skip to main content
Idioma:
Tipo de recurso Mostra resultados com: Mostra resultados com: Índice

Natural Products in the “Marketplace”: Interfacing Synthesis and Biology

Huffman, Benjamin J ; Shenvi, Ryan A

Journal of the American Chemical Society, 2019-02, Vol.141 (8), p.3332-3346 [Periódico revisado por pares]

United States: American Chemical Society

Texto completo disponível

Citações Citado por
  • Título:
    Natural Products in the “Marketplace”: Interfacing Synthesis and Biology
  • Autor: Huffman, Benjamin J ; Shenvi, Ryan A
  • É parte de: Journal of the American Chemical Society, 2019-02, Vol.141 (8), p.3332-3346
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-3
    content type line 23
    ObjectType-Review-2
    The manuscript was written through contributions of both authors. Authors have given approval to the final version of the manuscript.
    Author Contributions
  • Descrição: Drugs are discovered through the biological screening of collections of compounds, followed by optimization toward functional end points. The properties of screening collections are often balanced between diversity, physicochemical favorability, intrinsic complexity, and synthetic tractability (Huggins, D. J.; et al. ACS Chem. Biol. 2011, 6, 208; DOI: 10.1021/cb100420r). Whereas natural product (NP) collections excel in the first three attributes, NPs suffer a disadvantage on the last point. Academic total synthesis research has worked to solve this problem by devising syntheses of NP leads, diversifying late-stage intermediates, or derivatizing the NP target. This work has led to the discovery of reaction mechanisms, the invention of new methods, and the development of FDA-approved drugs. Few drugs, however, are themselves NPs; instead, NP analogues predominate. Here we highlight past examples of NP analogue development and successful NP-derived drugs. More recently, chemists have explored how NP analogues alter the retrosynthetic analysis of complex scaffolds, merging structural design and synthetic design. This strategy maintains the intrinsic complexity of the NP but can alter the physicochemical properties of the scaffold, like core instability that renders the NP a poor chemotype. Focused libraries based on these syntheses may exclude the NP but maintain the molecular properties that distinguish NP space from synthetic space (Stratton, C. F.; et al. Bioorg. Med. Chem. Lett. 2015, 25, 4802; DOI: 10.1016/j.bmcl.2015.07.014), properties that have statistical advantages in clinical progression (Luker, T.; et al. Bioorg. Med. Chem. Lett. 2011, 21, 5673, DOI: 10.1016/j.bmcl.2011.07.074; Ritchie, T. J.; Macdonald, S. J. F. Drug Discovery Today 2009, 14, 1011, DOI: 10.1016/j.drudis.2009.07.014). Research that expedites synthetic access to NP motifs can prevent homogeneity of chemical matter available for lead discovery. Easily accessed, focused libraries of NP scaffolds can fill empty but active gaps in screening sets and expand the molecular diversity of synthetic collections.
  • Editor: United States: American Chemical Society
  • Idioma: Inglês
Links
Voltar para lista de resultados

  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

Buscando em bases de dados remotas. Favor aguardar.