Optimized Biomimetic Syntheses of Discorhabdin B and Aleutianamine Drives a Deeper Exploration of Their Anticancer Potential

The structurally novel marine alkaloid aleutianamine was reported to have potent and selective activity against the PANC-1 pancreatic cancer cell line, inspiring the development of three exceptional recent syntheses. Our efforts toward a bioinspired, “Kita-style” synthesis met with challenges until we adopted the presumably biomimetic rearrangement of N- tosyl dihydrodiscorhabdin B discovered by Tokuyama and co-workers. With our previously reported, scalable synthesis of the tricyclic pyrroloiminoquinone (PIQ) core and the design of a brominated and sulfenylated tyramine reaction partner, a convergent condensation set up for a modified Tokuyama endgame. Early incorporation of the bromine atom increased convergence and obviated a troublesome late-stage halogenation. The discovery that efficient oxidative thioaminal formation required only oxygen permitted a synthesis of discorhabdin B in only nine steps in the longest linear sequence (LLS). Notably, no pyrrole N -protecting group was used throughout the sequence leading to discorhabdin B. Conversion to aleutianamine without N -protection was not so efficient, but delivered the target in only 10 steps LLS; alternatively, N -tosylation permitted higher yielding rearrangement, per Tokuyama. In this manner, we were able to make tens of milligrams of aleutianamine, permitting evaluation of its activity against the NCI 60-cell panel (plus 6 additional pancreatic cancer cell lines), wherein it showed potent activity against several pancreatic, leukemia, and melanoma cell lines. In addition, aleutianamine, N- Ts aleutianamine, desbromoaleutianamine, discorhabdin B, and the simpler PIQ makaluvamine J were evaluated against three pancreatic cancer cell lines, and each compound showed submicromolar activity in all cases. Critically, the more readily available discorhabdin B was equipotent to aleutianamine, showing that aleutianamine is not special among the broader family with regard to pancreatic cancer cytotoxicity. We thus optimized our route to discorhabdin B, which provided nearly 350 mg in one pass, setting the stage for further collaborative investigations. We also provide a potential mechanism for aleutianamine to undergo bioreductive activation and covalent modification of biomolecules and a proposal that makaluvamine F─thought to be a potential precursor of discorhabdin B and aleutianamine─might in fact be a degradation product of discorhabdin B.