title: Design, synthesis and evaluation of antiproliferative activity of melanoma-targeted histone deacetylase inhibitors.
abstract: The clinical validation of histone deacetylase inhibition as a cancer therapeutic modality has stimulated interest in the development of new generation of potent and tumor selective histone deacetylase inhibitors (HDACi). With the goal of selective delivery of the HDACi to melanoma cells, we incorporated the benzamide, a high affinity melanin-binding template, into the design of HDACi to generate a new series of compounds 10a-b and 11a-b which display high potency towards HDAC1 and HDAC6. However, these compounds have attenuated antiproliferative activities relative to the untargeted HDACi. An alternative strategy furnished compound 14, a prodrug bearing the benzamide template linked via a labile bond to a hydroxamate-based HDACi. This pro-drug compound showed promising antiproliferative activity and warrant further study.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
authors.forename: Idris
authors.initials: I
authors.lastname: Raji
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
authors.forename: Kabir
authors.initials: K
authors.lastname: Ahluwalia
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA. Electronic address: aoyelere@gatech.edu.
authors.forename: Adegboyega K
authors.initials: AK
authors.lastname: Oyelere
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011355:Prodrugs; D020033:Protein Isoforms; D014404:Tubulin; C037689:benzamide; D006655:Histone Deacetylases