Total solid-phase synthesis of the azathiocoraline class of symmetric bicyclic peptides.
Thiocoraline is a potent antitumor agent isolated from the marine organism Micromonospora sp. This symmetric bicyclic depsipeptide binds the minor groove of DNA. Here we report two solid-phase strategies for the syntheses of azathiocoraline and its analogues. The thioester linkage was replaced by an amide bond to improve the compound's pharmacokinetic properties. The first strategy is based on a convergent (4+4) approach, whilst the second is a stepwise synthesis, cyclizations in both approaches occurring on the solid support. These two strategies were designed to overcome problems caused by the presence of consecutive noncommercial N-methyl amino acids, to avoid epimerization during cyclization and/or fragment condensation, and to form the disulfide bridge under solid-phase conditions. The heterocyclic moiety was added in the last step of the synthesis to assist the preparation of libraries of new compounds with potential therapeutic applications.
Bayó-Puxan
Núria
N
Barcelona Biomedical Research Institute, University of Barcelona, Barcelona Science Park (PCB), 08028 Barcelona, Spain.
Fernández
Ariadna
A
Tulla-Puche
Judit
J
Riego
Estela
E
Cuevas
Carmen
C
Alvarez
Mercedes
M
Albericio
Fernando
F
D000596:Amino Acids / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D008847:Micromonospora / Q000737:chemistry*; D008956:Models, Chemical; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013438:Sulfhydryl Compounds / Q000737:chemistry
D000596:Amino Acids; D000903:Antibiotics, Antineoplastic; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D010455:Peptides; D013438:Sulfhydryl Compounds; C517593:azathiocoraline; D004247:DNA