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Selective Photorelease of an Organometallic-Containing Enzyme Inhibitor


Leonidova, Anna; Mari, Cristina; Aebersold, Christine; Gasser, Gilles (2016). Selective Photorelease of an Organometallic-Containing Enzyme Inhibitor. Organometallics, 35(6):851-854.

Abstract

Histone deacetylases (HDACs) are regarded as promising targets in cancer and a growing number of other diseases due to their crucial involvement in epigenetics and cellular signaling. Many organic HDAC inhibitors are known, and several efficient metal-based analogues have been recently developed. Many of them contain a hydroxamic acid group that binds to the catalytic HDAC zinc center. In this work, a light-activatable organometallic HDAC inhibitor (p-Fc-SAHA) was synthesized and characterized. More specifically, the hydroxamic acid moiety of a known ferrocene-containing HDAC inhibitor (Fc-SAHA) was blocked with a photolabile protecting group (PLPG), namely, 1-(bromomethyl)-4,5-dimethoxy-2-nitrobenzene. Upon UV-A (350 nm) irradiation, Fc-SAHA could be successfully released from p-Fc-SAHA. Importantly, p-Fc-SAHA was significantly less active on HDAC1, HDAC2, and HDAC6 than Fc-SAHA. As expected, the inhibition activity of Fc-SAHA was recovered upon light irradiation. To our knowledge, this is the first study presenting the selective photorelease of an organometallic enzyme inhibitor.

Abstract

Histone deacetylases (HDACs) are regarded as promising targets in cancer and a growing number of other diseases due to their crucial involvement in epigenetics and cellular signaling. Many organic HDAC inhibitors are known, and several efficient metal-based analogues have been recently developed. Many of them contain a hydroxamic acid group that binds to the catalytic HDAC zinc center. In this work, a light-activatable organometallic HDAC inhibitor (p-Fc-SAHA) was synthesized and characterized. More specifically, the hydroxamic acid moiety of a known ferrocene-containing HDAC inhibitor (Fc-SAHA) was blocked with a photolabile protecting group (PLPG), namely, 1-(bromomethyl)-4,5-dimethoxy-2-nitrobenzene. Upon UV-A (350 nm) irradiation, Fc-SAHA could be successfully released from p-Fc-SAHA. Importantly, p-Fc-SAHA was significantly less active on HDAC1, HDAC2, and HDAC6 than Fc-SAHA. As expected, the inhibition activity of Fc-SAHA was recovered upon light irradiation. To our knowledge, this is the first study presenting the selective photorelease of an organometallic enzyme inhibitor.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2016
Deposited On:09 Feb 2017 13:55
Last Modified:09 Feb 2017 13:57
Publisher:American Chemical Society (ACS)
ISSN:0276-7333
Publisher DOI:https://doi.org/10.1021/acs.organomet.6b00029

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