Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

Raffaella Cincinelli; Loana Musso; Giuseppe Giannini; Valentina Zuco; Michelandrea De Cesare; Franco Zunino; Sabrina Dallavalle

doi:10.1016/j.ejmech.2014.04.021

Influence of the adamantyl moiety on the activity of biphenylacrylohydroxamic acid-based HDAC inhibitors

Eur J Med Chem. 2014 May 22:79:251-9. doi: 10.1016/j.ejmech.2014.04.021. Epub 2014 Apr 8.

Authors

Raffaella Cincinelli¹, Loana Musso¹, Giuseppe Giannini², Valentina Zuco³, Michelandrea De Cesare³, Franco Zunino³, Sabrina Dallavalle⁴

Affiliations

¹ Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
² R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, RM, Italy.
³ Molecular Pharmacology Unit, Dept. Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, I-20133 Milan, Italy.
⁴ Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università di Milano, Via Celoria 2, 20133 Milano, Italy. Electronic address: sabrina.dallavalle@unimi.it.

PMID: 24742384
DOI: 10.1016/j.ejmech.2014.04.021

Abstract

To investigate the influence of the adamantyl group on the biological properties of known HDAC inhibitors with a 4-phenylcinnamic skeleton, a series of compounds having the adamantyl moiety in the cap structure were synthesized and compared to the corresponding hydroxamic acids lacking this group. An unexpected finding was the substantial reduction of inhibitory activity toward the tested enzymes, in particular HDAC6, following the introduction of the adamantyl group. In spite of the reduced ability to function as HDAC inhibitors, the compounds containing the adamantyl moiety still retained a good efficacy as antiproliferative and proapoptotic agents. A selected compound (2c; ST3056) of this series exhibited an appreciable antitumor activity against the colon carcinoma xenograft HCT116.

Keywords: Adamantyl moiety; Antiproliferative activity; HDAC inhibitors; Hydroxamic acids.

Publication types

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

MeSH terms

Adamantane / chemistry*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry
Biphenyl Compounds / pharmacology*
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HCT116 Cells
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / metabolism*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / pathology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Biphenyl Compounds
Histone Deacetylase Inhibitors
Hydroxamic Acids
Histone Deacetylases
Adamantane