A natural phenoxazinone derivative, cinnabarinic acid (2, CA, R = CO2H), could be obtained in vitro with the aid of purified laccase from the fungi Pycnoporus cinnabarinus by oxidative dimerization of 3‐hydroxyanthranilic acid (1, 3‐HAA, R = CO2H). With the aim of gaining access to a new class of water‐soluble chromophores and potential bioactive molecules, the regioselective sulfonation of 2‐hydroxyaniline was investigated. Straightforward insertion of a sulfonate group into a carbon–metal bond provided an efficient and selective process for the synthesis of 3‐hydroxyorthanilic acid (3, 3‐HOA, R = SO3H). This sulfonated compound was then subjected to laccase oxidation in order to mimic the cinnabarinic acid synthesis. A practical HPLC method to study the oxidized products was developed, and the major product of biotransformation – namely 2‐amino‐3‐oxo‐3H‐phenoxazin‐1,9‐disulfonic acid (4, LAO, R = SO3H) – was isolated and identified as the sulfonate analogue of cinnabarinic acid.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

Ginkgolides have been demonstrated to protect the myocardium in experimental ischemiareperfusion, but the extent to which this property is not related to platelet-activating factor (PAF) inhibition remains debated. This study was undertaken to determine whether a ginkgolide devoid of any anti-PAF activity could retain a cardioprotective activity. For this purpose, a new ginkgolide C (3) analogue, 7-O-(4-methylphenyl) ginkgolide C (4), was obtained from 3 with retention of configuration, using, in the key step, a copper-catalyzed arylation with tris-(4-methylphenyl) bismuth diacetate. No PAF inhibition on rabbit platelets in vitro was found for 4 up to 1.2.10 -4 M. However, 4 was found a significantly better preserving agent than 3 or ginkgolide B, a potent PAF inhibitor (all drugs at 0.35 µM), on hemodynamic and metabolic (i.e., myocardial ATP contents and enzymatic activities) indices measured in rat isolated hearts undergoing ischemia-reperfusion. The data provide additional support to a PAF-unrelated pharmacological activity for ginkgolides. Because the water solubility of 4, estimated by high-performance liquid chromatography analysis, was significantly lower than that of the parent molecule 3, a likely mechanism for the protective action of 4 involves its increased affinity for the myocardium, as compared to the relatively more hydrophilic 3. Drug Dev. Res. 54:191-201, 2001.

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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-a-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 3.4270.05 and 3.6470.07, respectively) than 1 (1.1570.03) and the strong PAF inhibitor ginkgolide B (GkB; 1.6570.03). The anti-PAF activities (IC 50 values in mM) 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 mM: (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.