TY - JOUR
T1 - Antiproliferative and differentiating activities of a novel series of histone deacetylase inhibitors
AU - Binaschi, Monica
AU - Boldetti, Andrea
AU - Gianni, Maurizio
AU - Maggi, Carlo Alberto
AU - Gensini, Martina
AU - Bigioni, Mario
AU - Parlani, Massimo
AU - Giolitti, Alessandro
AU - Fratelli, Maddalena
AU - Valli, Claudia
AU - Terao, Mineko
AU - Garattini, Enrico
PY - 2010/11/11
Y1 - 2010/11/11
N2 - 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.
AB - 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.
KW - macrolactone
KW - MDR reversing agents
KW - nonnatural natural product
KW - P-glycoprotein
KW - Taxanes
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U2 - 10.1021/ml1001163
DO - 10.1021/ml1001163
M3 - Article
AN - SCOPUS:78649235170
VL - 1
SP - 411
EP - 415
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 8
ER -