Late-stage olefination gives cyclic tetrapeptide natural products as HDAC1-selective inhibitors
- A Horner-Wadsworth-Emmons olefination diversifies the pendant tail of a cyclic tetrapeptide late in the synthesis, avoiding soluble heavy metals.
- The route gave two natural products and two analogues with a designed oxygenation pattern in the tail.
- All four inhibited HDAC1 over HDAC4 and HDAC6, though selectivity differed; the extra oxygen lowered potency and selectivity.
- Conformational and docking work suggested binding favors one ring conformation, and that the added oxygen contributes little to HDAC1 binding.
💡 Points Based on the abstract
Beating HDAC4 and HDAC6 is the easy bar; for a class I selectivity claim I would want HDAC2 and HDAC3 data, which I don't see here. The oxygen that adds little to binding yet costs potency is a useful negative SAR, so I'd probe the tail with lipophilic rather than polar edits next.
📄 Paper · The Journal of Organic Chemistry ↗ Late-Stage Chemical Editing as a Route to Naturally Occurring Cyclic Tetrapeptides as Selective Inhibitors of Histone Deacetylase 1