Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: enzyme and cellular studies.
Recently we described some (thiazol-2-yl)hydrazones as antiprotozoal, antifungal and anti-MAO agents as well as Gcn5 HAT inhibitors. Among these last compounds, CPTH2 and CPTH6 showed HAT inhibition in cells and broad anticancer properties. With the aim to identify HAT inhibitors more potent than the two prototypes, we synthesized several new (thiazol-2-yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones, and we tested the whole library existing in our lab against human p300 and PCAF HAT enzymes. Some compounds (1x, 1c', 1d', 1i' and 2m) were more efficient than CPTH2 and CPTH6 in inhibiting the p300 HAT enzyme. When tested in human leukemia U937 and colon carcinoma HCT116 cells (100 μM, 30 h), 1x, 1i' and 2m gave higher (U937 cells) or similar (HCT116 cells) apoptosis than CPTH6, and were more potent than CPTH6 in inducing cytodifferentiation (U937 cells).
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Simone
S
Carradori
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Dante
D
Rotili
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Celeste
C
De Monte
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Alessia
A
Lenoci
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Melissa
M
D'Ascenzio
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Veronica
V
Rodriguez
Institute of Molecular Biology and Pathology (IBPM), CNR National Research Council of Italy, c/o Sapienza Università di Roma, 00185 Rome, Italy.
Patrizia
P
Filetici
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, vico L. De Crecchio 7, 80138 Naples, Italy.
Marco
M
Miceli
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, vico L. De Crecchio 7, 80138 Naples, Italy.
Angela
A
Nebbioso
Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, vico L. De Crecchio 7, 80138 Naples, Italy; CNR-IGB, Institute of Genetics and Biophysics, via P. Castellino, 80100 Naples, Italy.
Lucia
L
Altucci
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
Daniela
D
Secci
Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: daniela.secci@uniroma1.it.
Antonello
A
Mai
D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*
D006835:Hydrazones; D051548:Histone Acetyltransferases
Apoptosis; Epigenetics; HAT inhibitor; Hydrazone; Thiazole