Synthesis and biological activity of novel quaternary ammonium derivatives of alkylglycerols as potent inhibitors of protein kinase C.
Synthesis and biological activity of novel quaternary ammonium derivatives of alkylglycerols as potent inhibitors of protein kinase C.
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作为蛋白激酶 C 有效抑制剂的新型烷基甘油季铵衍生物的合成和生物活性。
DOI：
10.1021/jm00165a016
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发表时间：
1990
影响因子：
7.3
通讯作者：
Daniel,LW
中科院分区：
文献类型：
--
作者：
MarascoJr,CJ;Piantadosi,C;Meyer,KL;Morris-Natschke,S;Ishaq,KS;Small,GW;Daniel,LW
烷基甘油如roc-IO-十八烷基-2-Q-甲基甘油磷酸胆碱（Et-18-OMe）已显示出对各种癌细胞系的转移和生长的抑制作用。烷基磷脂已被证明在几种细胞系的表面积累，其选择性仍不清楚。这种作用的结果可能导致细胞膜相关蛋白激酶C（PKC）的抑制。本研究的目的是开发PKC的醚脂抑制剂，以增强PKC的活性。这导致了一系列新的烷基甘油季铵衍生物的合成和体外测试。这些类似物对经roc-10-oleoyl-2-O-acetylglycerol刺激的PKC的生物学测试表明，几种类似物具有与Et-18-OMe相当的抑制作用。自从发现蛋白激酶C（PKC）1以来，这种普遍存在的激酶作为调节酶的功能已被广泛研究。我们感兴趣的中心是PKC与天然磷脂和甘油二酯之间的相互作用。1· 2磷脂酶C水解磷脂酰肌醇产生甘油二酯，甘油二酯作为PKC的刺激物。1* 3 PKC的激活导致酶移位至细胞膜，在细胞膜中，磷脂酰丝氨酸和二酰基甘油在钙存在下能够完全激活酶。2与二酰基甘油的作用相反，由β-磷酸胆碱水解产生的内源性烷基酰基甘油4 * 6是PKC的抑制剂。此外，
Alkylglycerols such as roc-lO-octadecyl-2-Q-methylglycerophosphochócholine (Et-18-OMe) have shown an inhibitory effect on the metastasis and growth of various cancer cell lines. Alkyl phospholipids have been shown to accumulate at the surface in several cell lines, the selectivity of which is still not clearly understood. A consequence of this action may lead to the inhibition of cell membrane related protein kinase C (PKC). The goal of this research was to develop ether lipid inhibitors ofPKC to augment antineoplastic activity. This led to the synthesis and in vitro testing of a series of novel quaternary ammonium derivatives of alkylglycerols. The biological testing of these analogues on PKC stimulated with roc-lO-oleoyl-2-O-acetylglycerol showed several analogues with inhibition comparable to that of Et-18-OMe.Since the discovery of protein kinase C (PKC), 1 the function of this ubiquitous kinase as a regulatory enzyme has been extensively investigated. Central to our interests is the interaction between PKC and naturally-occurring phospholipids anddiacylglycerols. 1· 2 The hydrolysis of phosphatidylinositol byphospholipase C yields diacylglycerol which acts as a stimulus for PKC. 1* 3 Activation of PKC results in the translocation of the enzyme to the cell membrane, where phosphatidylserine and diacylglycerol, in the presence of calcium, are able to fully ac-tivate the enzyme. 2 Contrary to the action of diacyl-glycerols, endogenous alkylacylglycerols derived by phos-phocholine hydrolysis4* 6 are inhibitors of PKC. In addi-