Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: enzyme and cellular studies

Simone Carradori; Dante Rotili; Celeste De Monte; Alessia Lenoci; Melissa D'Ascenzio; Veronica Rodriguez; Patrizia Filetici; Marco Miceli; Angela Nebbioso; Lucia Altucci; Daniela Secci; Antonello Mai

doi:10.1016/j.ejmech.2014.04.042

Evaluation of a large library of (thiazol-2-yl)hydrazones and analogues as histone acetyltransferase inhibitors: enzyme and cellular studies

Eur J Med Chem. 2014 Jun 10:80:569-78. doi: 10.1016/j.ejmech.2014.04.042. Epub 2014 Apr 15.

Affiliations

¹ Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
² Institute of Molecular Biology and Pathology (IBPM), CNR National Research Council of Italy, c/o Sapienza Università di Roma, 00185 Rome, Italy.
³ Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, vico L. De Crecchio 7, 80138 Naples, Italy.
⁴ 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.
⁵ 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.

PMID: 24835815
DOI: 10.1016/j.ejmech.2014.04.042

Abstract

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).

Keywords: Apoptosis; Epigenetics; HAT inhibitor; Hydrazone; Thiazole.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Drug Evaluation, Preclinical
Histone Acetyltransferases / antagonists & inhibitors*
Humans
Hydrazones / chemistry*
Hydrazones / pharmacology*

Substances

Hydrazones
Histone Acetyltransferases