Mooberry Susan L, Hilinski Michael K, Clark Erin A, Wender Paul A
Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, Texas 78245, USA.
Mol Pharm. 2008 Sep-Oct;5(5):829-38. doi: 10.1021/mp800043n. Epub 2008 Jul 29.
Laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. The identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. To determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis diversification strategy and their biological activities were evaluated. Five analogues, differing in potency from 233 nM to 7.9 muM, effectively inhibit cancer cell proliferation. Like laulimalide, they retain activity against multidrug resistant cells, stabilize microtubules and cause the formation of aberrant mitotic spindles, mitotic accumulation, Bcl-2 phosphorylation and initiation of apoptosis. Structural modifications in the C 23-C 27 dihydropyran side chain can be made without changing the overall mechanism of action, but it is clear that this subunit has more than a bystander role.
laulimalide是一种有效的微管稳定剂，也是一种很有前景的抗癌治疗先导物。鉴定出稳定、有效且易于获得的类似物对于将这种新型先导物应用于临床至关重要。为了确定laulimalide的哪些结构特征是有益功能所必需的，从而找到更优的临床候选药物，通过最后一步交叉复分解多样化策略制备了一系列侧链类似物，并评估了它们的生物活性。五种类似物的效力在233 nM至7.9 μM之间，能有效抑制癌细胞增殖。与laulimalide一样，它们对多药耐药细胞仍具有活性，能稳定微管并导致异常有丝分裂纺锤体的形成、有丝分裂积累、Bcl-2磷酸化以及细胞凋亡的启动。可以对C23 - C27二氢吡喃侧链进行结构修饰，而不改变整体作用机制，但很明显该亚基的作用不止于旁观者角色。
