Advances in Solution- and Solid-Phase Synthesis toward the Generation of Natural Product-like Libraries

Nandy, Jyoti Prokash; Prakesch, Michaël; Khadem, Shahriar; Reddy, P. Thirupathi; Sharma, Utpal; Arya, Prabhat

doi:10.1021/cr800188v

Cited by 166 publications

(91 citation statements)

References 445 publications

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“…This demands a continuous improvement of synthetic methods that allow the synthesis of collections of small molecules in a parallel and rapid manner. Consequently, the development of synthetic methods that allow, for example, the stereoselective synthesis of compound libraries or of 'unbiased' compound libraries (e.g., by application of traceless-linker methodologies) is still required (Arya et al, 2005;Leßmann and Waldmann, 2006;Nandy et al, 2009;Yoshida et al, 2009).…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Wilk¹,

Zimmermann²,

Kaiser

et al. 2010

Biological Chemistry

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Biology-oriented synthesis (BIOS) represents an alternative approach for the generation of compound collections for biological applications. In BIOS, biologically relevant and prevalidated scaffold structures, such as core structures of natural products or known drugs, are employed as scaffolds for the generation of compound collections with focused diversity. In this review, we discuss the underlying concept of the BIOS approach, and its practical implementation in library design and synthesis. To highlight its relevance for chemical biology applications, we finally present examples in which compound collections generated under the BIOS principle have been used to elucidate biological questions.

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Section: Conclusion and Prospectsmentioning

confidence: 99%

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Wilk¹,

Zimmermann²,

Kaiser

et al. 2010

Biological Chemistry

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“…With the enyne and diyne substrates 3 and 4 in hand, we were poised to investigate the key transition metal-mediated solid-phase cycloaddition and cyclization reactions (Scheme 2). Although there are several examples of such reactions being carried out successfully on solid phase (20), many of these specific reactions had not been carried out on solid support previously, and none had been explored in the context of the TBDAS linker. However, we hoped that this linker would continue to mirror faithfully the previously established reactivity profile of the TBDPS protecting group used in the original solution-phase experiments.…”

Section: Resultsmentioning

confidence: 99%

Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

Moura‐Letts¹,

DiBlasi²,

Bauer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Alkaloid and terpenoid natural products display an extensive array of chemical frameworks and biological activities. However such scaffolds remain underrepresented in current screening collections and are, thus, attractive targets for the synthesis of natural product-based libraries that access underexploited regions of chemical space. Recently, we reported a systematic approach to the stereoselective synthesis of multiple alkaloid/terpenoid-like scaffolds using transition metal-mediated cycloaddition and cyclization reactions of enyne and diyne substrates assembled on a tert-butylsulfinamide lynchpin. We report herein the synthesis of a 190-membered library of alkaloid/terpenoid-like molecules using this synthetic approach. Translation to solid-phase synthesis was facilitated by the use of a tert-butyldiarylsilyl (TBDAS) linker that closely mimics the tert-butyldiphenysilyl protecting group used in the original solution-phase route development work. Unexpected differences in stereoselectivity and regioselectivity were observed in some reactions when carried out on solid support. Further, the sulfinamide moiety could be hydrolyzed or oxidized efficiently without compromising the TBDAS linker to provide additional amine and sulfonamide functionalities. Principal component analysis of the structural and physicochemical properties of these molecules confirmed that they access regions of chemical space that overlap with bona fide natural products and are distinct from areas addressed by conventional synthetic drugs and drug-like molecules. The influences of scaffolds and substituents were also evaluated, with both found to have significant impacts on location in chemical space and three-dimensional shape. Broad biological evaluation of this library will provide valuable insights into the abilities of natural product-based libraries to access similarly underexploited regions of biological space. diversity-oriented synthesis | multiscaffold library | asymmetric synthesis | cheminformatics A major goal in the field of diversity-oriented synthesis is the efficient production of small-molecule libraries that address underexploited regions of biologically relevant chemical space to enable the discovery of new biological probes and potential therapeutic lead compounds (1). A key approach to addressing this challenge is to emulate natural products and other biogenetic molecules, which have coevolved with macromolecular biological targets (2). Toward this end, a variety of natural product-based libraries have been synthesized, with promising early results (3). These libraries can be validated initially by evaluation of their structural and physicochemical properties using principal component analysis (PCA) to determine the regions of chemical space that are accessed. Subsequently, screening across a wide range of biological assays provides direct biological validation of the functional capabilities of these libraries.Alkaloids and terpenoids have long served as important small-molecule drugs and leads for drug discovery (4, ...

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“…[34] 3. Biologie-orientierte Synthese (BIOS) [38] Angesichts der verschiedenen Ringsysteme und Kerngerüst-strukturen in Naturstoffen ist die Wahl eines bevorzugten Ringsystems als Ziel für die Bibliothekssynthese oft alles andere als trivial. Statistische Analysen der Gerüststrukturen der Naturstoffe im DNP zeigten, dass mehr als die Hälfte aller Naturstoffe in der Datenbank mit einem Molekulargewicht unter 1000 g mol À1 zwei, drei oder vier Ringe enthalten.…”

Section: Angewandte Chemieunclassified

Biologie‐orientierte Synthese (BIOS)

et al. 2011

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Welche Substanzklassen eignen sich am besten als Werkzeuge für chemisch‐biologische Forschung und als Inspiration für medizinalchemische Projekte? Der chemische Strukturraum ist riesig und kann durch Synthese von Verbindungen nicht vollständig exploriert werden. Daher werden Methoden benötigt, mit deren Hilfe die biologisch relevanten Anteile des chemischen Strukturraums identifiziert und kartiert werden können. Die mit diesen Methoden erzeugten Hypothesen inspirieren dann Syntheseprogramme, um die biologisch relevanten Teile des Strukturraumes mit realen Verbindungen zu füllen. Die Biologie‐orientierte Synthese baut darauf auf, dass die Evolution von Proteinen und Naturstoffen sich auf bestimmte Strukturklassen beschränkt. Sie nutzt eine hierarchische Klassifikation bioaktiver Substanzen, die auf Substrukturbeziehungen und der Art der biologischen Aktivität beruht. Mit dieser Methode werden Gerüststrukturen biologisch aktiver Substanzklassen ausgewählt und als Startpunkte für die Synthese von Substanzkollektionen mit fokussierter Diversität genutzt. Scaffold Hunter, ein intuitiv zugängliches und hochgradig interaktives Computerprogramm, ermöglicht die Navigation im chemischen Strukturraum. In Bibliotheken niedermolekularer Substanzen, die nach dem BIOS‐Konzept synthetisiert wurden, ist biologische Aktivität oft angereichert. Sie ermöglichen die Untersuchung komplexer biologischer Phänomene durch direkte Perturbation und können darüber hinaus auch als Inspiration in der Medikamentenentwicklung dienen.

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Advances in Solution- and Solid-Phase Synthesis toward the Generation of Natural Product-like Libraries

Cited by 166 publications

References 445 publications

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Principles, implementation, and application of biology-oriented synthesis (BIOS)

Solid-phase synthesis and chemical space analysis of a 190-membered alkaloid/terpenoid-like library

Biologie‐orientierte Synthese (BIOS)

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