Comparison of Inhibitory Activities of Stereo-Isomers of Cyclic Phosphatidic Acid (cPA) on Autotaxin
Comparison of Inhibitory Activities of Stereo-Isomers of Cyclic Phosphatidic Acid (cPA) on Autotaxin
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DOI：
10.1508/cytologia.76.73
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发表时间：
2011-03-01
期刊：
影响因子：
1
通讯作者：
Murakami-Murofushi, Kimiko
中科院分区：
文献类型：
--
作者：
Nozaki, Emi;Gotoh, Mari;Murakami-Murofushi, Kimiko
环状磷脂酸（cPA）与溶血磷脂酸（LPA）结构相似，但具有不同的生物学功能。例如，cPA 通过抑制自分泌运动因子 (ATX) 和短暂激活低分子量 GTP 酶 RhoA 来抑制癌细胞侵袭和转移。我们设计并化学合成了几种代谢稳定的 cPA 衍生物，并发现 2-carba-cPA 是癌细胞侵袭和转移最有效的抑制剂。我们开发了一种新的 2ccPA 对映体合成方法，在这里我们检查了天然 (R)-cPA、对映体纯 2ccPA 和 (S)-3ccPA（对应于 (R)-2ccPA 的构型）对 ATX 的影响。我们还通过量子力学和分子力学（QM/MM）相结合的计算方法预测了（R）-cPA、（R）-2ccPA和（S）-3ccPA对ATX活性的影响。通过这些方法，我们证明2ccPA是ATX最有效的抑制剂，并且2ccPA的手性不参与ATX抑制。这些结果表明外消旋-2ccPA 可用作癌症治疗的有效化合物。
Cyclic phosphatidic acid (cPA) has a similar structure to that of lysophosphatidic acid (LPA), but possesses distinct biological functions. For example, cPA suppresses cancer cell invasion and metastasis through the inhibition of autotaxin (ATX) and transient activation of low molecular weight GTPase, RhoA. We designed and chemically synthesized several metabolically stabilized derivatives of cPA, and revealed that 2-carba-cPA was the most potent inhibitor of cancer cell invasion and metastasis. We have developed a novel method of 2ccPA enantiomeric synthesis, and here we examined the effects of natural (R)-cPA, both enantiopure 2ccPA, and (S)-3ccPA (corresponding to the configuration of (R)-2ccPA) on ATX. We also predicted the effects of (R)-cPA, (R)-2ccPA and (S)-3ccPA on ATX activity by combined quantum mechanics and molecular mechanics (QM/MM) computational methods. By these methods, we demonstrated that 2ccPA was the most potent inhibitor on ATX, and the chirality of 2ccPA was not involved in ATX inhibition. These results suggest that racemic-2ccPA may be utilized as an effective compound for cancer therapeutics.