Amide analogues of trichostatin A as inhibitors of histone deacetylase andinducers of terminal cell differentiation

Inhibitors of histone deacetylase (HD) bear great potential as new drugs du e to their ability to modulate transcription and to induce apoptosis or dif ferentiation in cancer cells. We have described previously analogues of the complex natural HD inhibitors trapoxin B and trichostatin A with activitie s in the submicromolar range. Here we report structure-activity relationshi p analyses of further analogues of trichostatin A with respect to in vitro inhibition of maize HD-2 and their ability to induce terminal cell differen tiation in Friend leukemic cells. This is the first report that shows the c orrelation between HD inhibitory activity and action on cancer cells on a l arger series of similar compounds. Only the compounds that inhibit HD induc e differentiation and/or exert antiproliferative activities in cell culture . Our studies support the use of in vitro systems as screening tools and pr ovide structure-activity relationships that merit further investigation of this interesting target.