Optimized Biomimetic Syntheses of Discorhabdin B and Aleutianamine Drives a Deeper Exploration of their Anticancer Activities

The marine alkaloid aleutianamine was reported to have potent and selective activity against the PANC-1 pancreatic cancer cell line, and this exciting activity and its novel structure inspired the development of three exceptional recent syntheses. Our efforts toward an efficient, bioinspired, “Kita-style” synthesis were met with challenges until we adopted the presumably biomimetic rearrangement of dihydrodiscorhabdin B discovered by Tokuyama and co-workers. With our previously reported, scalable synthesis of the tricyclic pyrroloiminoquinone (PIQ) core and the development of a brominated and sulfenylated tyramine reaction partner, a convergent condensation set up for a modified Tokuyama endgame. The early incorporation of the bromine atom increased convergence and obviated a troublesome late-stage halogenation; further, the oxidative thioami-nal formation was dramatically improved, leading to discorhabdin B in only eight steps in the longest linear sequence (LLS) and in hundred milligram quantities. Another notable feature of this work is that no pyrrole N-protecting group was used throughout the sequence. 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 hundreds 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 and leuke-mia 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 sub-micromolar activi-ty in all cases. Critically, the readily available discorhabdin B was the most potent, thus showing that aleutianamine is not special with regard to anti-pancreatic-cancer activity. Finally, the activity of the two aleutianamine analogues yields some potential insight into mechanism of action and offers design principles for chemical probes for target identification.