Palmadorin chemodiversity from the Antarctic nudibranch Austrodoris kerguelenensis and inhibition of Jak2/STAT5-dependent HEL leukemia cells

Detailed investigation of the Antarctic nudibranch Austrodoris kerguelenensis has resulted in the isolation of a diverse suite of new diterpenoid glyceride esters (1-16) related to the palmadorins (17-19), including one (palmadorin L (9)) that is the first halogenated diterpene from this well-studied nudibranch. Previous collections of A. kerguelenensis from McMurdo Sound, the Weddell Sea and the Western Antarctic Peninsula have afforded related diterpene glycerides, a natural product class implicated as a chemical defense in nudibranchs. In this paper we describe the isolation, structure elucidation, and stereochemical analysis of sixteen new palmadorins using a combination of one- and two-dimensional NMR techniques. Palmadorin A (17), B (18), D (1), M (10), N (11), and O (12) inhibit human erythroleukemia (HEL) cells with low micromolar IC50's, and palmadorin M inhibits Jak2, STAT5, and Erk1/2 activation in HEL cells and causes apoptosis, at 5 μM.