Structural features of prostanoid analogues involved in hepatocytes protection against CCl4-induced injury

• Published in: Prostaglandins & other lipid mediators 2010-11, Vol.93 (3-4), p.134-142
• Main Authors: Sholukh, M V, Hubich, A I, Pashkovsky, F S, Lakhvich, F A
• Format: Article
• Language: English
• Subjects: Animals; Carbon Tetrachloride - toxicity; Cytoprotection - drug effects; Hepatocytes - drug effects; Male; Prostaglandins - chemical synthesis; Prostaglandins - chemistry; Prostaglandins - pharmacology; Rats; Rats, Wistar; Structure-Activity Relationship
• ISSN: 1098-8823
• DOI: 10.1016/j.prostaglandins.2010.10.001

The ability of natural prostaglandins (PGs) and synthetic prostanoids of B, H and E(1)-types to prevent CCl(4)-induced liver injury in vitro was examined. Seven analogs of PGB, 3 derivatives of PGH and two 11-deoxy-analogs of PGE(1) decreased cytotoxic index of CCl(4) by 2-fold and were more effective then such well-known hepatoprotectors as silymarin, curcumin and PGI(2). These prostanoids reduced trien conjugates formation by 25-95% and strongly prevented LDH leakage through plasma membrane. The results from the structure-activity relationship (SAR) analysis can be summarized as follows: (1) the presence of 2-pyridyl at the 15 position of ω-chain plays the main role in cytoprotection for synthetic analogs of PGH; (2) among 11-deoxy-analogs of PGE(1) the most active substances possess the phenyl residue at C-15 connected with C-13 isoxazolin or C-13 isoxazol; (3) C-13 cyclohexylamine or C-15 phenyl groups in ω-chain and metoxy-group in α-chain are important for protective activity of PGB analogs; (4) synthetic analogs of PGB demonstrate more pronounced cytoprotective properties than prostanoids of H and E-types. This information suggests paths for further exploration in the area of hepatoprotection and the design of novel therapeutic agents.