基于设计的laulimalide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laulimalide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 ₁ , Rachel M. Leal ₁ , Sayee G. Hegde ₁ , Robert D. Hubbard ₁ , Lei Zhang ₁ , Paul A. Wender ₁

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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Mycofijiensis中分离出来的。劳来那肽表现出与其他微管结合剂不同的活性，特别是对紫杉醇耐药性细胞的有效性，但本质上是不稳定的。劳来那肽的五个类似物被设计为具有增强的化学稳定性，但仍保留其卓越的生物学活性。这些类似物的评估表明，所有类似物都是癌细胞增殖的有效抑制剂，但效能（IC（50）范围为0.12-16.5 microM）存在显着差异。尽管所有类似物都引发了与劳来那利类似的细胞变化，包括相间微管密度增加，有丝分裂纺锤体异常并最终导致细胞凋亡，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）-des-epoxy laulimalide和C（20）-甲氧基laulimalide似乎具有与laulimalide相同的作用机理。C（16）-C（17）-des-epoxy，C（20）-甲氧基laulimalide衍生物，结合了最有效的类似物的两种化学变化，其效力显着降低，并开始形成不同于母体的独特相间微管化合物和其他类似物。两个C（2）-C（3）-alkatenoate衍生物具有较低的效力，他们启动异常的微管结构，但不会引起微核或广泛的G（2）/ M积累。重要的是，抗紫杉醇和埃博霉素的细胞系对劳来那肽类似物的抗性较低。总之，

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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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