Synthesis of agelastatin A and derivatives premised on a hidden symmetry element leading to analogs displaying anticancer activity

TETRAHEDRON

卷:94

Article

Xue, Haoran^1,2,4  Svatek, Haleigh^2,3  Bertonha, Ariane F.¹  Reisenauer, Keighley^2,3  Robinson, Joshua^1,2  Kim, Minwoo^1,2  Ingros, Alec^2,3  Ho, Matthew^1,2  Taube, Joseph^2,3  Romo, Daniel^1,2,4 

[1] Baylor Univ, Dept Chem & Biochem, One Bear Pl 97348, Waco, TX 76798 USA

[2] Baylor Univ, Baylor Undergrad MiniPharma Program, One Bear Pl 97348, Waco, TX 76798 USA

[3] Baylor Univ, Dept Biol, One Bear Pl 97348, Waco, TX 76798 USA

[4] Baylor Univ, Baylor Synth & Drug Lead Discovery Lab, One Bear Pl 97348, Waco, TX 76798 USA

关键词: Natural product;    Alkaloids;    Molecular modeling;    Docking;    Anticancer activity;   

DOI  :  10.1016/j.tet.2021.132340

来源: Elsevier

【 摘 要 】

Concise total syntheses of (+/-)-7-hydroxy debromo agelastatin A (AglA), (+/-)-AglA, and 11-nitro AglA are presented based on an identified pseudo-symmetry element. This synthetic strategy was developed based on a desire to improve solubility of this potent anticancer agent while also developing a synthetic strategy that would enable late-stage variation of the pyrrole moiety. A stability study of pyrrole-derived carbinolamines revealed critical substituent effects impacting the equilibrium between the cyclic carbinolamine and keto pyrrole forms. 7-Hydroxy AglA existed primarily in the ketopyrrole form however the des-bromo variant existed primarily in the cyclic carbinolamine form. Cytotoxicity assays revealed activity for a 13-nitro AglA derivative (similar to 14-63 mu M) for breast cancer cells (MDA-MB-231 and MCF7) and a glioblastoma cell line (U87) while for 7-hydroxy des-bromo AglA, measurable activity was only observed against the glioblastoma cell line. (C) 2021 Published by Elsevier Ltd.

【 授权许可】

Free