title: A case study in conformation design: learning by doing.
abstract: Efforts are described to design simple, fully flexible but conformationally preorganised omega-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 omega-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 omega-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.
authors.affiliation: Fachbereich Chemie der Philipps Universität Marburg, D 35032 Marburg, Germany.
authors.forename: Henner
authors.initials: H
authors.lastname: Knust
authors.forename: Reinhard W
authors.initials: RW
authors.lastname: Hoffmann
mesh_terms: D015195:Drug Design; D007858:Learning; D008235:Lyngbya Toxins / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation
chemical_list: D008235:Lyngbya Toxins; C006610:aplysiatoxin