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

02 June 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

natural products
alkaloids
total synthesis
biomimetic
pancreatic cancer

Supplementary materials

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Supporting Information
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Experimental details, tabulated spectral data, biological data, NMR spectra.
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