title: 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.
authors.affiliation: Menarini Ricerche S.p.A., Via Tito Speri 10, 00040 Pomezia (Roma), Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Binaschi
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Boldetti
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gianni
authors.affiliation: Menarini Ricerche S.p.A., Via Tito Speri 10, 00040 Pomezia (Roma), Italy.
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
authors.affiliation: Menarini Ricerche S.p.A., Via Tito Speri 10, 00040 Pomezia (Roma), Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Gensini
authors.affiliation: Menarini Ricerche S.p.A., Via Tito Speri 10, 00040 Pomezia (Roma), Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Bigioni
authors.affiliation: Menarini Ricerche S.p.A., Via Tito Speri 10, 00040 Pomezia (Roma), Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Parlani
authors.affiliation: Menarini Ricerche S.p.A., Via Tito Speri 10, 00040 Pomezia (Roma), Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Giolitti
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Valli
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
authors.affiliation: Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche "Mario Negri", via La Masa 19, 20156 Milano, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
keywords: HDAC inhibitors; antiproliferative effect; differentiation; hydroxamic acid; retinoic acid