Uracil- and Pyridine-Containing HDAC Inhibitors Displayed Cytotoxicity in Colorectal and Glioblastoma Cancer Stem Cells.

Autor: Fiorentino F; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Fabbrizi E; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Raucci A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Noce B; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Fioravanti R; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Valente S; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Paolini C; IRBM S.p.A., Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., De Maria R; Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168, Rome, Italy.; Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168, Rome, Italy., Steinkühler C; Research and Development, Italfarmaco Group, Via dei Lavoratori 54, 20092, Cinisello Balsamo, Italy., Gallinari P; Exiris S.r.l., Tecnopolo Castel, Romano, Via Castel Romano 100, 00128, Rome, Italy., Rotili D; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy., Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le Aldo, Moro n. 5, 00185, Rome, Italy.; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. de Aldo Moro n. 5, 00185, Rome, Italy.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2024 Jul 02; Vol. 19 (13), pp. e202300655. Date of Electronic Publication: 2024 Apr 29.
DOI: 10.1002/cmdc.202300655
Abstrakt: Cancer stem cells (CSCs) are a niche of highly tumorigenic cells featuring self-renewal, activation of pluripotency genes, multidrug resistance, and ability to cause cancer relapse. Seven HDACi (1-7), showing either hydroxamate or 2'-aminoanilide function, were tested in colorectal cancer (CRC) and glioblastoma multiforme (GBM) CSCs to determine their effects on cell proliferation, H3 acetylation levels and in-cell HDAC activity. Two uracil-based hydroxamates, 5 and 6, which differ in substitution at C5 and C6 positions of the pyrimidine ring, exhibited the greatest cytotoxicity in GBM (5) and CRC (6) CSCs, followed by the pyridine-hydroxamate 2, with 2- to 6-fold higher potency than the positive control SAHA. Finally, increased H3 acetylation as well as HDAC inhibition directly in cells by selected 2'-aminoanilide 4 and hydroxamate 5 confirmed target engagement. Further investigation will be conducted into the broad-spectrum anticancer properties of the most potent derivatives and their effects in combination with approved, conventional anticancer drugs.
(© 2024 Wiley-VCH GmbH.)
Databáze: MEDLINE
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