148 KB) - A biomimetic polyketide-inspired approach to small-molecule ligand discovery | Supplementary information | Chemical compounds
Subject terms: Chemical biology | Organic chemistry
See also: News and Views by Aubé
Jeffrey Aubé
doi:10.1038/nchem.1254
The design of a small-molecule library for drug discovery attempts to combine the favourable diversity of natural product structures with the modularity of peptide synthesis.
Full Text - Small-molecule librariesNaturally inspired oligomers | PDF (160 KB) - Small-molecule librariesNaturally inspired oligomers
Subject terms: Organic chemistry | Medicinal chemistry
See also: Article by Aquino et al.
Björn Over, Stefan Wetzel, Christian Grütter, Yasushi Nakai, Steffen Renner, Daniel Rauh & Herbert Waldmann
doi:10.1038/nchem.1506
Natural products populate areas of chemical space not occupied by average synthetic molecules. Here, an analysis of more than 180,000 natural product structures results in a library of 2,000 natural-product-derived fragments, which resemble the properties of the natural products themselves and give access to novel inhibitor chemotypes.
Abstract - Natural-product-derived fragments for fragment-based ligand discovery | Full Text - Natural-product-derived fragments for fragment-based ligand discovery | PDF (4,608 KB) - Natural-product-derived fragments for fragment-based ligand discovery | Supplementary information | Chemical compounds
Subject terms: Chemical biology | Medicinal chemistry
See also: News and Views by Shoichet
Brian K. Shoichet
doi:10.1038/nchem.1537
Natural products contain a range of chemical structures optimized for biological interactions. Fragmenting these compounds could help to combine this diversity with the broad coverage of chemical space offered by fragment-based drug discovery, and help to improve the efficiency with which screening hits can become successful drugs.
Full Text - Drug discoveryNature's pieces | PDF (197 KB) - Drug discoveryNature's pieces
Subject terms: Medicinal chemistry | Theoretical chemistry
See also: Article by Over et al.
Robert W. Huigens III, Karen C. Morrison, Robert W. Hicklin, Timothy A. Flood Jr, Michelle F. Richter & Paul J. Hergenrother
doi:10.1038/nchem.1549
An approach for the construction of complex and diverse compound libraries is described, whereby natural products are altered through a series of ring system distortion reactions. The compounds produced have markedly different physiochemical properties from those in standard screening collections and thus could offer advantages in the search for lead molecules that can be developed into drug candidates.
Abstract - A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products | Full Text - A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products | PDF (513 KB) - A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products | Supplementary information | Chemical compounds
Subject terms: Medicinal chemistry | Organic chemistry | Synthesis
See also: News and Views by Sharma & Tan
Indrajeet Sharma & Derek S. Tan
doi:10.1038/nchem.1581
A synthetic strategy that uses a series of simple reactions to distort the core architecture of complex natural products could provide libraries of stereochemically rich compounds that will help in the search for new biological probes and drugs.
Full Text - Drug discoveryDiversifying complexity | PDF (123 KB) - Drug discoveryDiversifying complexity
Subject terms: Chemical biology | Medicinal chemistry | Organic chemistry
See also: Article by Huigens III et al.
Henning S. G. Beckmann, Feilin Nie, Caroline E. Hagerman, Henrik Johansson, Yaw Sing Tan, David Wilcke & David R. Spring
doi:10.1038/nchem.1729
Diversity oriented synthesis (DOS) aims to build structurally diverse compound libraries — potentially useful in drug discovery — from a small number of starting materials. Here, the build/couple/pair algorithm — commonly used in DOS — is extended to incorporate variations in the coupling step as well as in the starting materials. This produces a compound library with exceptionally high diversity in fewer than five steps from a common precursor.
Abstract - A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling | Full Text - A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling | PDF (1,569 KB) - A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling | Supplementary information | Chemical compounds
Haruki Mizoguchi, Hideaki Oikawa & Hiroki Oguri
doi:10.1038/nchem.1798
Emulating the biogenesis of natural products, a synthetic strategy is described in which an achiral multipotent intermediate reacts through three distinct [4 + 2] cyclizations and two types of redox-mediated annulation. This results in divergent access to natural product-like scaffolds in 6–9 steps. The efficiency of this approach is highlighted in the total syntheses of three natural products.
Abstract - Biogenetically inspired synthesis and skeletal diversification of indole alkaloids | Full Text - Biogenetically inspired synthesis and skeletal diversification of indole alkaloids | PDF (1,267 KB) - Biogenetically inspired synthesis and skeletal diversification of indole alkaloids | Supplementary information | Chemical compounds
Michael C. McLeod, Gurpreet Singh, James N. Plampin, III, Digamber Rane, Jenna L. Wang, Victor W. Day & Jeffrey Aubé
doi:10.1038/nchem.1844
It has been suggested that bioactive natural products are an attractive starting point for the construction of screening libraries. Here, four families of biologically active alkaloids are used as the basis for the construction of 686 new compounds suitable for screening. The libraries thus prepared have characteristics comparable to representative natural products and are highly rule-of-five compliant.
Abstract - Probing chemical space with alkaloid-inspired libraries | Full Text - Probing chemical space with alkaloid-inspired libraries | PDF (1,916 KB) - Probing chemical space with alkaloid-inspired libraries | Supplementary information | Chemical compounds
ADVERTISEMENT
© 2018 Macmillan Publishers Limited, part of Springer Nature. All Rights Reserved.
