Largazole Analogues Embodying Radical Changes in the Depsipeptide Ring: Development of a More Selective and Highly Potent Analogue

A number
of analogues of the marine-derived histone deacetylase
inhibitor largazole incorporating major structural changes in the
depsipeptide ring were synthesized. Replacing the thiazole-thiazoline
fragment of largazole with a bipyridine group gave analogue 7 with potent cell growth inhibitory activity and an activity
profile similar to that of largazole, suggesting that conformational
change accompanying switching hybridization from sp3 to
sp2 at C-7 is well tolerated. Analogue 7 was
more class I selective compared to largazole, with at least 464-fold
selectivity for class I HDAC proteins over class II HDAC6 compared
to a 22-fold selectivity observed with largazole. To our knowledge 7 represents the first example of a potent and highly cytotoxic
largazole analogue not containing a thiazoline ring. The elimination
of a chiral center derived from the unnatural amino acid R-α-methylcysteine makes the molecule more amenable to chemical
synthesis, and coupled with its increased class I selectivity, 7 could serve as a new lead compound for developing selective
largazole analogues.