Premium
Influence of lipophilicity and stereochemistry at the C 7 position on the cardioprotective and antioxidant effect of ginkgolides during rat heart ischemia and reperfusion
Author(s) -
Billottet Ludovic,
Martel Sophie,
Culcasi Marcel,
Drieu Katy,
Carrupt PierreAlain,
Pietri Sylvia
Publication year - 2005
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10424
Subject(s) - ginkgolides , lipophilicity , chemistry , cardioprotection , antioxidant , ischemia , pharmacology , platelet activating factor , clinical chemistry , stereochemistry , biochemistry , ginkgo biloba , medicine
The extent to which the cardioprotective effect of ginkgolides is related to their lipophilicity rather than to their anti‐platelet activating factor (PAF) effect was addressed in isolated rat hearts submitted to ischemia and reperfusion. A new derivative of ginkgolide C ( 1 ), the 7‐α‐ O ‐(4‐methylphenyl) ginkgolide C ( 4 ) was synthesized and compared to 7‐ O ‐(4‐methylphenyl) ginkgolide C ( 2 ) that had the same absolute configuration at C 7 as 1 for its lipophilicity, anti‐PAF activity, and cardioprotective and antioxidant effects. Using reversed‐phase high‐performance liquid chromatography HPLC, 4 and 2 were found to be significantly more lipophilic (i.e., log k w of 3.42±0.05 and 3.64±0.07, respectively) than 1 (1.15±0.03) and the strong PAF inhibitor ginkgolide B (GkB; 1.65±0.03). The anti‐PAF activities (IC 50 values in μM) were 8.2, 17.1, and 2.2 for 4 , 1 , and GkB, respectively, while 2 was inactive. In preischemic and/or reperfused hearts perfused with ginkgolides at 0.7 μM: (i) 2 and 4 were more efficient in improving postischemic hemodynamic and metabolic recovery than 1 , (ii) a key‐step in cardioprotection occurred during ischemia where 2 and 4 limited myocardial ATP depletion and contracture development, (iii) a strong anti‐lipoperoxidant effect was observed with 2 and 4 , but not 1 . In vivo administration of 2 to rats (4 mg/kg/day for 20 days) was more effective than that of 1 regarding ischemic heart protection, suggesting a positive role for lipophilicity. It was concluded that a high lipophilicity is not an absolute prerequisite for a strong anti‐PAF effect for ginkgolides, whereas it appears essential for cardioprotection. Drug Dev. Res. 64:157–171, 2005. © 2005 Wiley‐Liss, Inc.