The total synthesis and biological properties of the cytotoxic macrolide FD-891 and its non-natural (Z)-C12 isomer.
A total, stereoselective synthesis of the naturally occurring, cytotoxic macrolide FD-891 and of its non-natural (Z)-C12 isomer is described. Three fragments of the main carbon chain were stereoselectively prepared by using asymmetric aldol and allylation reactions as the key steps. The molecule was then assembled by using two Julia-Kocienski olefinations to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring. Some specific biological properties (cytotoxicity, binding to tubulin) have been determined for both macrolides. The E configuration of the C12-C13 olefinic bond seems to be an important feature in determining the cytotoxicity but the precise biological mechanism of the latter still remains to be cleared.
García-Fortanet
Jorge
J
Depart. de Q. Inorgánica y Orgánica, Univ. Jaume I, Avda. Sos Baynat s/n, 12071 Castellón, Spain.
Murga
Juan
J
Carda
Miguel
M
Marco
J Alberto
JA
Matesanz
Ruth
R
Díaz
J Fernando
JF
Barasoain
Isabel
I
D000447:Aldehydes / Q000737:chemistry; D000475:Alkenes / Q000138:chemical synthesis / Q000494:pharmacology*; D000498:Allyl Compounds / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D007536:Isomerism; D018942:Macrolides / Q000138:chemical synthesis / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism / Q000648:ultrastructure
D000447:Aldehydes; D000475:Alkenes; D000498:Allyl Compounds; D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; C091118:FD 891