Total synthesis and biological activity of neopeltolide and analogues.
Combining the core structure of neopeltolide, lactone 16 a, with the oxazole-containing side chain 23 via a Mitsunobu reaction provided the cytotoxic natural product neopeltolide (2). The side chain 23 was prepared from oxazolone 24 via the corresponding triflate. Key steps in the preparation of 23 were a Sonogashira coupling, an enamine alkylation, and a Still-Gennari Horner-Emmons reaction. By changing the Leighton reagent in the allylation step, the 11-epimer of lactone 16 a, compound 50 was prepared. This led to 11-epi-neopeltolide 51. The 5-epimer of neopeltolide, compound 52, could be obtained from the minor isomer of the Prins cyclization. Furthermore, a range of analogues with modifications in the side chain were prepared. All derivatives were checked for toxicity effects on mammalian cell cultures and inhibitory effects on NADH oxidation in submitochondrial particles of bovine heart. Modifications in the lactone part are tolerated to some degree. On the other hand, shortening the distance between the oxazole and the lactone causes a significant drop in activity. Analogue 65 with an additional double bond is equally or even more active than neopeltolide itself.
Vintonyak
Viktor V
VV
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Kunze
Brigitte
B
Sasse
Florenz
F
Maier
Martin E
ME
D000818:Animals; D001688:Biological Products / Q000138:chemical synthesis; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D007783:Lactones; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology*; D009206:Myocardium / Q000648:ultrastructure; D009243:NAD / Q000187:drug effects / Q000378:metabolism; D010080:Oxazoles; D013329:Structure-Activity Relationship; D013367:Submitochondrial Particles / Q000378:metabolism
D001688:Biological Products; D007783:Lactones; D018942:Macrolides; D010080:Oxazoles; C519136:neopeltolide; D009243:NAD