<br>基于设计的月桂马内酯类似物的微管稳定剂。,Proceedings of the National Academy of Sciences of the United States of America

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基于设计的月桂马内酯类似物的微管稳定剂。
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2004 Jun 8 , DOI: 10.1073/pnas.0402759101
Susan L Mooberry ₁ , Deborah A Randall-Hlubek , Rachel M Leal , Sayee G Hegde , Robert D Hubbard , Lei Zhang , Paul A Wender

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Laulimalide 是一种有效的、结构独特的微管稳定剂，最初是从海洋海绵 Cacospongia mycofijiensis 中分离出来的。 Laulimalide 表现出与其他微管结合剂不同的活性特征，特别是对紫杉醇耐药细胞的有效性，但它本质上不稳定。月桂马利特的五种类似物旨在表现出增强的化学稳定性，同时保留其卓越的生物活性。对这些类似物的评估表明，它们都是癌细胞增殖的有效抑制剂，但效力差异很大，IC(50) 范围为 0.12-16.5 microM。尽管所有类似物都会引发类似于月桂马利特的细胞变化，包括间期微管密度增加、有丝分裂纺锤体异常以及最终的细胞凋亡，但类似物之间的差异是明显的。两种最有效的类似物 C(16)-C(17)-脱环氧月桂马内酯和 C(20)-甲氧基月桂马内酯似乎具有与月桂马内酯相同的作用机制。 C(16)-C(17)-去环氧、C(20)-甲氧基月桂马内酯衍生物结合了最有效类似物的两种化学变化，但其效力明显较低，并且与母体不同，它引发了独特的间期微管的形成化合物和其他类似物。两种C(2)-C(3)-炔酸酯衍生物的效力较低，它们引发异常的微管结构，但不会引起微核或广泛的G(2)/M积累。值得注意的是，紫杉醇和埃坡霉素耐药的细胞系对月桂马内酯类似物的耐药性较低。总之，已经合成了旨在最小化或消除其内在不稳定性的月桂马内酯类似物，并且已发现一些类似物保留了月桂马内酯独特的生物活性。

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Microtubule-stabilizing agents based on designed laulimalide analogues.

Laulimalide is a potent, structurally unique microtubule-stabilizing agent originally isolated from the marine sponge Cacospongia mycofijiensis. Laulimalide exhibits an activity profile different from other microtubule-binding agents, notably including effectiveness against paclitaxel-resistant cells, but it is intrinsically unstable. Five analogues of laulimalide were designed to exhibit enhanced chemical stability yet retain its exceptional biological activities. Evaluations of these analogues showed that all are effective inhibitors of cancer-cell proliferation yet differ substantially in potency with an IC(50) range of 0.12-16.5 microM. Although all of the analogues initiated cellular changes similar to laulimalide, including increased density of interphase microtubules, aberrant mitotic spindles, and ultimately apoptosis, differences among the analogues were apparent. The two most potent analogues, C(16)-C(17)-des-epoxy laulimalide and C(20)-methoxy laulimalide, appear to have a mechanism of action identical to laulimalide. The C(16)-C(17)-des-epoxy, C(20)-methoxy laulimalide derivative, which incorporates both chemical changes of the most potent analogues, was significantly less potent and initiated the formation of unique interphase microtubules unlike the parent compound and other analogues. Two C(2)-C(3)-alkynoate derivatives had lower potency, and they initiated abnormal microtubule structures but did not cause micronucleation or extensive G(2)/M accumulation. Significantly, paclitaxel- and epothilone-resistant cell lines were less resistant to the laulimalide analogues. In summary, analogues of laulimalide designed to minimize or eliminate its intrinsic instability have been synthesized, and some have been found to retain the unique biological activities of laulimalide.

更新日期：2017-01-31

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