A case study in conformation design: Learning by doing
2002; Wiley; Volume: 2; Issue: 6 Linguagem: Inglês
10.1002/tcr.10038
ISSN1527-8999
AutoresHenner Knust, Reinhard W. Hoffmann,
Tópico(s)Microbial Natural Products and Biosynthesis
ResumoAbstract Efforts are described to design simple, fully flexible but conformationally preorganised ω‐hydroxy‐nonanoic acids that could serve as the conformation controlling unit in analogues of the potent protein‐kinase C activator aplysiatoxin. Such analogues are macrodilactones incorporating the designed ω‐hydroxy‐nonanoic acid and 3,4‐dihydroxy‐pentanoic acid, which contains the pharmacophoric groups. The design process (replacement of CH 2 groups by an oxygen atom, annelation of a six‐membered ring and placement of alkyl substituents) of the ω‐hydroxy‐nonanoic acids was monitored by force‐field calculations. In the end of this process simple analogues of aplysiatoxin are proposed in which the proper disposition of the pharmacophoric groups is secured by a conformationally flexible but preorganised template structure as part of the macrodilactone ring. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 405–418, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10038
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