title: Light-Controlled Histone Deacetylase (HDAC) Inhibitors: Towards Photopharmacological Chemotherapy.
abstract: Cancer treatment suffers from limitations that have a major impact on the patient's quality of life and survival. In the case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their efficacy and causes severe side effects due to nonselective toxicity. Photopharmacology allows a novel approach to address these problems because it employs external, local activation of chemotherapeutic agents by using light. The development of photoswitchable histone deacetylase (HDAC) inhibitors as potential antitumor agents is reported herein. Analogues of the clinically used chemotherapeutic agents vorinostat, panobinostat, and belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable cis form and a significantly lower activity for the trans form, both in terms of HDAC activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photoactivation of HDAC inhibition to avoid severe side effects in chemotherapy.
authors.affiliation: Centre for Systems Chemistry, Stratingh Institute for Chemistry University of Groningen Nijenborgh 4, 9747 AG, Groningen (The Netherlands).|Department of Radiology University of Groningen, University Medical Center Groningen Hanzeplein 1, 9713 GZ, Groningen (The Netherlands).
authors.forename: Wiktor
authors.initials: W
authors.lastname: Szymanski
authors.affiliation: Department of Pharmaceutical Gene Modulation University of Groningen Antonius Deusinglaan 1, 9713 AV Groningen (The Netherlands).
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ourailidou
authors.affiliation: Centre for Systems Chemistry, Stratingh Institute for Chemistry University of Groningen Nijenborgh 4, 9747 AG, Groningen (The Netherlands).
authors.forename: Willem A
authors.initials: WA
authors.lastname: Velema
authors.affiliation: Department of Pharmaceutical Gene Modulation University of Groningen Antonius Deusinglaan 1, 9713 AV Groningen (The Netherlands).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dekker
authors.affiliation: Centre for Systems Chemistry, Stratingh Institute for Chemistry University of Groningen Nijenborgh 4, 9747 AG, Groningen (The Netherlands).
authors.forename: Ben L
authors.initials: BL
authors.lastname: Feringa
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008027:Light; D000077767:Panobinostat; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D013449:Sulfonamides; D000077337:Vorinostat; D000077767:Panobinostat; C487081:belinostat
keywords: cancer; cytotoxicity; drug design; inhibitors; photochemistry