A rapid access to the piperizinohydroisoquinoline motif, which has feature of the saframycins and related pentacyclic antitumor alkaloids is described. The key features of the synthetic strategy include (1) a controlled mono-Pictet-Spengler cyclization of the symmetrical 3,6-bis-[(2,5-dimethoxy-phenyl)methyl]piperizine-2,5-dione (1), with aldehydes to give 2, under a critically controlled ratio of acetic acid and trifluoroacetic acid as solvent and (2) reduction of the activated amide to the hemiaminal, which then undergoes an unexpected dehydrogenation reaction to remove the steric hindrance for the second Pictet-Spengler cyclization to form the pentacyclic piperizinohydroisoquinoline 6. The in vitro antitumor activity of these compounds was tested against five human cancer cell lines (A549 lung, HeLa cervical, SAS oral, SKHep1 hepatoma and PC-3 prostate carcinoma). The pentacyclic saframycin analogues 6, 7 and 9 showed only weak activities. Interestingly, compound 6, having a closer relation to cribrostatin IV, is selective towards oral cancer.
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry