Synthesis of agelastatin A and derivatives premised on a hidden symmetry element leading to analogs displaying anticancer activity. (13th August 2021)

• Record Type: Journal Article
• Authors: Xue, Haoran; Svatek, Haleigh; Bertonha, Ariane F.; Reisenauer, Keighley; Robinson, Joshua; Kim, Minwoo; Ingros, Alec; Ho, Matthew; Taube, Joseph; Romo, Daniel
• Is Part Of: Tetrahedron. Volume 94(2021)
• Publication Date: 2021-08-13
• Subjects: Natural product -- Alkaloids -- Molecular modeling -- Docking -- Anticancer activity; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2021.132340
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: 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 (∼14–63 μM) 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. Graphical abstract: Image 1