Molecular editing and biological evaluation of amphidinolide X and Y.
Scarce and precious: A collection of compounds with deep-seated structural "point mutations" within the framework of the marine natural products amphidinolide X and Y was prepared by "diverted total synthesis". The resulting products provided first insights into the cytotoxicity profile of these extremely scarce macrolides.Deliberate deviations from the previously described total syntheses of amphidinolide X (1) and Y (2) allowed a collection of seven designed analogues of these extremely scarce marine natural products to be obtained. These fully synthetic "natural product-like" compounds enabled first insights into the previously unknown structure-activity relationships governing this series. Although the average cytotoxicity is moderate, it was found that certain bladder, colon and prostate cancer cell lines are fairly sensitive, and that the best synthetic analogues are more active than the natural products themselves. The syntheses rely on the 9-MeO-9-BBN variant of the Suzuki coupling for the formation of the carbon frameworks, as well as on Yamaguchi lactonization reactions for the cyclization of the macrocyclic rings.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Kattnig
Egmont
E
Kelter
Gerhard
G
Fiebig
Heinz-Herbert
HH
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D003500:Cyclization; D004141:Dinoflagellida / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000737:chemistry* / Q000494:pharmacology*; D008386:Marine Biology; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D000097442:Amphidinolides
D000970:Antineoplastic Agents; D018942:Macrolides; C480942:amphidinolide X; D000097442:Amphidinolides; C482967:amphidinolide Y