Grant-in-Aid for Scientific Research (B)
|Allocation Type||Single-year Grants|
|Research Institution||KYOTO UNIVERSITY|
FUJII Nobutaka(1999) Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (60109014)
井深 俊郎 京大, 薬学研究科, 教授 (80025692)
OHTAKA Akira Kyoto University, Graduate School of Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (20201973)
YAMAMOTO Yoshinori Tohoku University, Graduate School of Sciences, Professor, 理学研究科, 教授 (60029519)
IBUKA Toshiro Kyoto University, Graduate School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (80025692)
TANAKA Hirokazu Fujisawa Pharmaceutical Co., Ltd., Manager of Research Information, 研究情報部, 研究情報担当部長
HOSOTANI Ryo Kyoto University, Graduate School of Medical Sciences, Associate Professor, 医学研究科, 助教授 (00139908)
玉村 啓和 京都大学, 薬学研究科, 講師 (80217182)
藤井 信孝 京都大学, 薬学研究科, 教授 (60109014)
|Project Fiscal Year
1997 – 1999
Completed(Fiscal Year 1999)
|Budget Amount *help
¥13,000,000 (Direct Cost : ¥13,000,000)
Fiscal Year 1999 : ¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 1998 : ¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 1997 : ¥6,000,000 (Direct Cost : ¥6,000,000)
|Keywords||Organocopper Compound / Bombesin Antagonist / SN2-type Ring-Opening / Alkene Isostere / Aziridinylenoate / Vinylaziridine / Organopalladium Compound / Allylpalladium Complex / トリプトファン・イソスター / トリプトフアン・イソスター|
1.We found a convenient method for the transformation of undesired anti-amino alcohols into desired cis-2-vinylaziridines, which are key synthetic intermediates for biologically active(E)-alkene peptide-isosteres, via trans-2-vinylaziridines by Pd(0)-catalyzed equilibration reaction.
2.Various cis-aziridine derivatives were efficiently synthesized from 4-alkyl-5-vinyloxazilidin-2-ones and β-aziridinyl-α, β-unsaturated esters by the Pd(0)-mediated equilibration reaction.
3.The ab initio calculations revealed that cis-β-aziridinyl-α, β-unsaturated esters, possessing cis-(E)-configuration, are more stable than their diastereoisomers. These results are compatible with the experimental results.
4.In combination with Pd(0)-mediated isomerization and the regio- and stereo-specific SN2-type ring-opening reactions of β-aziridinyl-α,β-unsaturated esters with Brφnsted acids, the completely stereocontrolled synthetic process for(L,L)-, (L,D)-, (D,D)-, and (D,L)-type(E)-alkene dipeptide isosteres starting from amino acids has been established.
5.Various peptide-isosteres containing Trp-, Asp-, Cys-, and Glu-analogues were synthesized by the reductive alkylation with organocopper reagents or by the nucleophilic alkylation with zinc-copper mixed reagents.
6.Several bombesin analogues with(E)-alkene bond were prepared by replacing a constituent amino acid of bombesin with the synthesized peptide-isosteres, and these compounds were revealed to be potent bombesin receptor antagonists.