Development of novel anti-angiogenetic epoxycarolide to antitumor lead

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K05718
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Wakayama Medical University (2021); Iwate Medical University (2019-2020)
• Principal Investigator: Tamura Satoru 和歌山県立医科大学, 薬学部, 教授 (30362619)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 血管新生阻害 / 抗がん / ブテノリド / 構造活性相関

Outline of Final Research Achievements

Angiogenesis is an important target for anti-tumors because angiogenesis is essential for growth of solid tumors. We found a novel anti-angiogenetic compound named as expoxycarolide to show the selective anti-proliferation to vascular endothelial cells, which is a key of angiogenesis. We synthesized stereoisomers of epoxycarolide and assessed anti-proliferation of them to reveal an stereoisomer with comparative potent and vascular-endothelial-cell-selective anti-proliferation to epoxycarolide. On the basis of the structure of the promising stereoisomer, SAR analysis was performed to disclose that epoxide moiety in the side chain of epoxycarolide is important for potent and selective anti-proliferation.Through the SAR analysis, we improved the synthetic route to be more versatile one for the future study on epoxycarolide to develop anti-tumors.

Free Research Field

天然物化学、ケミカルバイオロジー、創薬化学

Academic Significance and Societal Importance of the Research Achievements

対象としているepoxycarolideは、分子量が非常に小さい上に多彩な官能基を備えているため、有機合成的な改変、開発に適している。今回、種々の立体異性体を合成可能なルートの開発を達成し、さらに改良できたことで、今後のepoxycarolideをシーズ分子とした血管新生阻害作用を作用メカニズムとした新規抗がん剤の開発に向けて大きな一歩となった。また、側鎖上のエポキシド構造が活性発現に必須であることを明らかにできたことから、今後はエポキシド部分を残した開発が必要であることを示唆できた。