10.1002/anie.200460218
The research focuses on the synthesis and biological evaluation of a b-carboline-1-one mimic of the anticancer Amaryllidaceae constituent pancratistatin. The purpose of the study was to develop a more soluble analogue of pancratistatin, which has shown activity against various cancer cell lines but has poor bioavailability. The researchers hypothesized that the potency of pancratistatin and related compounds might be due to the hydrogen-bonding donor-acceptor pairing of the b-ketoamide motifs present in these compounds. They synthesized compound 5, a b-carboline-1-one analogue of pancratistatin, to test this hypothesis and evaluated its activity against a series of cancer cell lines. The synthesis involved several interesting transformations and used chemicals such as vinylaziridine, methyl indole-2-carboxylate, tosylamide, and various reagents for hydrolysis, iodolactonization, and detosylation steps. The biological evaluation showed that compound 5 had borderline activity in a murine P388 lymphocytic leukemia assay, while some intermediates in the synthesis process showed promising activities against certain cancer cell lines. The study concluded that the presence of both oxygen atoms in the methylenedioxy bridge of pancratistatin is essential for high activity, and that future analogues could be structured around different scaffolds based on the activity of intermediates like iodolactone 11. The synthesis of compound 5, with nine steps, is the shortest existing preparation of pancratistatin analogues containing the aminoinositol motif, and the researchers plan to focus on heteroatom alterations in the aromatic portion of pancratistatin for future analogues.