具有侧链取代基的硬脂酰肉毒碱的合成及对蛋白激酶C的抑制活性测定

Synthesis of Branched-Chain Analogues of Stearoyl Carnitine and Tests for Their Abilities to Inhibite Protein Kinase C

本文合成4个8-位有取代基的有代表性的硬脂酰肉毒碱衍生物,并检测了它们对蛋白激酶C(PKC)的活性。与母体化合物硬脂酰肉毒碱相比,8-正丁基和8-苯基取代的衍生物在低浓度时抑制活性较低,在高浓度时抑制活性增强。8-甲基硬脂酰肉毒碱则在所测定的浓度范围内均比母体化合物抑制活性明显增强,IC_(50)为7.7μmol/L。动力学测定表明,这几个硬脂酰肉毒碱均与磷脂酰丝氨酸(PKC的磷脂辅助因子)和二油酰甘油(内源型PKC脂类活化剂)相竞争。实验结果显示8-甲基硬脂酰肉毒碱为PKC强抑制剂,预示8-甲基硬脂酸有可能成为一个抗癌制剂。

The four representative branched-chain analogues of stearoyl carnitine (SC) and SC were synthesized and tested for their abilities to inhibite protein kinase C (PKC). Substitutions with 8-butyl, 8-phehyl derivatives decreased inhibitory activities of the resulting analogues at low concentrations while increasing activities at high concentrations relative to those of the parental acylcarnitine SC. 8-methyl stearoyl carnitine improved the inhibitory activity of Parental acylcarnitine SC greatly at various concentrations. The IC50 is 7.7μmol/L on these parameters. Kinetic analysis indicated that those acylcanitine analogues inhibited the enzyme competitively with respect to phospha-tidyl serine (PS, a phospholipid cofactor) and diolein (a endogenous PKC lipid activator). The present finding demonstrated 8-Methyl stearoyl carnitine is a potent PKC inhibitor and perhaps 8-Methyl stearic acid is a anticancer agent.