Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide
Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide
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DOI：
10.1021/ja508846g
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发表时间：
2014-11-05
影响因子：
15
通讯作者：
Fuerstner, Alois
中科院分区：
文献类型：
--
作者：
Mailhol, Damien;Willwacher, Jens;Fuerstner, Alois
最近通过全合成的方式解决了有关leiodermatolide (1)立体结构的问题；随着目标的明确界定，合成的使命发生了变化，以确保有效供应这种源自深海海绵的极其稀有的天然产品。为此，开发了一条包含 19 个步骤（最长线性序列）的可扩展路线，其特点是高度烯醇化的 β-酮内酯的催化不对称炔丙基化、闭环炔复分解和改进的 Stille 偶联作为关键转化。故意偏离这个强大的蓝图带来了第一组类似物，从而可以评估 1 的先导质量。获得的生物数据表明，1 在人类肿瘤细胞增殖测定中是一种有效的细胞毒素，即使对于表达 Pgp 外排转运蛋白的细胞系，GI(50) 值也在 =3 nM 范围内。对人类 U2OS 细胞的研究表明 1 导致有丝分裂停滞、微核诱导、中心体扩增和微管蛋白破坏，尽管在无细胞测定中尚未发现微管蛋白直接结合的证据；此外，该化合物似乎并不通过激酶抑制发挥作用。间接证据表明中心体去簇是一种可能的作用机制，这提供了潜在的有益前景，因为中心体去簇剂有望对恶性人体组织具有固有的选择性，而不是对健康的人体组织。
It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable beta-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI(50) values in the =3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue.