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Antiproliferative and differentiating activities of a novel series of histone deacetylase inhibitors.

ABSTRACT: Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure-activity studies. Thirteen tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations between acetylation of the three substrates, tumor cell growth inhibition, and ATRA-dependent cytodifferentiation were performed, providing information on the chemical functionalities governing these activities. For two analogues, antitumor activity in the animal was demonstrated.

SUBMITTER: Binaschi M 

PROVIDER: S-EPMC4007903 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Antiproliferative and differentiating activities of a novel series of histone deacetylase inhibitors.

Binaschi Monica M   Boldetti Andrea A   Gianni Maurizio M   Maggi Carlo Alberto CA   Gensini Martina M   Bigioni Mario M   Parlani Massimo M   Giolitti Alessandro A   Fratelli Maddalena M   Valli Claudia C   Terao Mineko M   Garattini Enrico E  

ACS medicinal chemistry letters 20100720 8

Histone deacetylases are promising molecular targets for the development of antitumor agents. A novel series of histone deacetylase inhibitors of the hydroxamic acid type were synthesized for structure-activity studies. Thirteen tricyclic dibenzo-diazepine, -oxazepine, and -thiazepine analogues were studied and shown to induce variable degrees of histone H3/H4 and tubulin acetylation in a cellular model of myeloid leukemia sensitive to all-trans retinoic acid (ATRA). Multiparametric correlations  ...[more]