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Paper | Regular issue | Vol 89, No. 8, 2014, pp.1860-1876
Published online, 11th July, 2014
DOI: 10.3987/COM-14-13042
Synthesis of Sunitinib-Metastin Conjugate, a Novel Esterase-Sensitive Prodrug System Based on Lactonization Reaction

Yuki Takahashi, Sunao Shoji, Takuya Morishige, Aya Katsumata, Fumihiro Tsurifune, Mitsuhiro Tsutsumi, Yoshiharu Honda, Tomoyo Hasuda, Yukio Hitotsuyanagi, Toshiro Terachi, Toyoaki Uchida, and Koichi Takeya*

*Department of Natural Products and Medicinal Chemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

We describe a strategy for preparing sunitinibmetastin conjugate, a prodrug composed of the anticancer agent sunitinib for renal cell carcinoma and the carrier protein metastin, which are conjugated to each other by a linker. We designed a modified L-homoserine linker, which is composed of an acyl group that acts as the masking group for hydrolysis with an esterase, as well as a carbon chain of appropriate length between sunitinib and metastin. The sunitinibmetastin conjugate was converted into a hydrolyte by hydrolysis of the acyl group with an esterase, and sunitinib was released by intramolecular lactonization. Sunitinibmetastin conjugate, an esterase-sensitive amide prodrug that has a modified L-homoserine linker that participates in the intramolecular lactonization, was synthesized.