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

Takayoshi Suzuki; Shinya Hisakawa; Yukihiro Itoh; Nobuaki Suzuki; Katsumasa Takahashi; Masatoshi Kawahata; Kentaro Yamaguchi; Hidehiko Nakagawa; Naoki Miyata

doi:10.1016/j.bmcl.2007.05.040

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

Bioorg Med Chem Lett. 2007 Aug 1;17(15):4208-12. doi: 10.1016/j.bmcl.2007.05.040. Epub 2007 May 17.

Authors

Takayoshi Suzuki¹, Shinya Hisakawa, Yukihiro Itoh, Nobuaki Suzuki, Katsumasa Takahashi, Masatoshi Kawahata, Kentaro Yamaguchi, Hidehiko Nakagawa, Naoki Miyata

Affiliation

¹ Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan. suzuki@phar.nagoya-cu.ac.jp

PMID: 17532630
DOI: 10.1016/j.bmcl.2007.05.040

Abstract

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.

Publication types

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

MeSH terms

Carrier Proteins / drug effects*
Cell Line, Tumor
Drug Design
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Folate Receptors, GPI-Anchored
Histone Deacetylase Inhibitors*
Humans
Prodrugs / chemical synthesis*
Prodrugs / pharmacology*
Receptors, Cell Surface / drug effects*
Sulfhydryl Compounds / chemistry*

Substances

Carrier Proteins
Enzyme Inhibitors
Folate Receptors, GPI-Anchored
Histone Deacetylase Inhibitors
Prodrugs
Receptors, Cell Surface
Sulfhydryl Compounds