Design, synthesis, and biological activity of folate receptor-targeted prodrugs of thiolate histone deacetylase inhibitors

Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. One of the folate conjugates showed growth-inhibitory activity toward folate receptor...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-08, Vol.17 (15), p.4208-4212
Main Authors: Suzuki, Takayoshi, Hisakawa, Shinya, Itoh, Yukihiro, Suzuki, Nobuaki, Takahashi, Katsumasa, Kawahata, Masatoshi, Yamaguchi, Kentaro, Nakagawa, Hidehiko, Miyata, Naoki
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Carrier Proteins - drug effects
Cell Line, Tumor
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Folate conjugate
Folate Receptors, GPI-Anchored
General aspects
Histone deacetylase inhibitor
Histone Deacetylase Inhibitors
Humans
Medical sciences
Pharmacology. Drug treatments
Prodrug
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Receptors, Cell Surface - drug effects
Selective anticancer activity
Sulfhydryl Compounds - chemistry
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Summary:Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. One of the folate conjugates showed growth-inhibitory activity toward folate receptor-positive MCF-7 breast cancer cells. Aiming to develop selective anticancer drugs, we designed and synthesized three disulfides bearing a folic acid moiety as candidate folate receptor (FR)-targeted prodrugs of thiolate histone deacetylase inhibitors. Among them, compound 1 displayed growth-inhibitory activity toward folate receptor-positive MCF-7 breast cancer cells. The activity of 1 was significantly reduced by free folic acid, suggesting that cellular uptake of 1 is mediated by FR.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2007.05.040