Total synthesis of tubulysins U and V
Total synthesis of tubulysins U and V
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DOI：
10.1002/anie.200604557
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Zanda, Matteo
中科院分区：
文献类型：
--
作者：
Sani, Monica;Fossati, Giacomo;Zanda, Matteo
Tubulysins（方案1）是由两种不同种类的粘菌：gephyra Archangium和盘状血管球菌（Angiococcus disformis）以相当小的量（< 4 mg LÀ1培养液）产生的四肽家族最近，Höfle、Reichenbach和同事确定了这些微管溶素的结构、立体化学和生物合成途径，他们还报道了这些化合物的强细胞毒性（在纳摩尔浓度范围内）管溶素的细胞毒性源于它们能够结合微管蛋白并分解分裂细胞的微管，从而诱导细胞凋亡。从结构的角度来看，微管蛋白来源于N端N-甲基管果酸残基（Mep），第二位置的异亮氨酸（唯一的蛋白质原氨基酸），一种不寻常的含噻唑的氨基酸，管缬氨酸（Tuv），其在第三位置具有两个立体中心，在C端有两种可能的G -氨基酸：管丁氨酸（Tut，微管蛋白a， B， C， G和I）或管苯丙氨酸（Tup，微管蛋白D， E， F和H）。此外，Tuv的N端残基被不同酯基的N， o -缩醛取代基功能化（方案1）。
Tubulysins (Scheme 1) are a family of tetrapeptides produced in rather small quantities (< 4 mg LÀ1 culture broth) by two different species of myxobacteria: Archangium gephyra and Angiococcus disciformis.[1] The structure, stereochemistry, and biosynthetic pathway of the tubulysins were recently determined by Höfle, Reichenbach, and co-workers, who also reported the potent cytotoxicity (in the nanomolar concentration range) of these compounds.[2] The cytotoxicity of the tubulysins stems from their ability to bind tubulin and disintegrate microtubules of dividing cells, thus inducing apoptosis.[3]From a structural point of view, tubulysins are derived from an N-methylpipecolic acid residue (Mep) at the N terminus, isoleucine (the only proteinogenic amino acid) at the second position, an unusual thiazole-containing amino acid, tubuvaline (Tuv), which features two stereogenic centers at the third position, and two possible g-amino acids at the C terminus: either tubutyrosine (Tut, tubulysins A, B, C, G, and I) or tubuphenylalanine (Tup, tubulysins D, E, F, and H). Additionally, the N-terminal residue of Tuv is functionalized with a highly unusual N, O-acetal substituent with different ester groups (Scheme 1).