Synthetic Studies on Biological Active Natural Products Directed Toward Developing Novel Molecular-Targeted Agents

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Tohoku Pharmaceutical University
• Principal Investigator: KATOH Tadashi 東北薬科大学, 薬学部, 教授 (50382669)
• Co-Investigator(Kenkyū-buntansha): WATANABE Kazuhiro 東北薬科大学, 薬学部, 講師 (10382673)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 分子標的治療薬 / 生物活性天然物 / 抗腫瘍活性物質 / 全合成 / TAN-1813 / HDAC阻害剤 / FK228 / スピルコスタチン

Outline of Final Research Achievements

In the course of our synthetic studies on a novel p21ras farnesyltransferase inhibitor, TAN-1813, a new method for construction of maleimide and a new coupling reaction of maleimide using phenylthio group as a leaving group were successfully developed. The reaction was applied to the coupling reaction of the maleimide segment with the decalin segment, which afforded the advanced key intermediate possessing whole carbon skeleton with all asymmetric carbon centers and functional groups present in the natural product.
A new synthetic route for the synthesis of FK228 analogues as novel HDAC inhibitors, was developed in a highly convergent and unified manner. Eight analogues were synthesized, and their biological evaluation disclosed novel aspects of structure-activity relationships. Further investigation of FK228 analogues identified FK-A11 as a promising candidates for novel anticancer agent. FK-A11 is currently conducting preclinical studies in Tohoku University Hospital.

Free Research Field

医歯薬