Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity
Stereodivergent Synthesis of Bispyrrolidinoindoline Alkaloidal Scaffolds and Generation of a Lead Candidate with Stereospecific Antiproliferative Activity
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DOI：
10.1002/cbic.201800815
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发表时间：
2019-03
期刊：
影响因子：
3.2
通讯作者：
M. Wada;Hiroyuki Suzuki;Mitsuyasu Kato;H. Oikawa;A. Tsubouchi;H. Oguri
中科院分区：
文献类型：
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作者：
M. Wada;Hiroyuki Suzuki;Mitsuyasu Kato;H. Oikawa;A. Tsubouchi;H. Oguri
真菌次级代谢产物（+）-WIN 64821和（-）-ditryptophenaline通过l-色氨酸和l-苯丙氨酸缩合，然后还原二聚化产生立体化学变化而生物合成。受立体分散性生物发生过程的启发，我们设计并合成了一系列双吡咯烷吲哚啉二酮哌嗪生物碱及其类似物，并对真菌生物碱的特权结构基序的立体化学进行了系统的多样化。（+）-WIN 64821不仅在3-/3′-、11-/11′-和15-/15′-位进行了立体化学修饰，而且二酮哌嗪部分也发生了环裂解，从而生成了对人结肠癌细胞具有强效生长抑制活性（IC 50 =3.03 μm）的先导化合物。构效关系研究表明，所有六个立体中心的药效团是必不可少的。高细胞密度显著增强了先导化合物的细胞毒活性。
The fungal secondary metabolites (+)‐WIN 64821 and (−)‐ditryptophenaline are biosynthesized through condensation of l‐tryptophan and l‐phenylalanine, followed by reductive dimerization with generation of stereochemical variations. Inspired by the stereodivergent biogenetic process, we designed and synthesized a collection of bispyrrolidinoindoline diketopiperazine alkaloids and their analogues with systematic diversification of the stereochemistry of the privileged structural motif of the fungal alkaloids. Not only the stereochemical modifications of (+)‐WIN 64821 at the 3‐/3′‐, 11‐/11′‐, and 15‐/15′‐positions, but also ring cleavage of the diketopiperazine moieties, allowed the generation of a lead compound exhibiting potent growth inhibitory activity (IC50=3.03 μm) toward human colon cancer cells. Structure–activity relationship studies revealed that all six stereogenic centers were essential for the pharmacophore. High cell densities dramatically intensified the cytotoxic activities of the lead compound.