Synthesis and thrombolytic activity of carboline-3-carboxylic acid modified metabolites of Ala-Arg-Pro-Ala-Lys.
From the metabolism of H-Ala-Arg-Pro-Ala-Lys-OH, four metabolites, H-Pro-Ala-Lys-OH, H-Arg-Pro-Ala-Lys-OH, H-Ala-Arg-Pro-OH, and H-Ala-Arg-Pro-Ala-OH were identified. In order to find a new lead compound of thrombolytic peptide, 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid was introduced to the N- and C-terminal of the metabolites by use of the common coupling strategy. Under this condition, the pseudopeptides (5a-d and 7a-d) were obtained with a good yield. The thrombolytic activities of 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid containing oligopeptides were evaluated in vitro and in vivo. The result indicated that the thrombolytic activity of the pseudopeptide depended on the sequence and the modification pattern of the metabolites, and only when 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid was introduced into the C-terminal of H-Pro-Ala-Lys-OH or H-Arg-Pro-Ala-Lys-OH, the desirable thrombolytic activity was retained and enhanced significantly.
Zhao
Ming
M
College of Pharmaceutical Sciences, Peking University, Haidian Region, Beijing, PR China.
Wang
Chao
C
Wu
Yanfen
Y
Zhou
Kexiang
K
Peng
Shiqi
S
D000818:Animals; D002243:Carbolines; D005340:Fibrinogen; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D010455:Peptides / Q000138:chemical synthesis*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin; D013927:Thrombosis / Q000188:drug therapy
D002243:Carbolines; D005343:Fibrinolytic Agents; D010455:Peptides; C049236:carboline-3-carboxylic acid; D005340:Fibrinogen; D013917:Thrombin