tert‐Butylcarbamate‐Containing Histone Deacetylase Inhibitors: Apoptosis Induction,Cytodifferentiation, and Antiproliferative Activities in Cancer Cells |
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| Authors: | Dr. Sergio Valente Dr. Daniela Trisciuoglio Dr. Maria Tardugno Dr. Rosaria Benedetti Dr. Donatella Labella Prof. Daniela Secci Dr. Ciro Mercurio Dr. Roberto Boggio Dr. Stefano Tomassi Dr. Salvatore Di Maro Prof. Ettore Novellino Prof. Lucia Altucci Dr. Donatella Del Bufalo Prof. Antonello Mai Dr. Sandro Cosconati |
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| Affiliation: | 1. Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, “Sapienza” Università di Roma, P.le A. Moro 5, 00185 Roma (Italy);2. Regina Elena National Cancer Institute, Laboratorio di Chemioterapia Sperimentale Preclinica, Via delle Messi d'Oro 156, 00158 Roma (Italy);3. Dipartimento di Patologia Generale, Seconda Università degli Studi di Napoli vico L. De Crecchio 7, 80138 Napoli (Italy);4. Genextra Group, DAC s.r.l., Via Adamello 16, 20139 Milano (Italy);5. Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milano (Italy);6. Present address: Nerviano Medical Sciences, Via Pasteur 10, 20014 Nerviano (Italy);7. Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli (Italy);8. IGB‐CNR, Via P. Castellino Napoli (Italy);9. DiSTABiF, Seconda Università di Napoli, Via G. Vivaldi 43, 81100 Caserta (Italy) |
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| Abstract: | Herein we report novel pyrrole‐ and benzene‐based hydroxamates ( 8 , 10 ) and 2′‐aminoanilides ( 9 , 11 ) bearing the tert‐butylcarbamate group at the CAP moiety as histone deacetylase (HDAC) inhibitors. Compounds 8 b and 10 c selectively inhibited HDAC6 at the nanomolar level, whereas the other hydroxamates effected an increase in acetyl‐α‐tubulin levels in human acute myeloid leukemia U937 cells. In the same cell line, compounds 8 b and 10 c elicited 18.4 and 21.4 % apoptosis, respectively (SAHA: 16.9 %), and the pyrrole anilide 9 c displayed the highest cytodifferentiating effect (90.9 %). In tests against a wide range of various cancer cell lines to determine its antiproliferative effects, compound 10 c exhibited growth inhibition from sub‐micromolar (neuroblastoma LAN‐5 and SH‐SY5Y cells, chronic myeloid leukemia K562 cells) to low‐micromolar (lung H1299 and A549, colon HCT116 and HT29 cancer cells) concentrations. In HT29 cells, 10 c increased histone H3 acetylation, and decreased the colony‐forming potential of the cancer cells by up to 60 %. |
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| Keywords: | anilides apoptosis hydroxamates pyrroles tert‐butylcarbamates |
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