Synthesis Of Agelastatin A And Derivatives Premised On A Hidden Symmetry Element Leading To Analogs Displaying Anticancer Activity

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.