Novel cysteine derivatives for the next generation anticancer agents acting on KSP

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460150
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: University of Shizuoka
• Principal Investigator: Ogo Naohisa 静岡県立大学, 薬学研究院, 講師 (20501307)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 構造最適化 / 抗がん剤 / 構造活性相関 / システイン誘導体 / KSP / 抗腫瘍効果 / 溶解度 / プロドラッグ

Outline of Final Research Achievements

We performed optimizations of S-Trityl-L-cysteine derivatives using docking modeling, which led to the discovery of novel derivatives with fused phenyl rings in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth in correlation with KSP inhibitory activities and significantly suppressed tumor growth in the xenograft model. We also performed SARs focused on the amino acid to enhance the drug-like properties. As a result, the introduction of various polar groups to the carboxyl group on STLC was tolerable. Additionally, we tried to synthesize new chemotype, where the sulfur atom is replaced with carbon atom. Although the final compound is not still obtained, the hydantoin intermediate showed potent inhibitory activity. Thus, the novel cysteine related derivatives could be new lead compounds in the design of clinical candidates for next-generation KSP inhibitors as antitumor chemotherapies.

Free Research Field

創薬化学