Synthesis and structure-activity relationship of cytotoxic marine cyclodepsipeptide IB-01212 analogues.
Several recently discovered marine products have remarkable in vitro and in vivo anticancer profiles against a wide range of tumor cell lines. Some of these compounds are currently in clinical trials. These compounds show complex structures and mechanisms of action of interest. Herein, we describe the preparation of a series of totally synthetic molecules that are structurally related to the natural marine product IB-01212 and evaluated them as antitumor agents. For this, total solid-phase syntheses of the products were performed in parallel by two distinct routes: linear synthesis and convergent synthesis. Structural modifications were introduced in several residue positions to afford 21 IB-01212 analogues for structure-relationship studies. An increase in the number of methyl groups in the macrocycle enhanced cytotoxic activity. Also, the replacement of an ester bond by an amide bond favored antitumor activity against several human cell lines. In addition, the L configuration analogues were more active against all the tumor cell lines than those containing the D configuration. A significant increase in the size and asymmetry of the macrocycle diminished biological activity with respect to that of IB-01212. These results are of great value for the discovery of new and more effective anticancer agents.
Cruz
Luis J
LJ
Institute for Research in Biomedicine, Barcelona Science Park, University of Barcelona, 08028-Barcelona, Spain. jcruz@pcb.ub.es
Francesch
Andres
A
Cuevas
Carmen
C
Albericio
Fernando
F
D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008386:Marine Biology; D013058:Mass Spectrometry; D011487:Protein Conformation; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D047630:Depsipeptides; C519452:IB-01212