Discovery of Novel Thieno[2,3-d]pyrimidin-4-yl Hydrazone-Based Cyclin-Dependent Kinase 4 Inhibitors: Synthesis, Biological Evaluation and Structure–Activity Relationships

Takao Horiuchi; Yasuyuki Takeda; Noriyasu Haginoya; Masaki Miyazaki; Motoko Nagata; Mayumi Kitagawa; Kouichi Akahane; Kouichi Uoto

doi:10.1248/cpb.59.991

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Discovery of Novel Thieno[2,3-d]pyrimidin-4-yl Hydrazone-Based Cyclin-Dependent Kinase 4 Inhibitors: Synthesis, Biological Evaluation and Structure–Activity Relationships

Takao Horiuchi, Yasuyuki Takeda, Noriyasu Haginoya, Masaki Miyazaki, Motoko Nagata, Mayumi Kitagawa, Kouichi Akahane, Kouichi Uoto

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Keywords: cyclin-dependent kinase 4 inhibitor, thieno[2,3-d]pyrimidine-4-yl hydrazone

JOURNAL FREE ACCESS

2011 Volume 59 Issue 8 Pages 991-1002

DOI https://doi.org/10.1248/cpb.59.991

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Abstract

The design, synthesis, and evaluation of novel thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as cyclin-dependent kinase 4 (CDK4) inhibitors are described. In continuing our program aim to search for potent CDK4 inhibitors, the introduction of a thiazole group at the hydrazone part has led to marked enhancement of chemical stability. Furthermore, by focusing on the optimization at the C-4′ position of the thiazole ring and the C-6 position of the thieno[2,3-d]pyrimidine moiety, compound 35 has been identified with efficacy in a xenograft model of HCT116 cells. In this paper, the potency, selectivity profile, and structure–activity relationships of our synthetic compounds are discussed.

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