Total synthesis of iejimalide A-D and assessment of the remarkable actin-depolymerizing capacity of these polyene macrolides.
A concise and convergent total synthesis of the highly cytotoxic marine natural products iejimalide A-D (1-4) is reported, which relies on an effective ring-closing metathesis (RCM) reaction of a cyclization precursor containing no less than 10 double bonds. Because of the exceptional sensitivity of this polyunsaturated intermediate and its immediate precursors toward acid, base, and even gentle warming, the assembly process hinged upon the judicious choice of protecting groups and the careful optimization of all individual transformations. As a consequence, particularly mild protocols for Stille as well as Suzuki reactions of elaborate coupling partners have been developed that hold considerable promise for applications in other complex settings. Moreover, a series of non-natural "iejimalide-like" compounds has been prepared, differing from the natural lead in the polar head groups linked to the macrolide's N-terminus. With the aid of these compounds it was possible to uncover the hitherto unknown effect of iejimalide and analogues on the actin cytoskeleton. Their capacity to depolymerize this microfilament network rivals that of the latrunculins which constitute the standard in the field. Structural modifications of the peptidic terminus in 2 are thereby well accommodated, without compromising the biological effects. The iejimalides hence constitute an important new class of probe molecules for chemical biology in addition to their role as promising lead structures for the development of novel anticancer agents.
Fürstner
Alois
A
Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany. fuerstner@mpi-muelheim.mpg.de
Nevado
Cristina
C
Waser
Mario
M
Tremblay
Martin
M
Chevrier
Carine
C
Teplý
Filip
F
Aïssa
Christophe
C
Moulin
Emilie
E
Müller
Oliver
O
D000199:Actins / Q000737:chemistry*; D000215:Acylation; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis*; D053148:Caspase 3 / Q000096:biosynthesis; D007202:Indicators and Reagents; D007783:Lactones / Q000138:chemical synthesis; D018942:Macrolides / Q000138:chemical synthesis*; D051379:Mice; D041681:NIH 3T3 Cells; D011090:Polyenes / Q000138:chemical synthesis*; D011108:Polymers / Q000737:chemistry; D015854:Up-Regulation / Q000187:drug effects
D000199:Actins; D002219:Carbamates; D007202:Indicators and Reagents; D007783:Lactones; D018942:Macrolides; D011090:Polyenes; D011108:Polymers; C520299:iejimalide C; C520301:iejimalide B; C520298:iejimalide D; C520300:iejimalide A; D053148:Caspase 3