Development of New Cysteine Proteinase Inhibitors Involving the Generation of Conjugated Allenyl Esters as the Latent Active Species

涉及生成共轭烯酯作为潜在活性物质的新型半胱氨酸蛋白酶抑制剂的开发

• 批准号: 06453215
• 负责人: NAGAO Yoshimitsu
• 金额: $ 2.82万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06453215/
• 关键词: cathepsin; enzymatic inhibitor; alkynylmalonate; allenyl ester; cysteine proteinase; pyrrolinone; biomimetic reaction; enzymatic hydrolysis; アレン; 酵素阻害剤; ペプチド; 生体模倣反応; マイケル型反応; チオール基

With the background of bioorganic chemistry of cysteine proteinases and on the basis of a series of studies on enzymatic and non-enzymatic chiral induction on to b-sysmmetric diesters and diamides by us, we envisaged dietthl alpha-alkynylmalonates (DAM) as new lead compounda for developing the cathepsin inhibitors. Enzymatic(with PLE) and alkaline hydrolyses of an ethoxycarbonyl group of various DAM derivatives followed by decarboxylation produced the corresponding allenylesters, which reacted chemoselectively with EtSH to give the thiol adducts. As we anticipated, these DAM derivatives exhibited significant inhibition in their 10^<-4>-10^<-5>M concentration order against the hydrolysis with cathepsins B and L in vitro. DAM-NH-L-Ile-Pro-CO_2H derivatives bearing the cathepsin B-recognition moiety inhibited the enzymatic hydrolysis with cathepsin B in their 10^<-6>-10^<-7>M concentration order. A new compound, pyrrolin-2-one-NH-L-Ile-L-Pro-CO_2H derived from the corresponding DAM-NH-L-Ile-L-Pro-CO_2H inhibited selectively theenzymatic action of cathepsin B at 1^<-7>M (91% inhibition). DAM-NH-L-Phe-NHBzl and pyrrolin-2-one-NH-L-Phe-NHBzl inhibited the enzymatic hydrolysis with cathepsin L in their 10^<-6>-10^<-7>M concentration order.

本论文以半胱氨酸蛋白酶的生物有机化学为背景，在我们对α-炔基丙二酸二乙酯（dietthl alpha-alkynylmalonates，DAM）对β-对称二酯和二酰胺的酶促和非酶促手性诱导研究的基础上，设想将其作为开发组织蛋白酶抑制剂的先导化合物。各种DAM衍生物的乙氧羰基的酶促（用PLE）和碱水解，然后脱羧产生相应的丙二烯基酯，其与EtSH化学选择性反应以得到硫醇加合物。正如我们所预期的，这些DAM衍生物在<-4><-5>体外对组织蛋白酶B和L的水解在其10^-10 ^M浓度级表现出显著的抑制作用。含组织蛋白酶B识别基团的DAM-NH-L-Ile-Pro-CO_2 H衍生物在10 ~ 10 μ M浓度范围内抑制组织蛋白酶B的酶促水解<-6><-7>。从相应的DAM-NH-L-Ile-L-Pro-CO_2 H衍生的新化合物吡咯啉-2-酮-NH-L-Ile-L-Pro-CO_2 H在1 μ M时选择性地抑制组织蛋白酶B的酶促作用<-7>（抑制率为91%）。DAM-NH-L-Phe-NHBzl和吡咯啉-2-酮-NH-L-Phe-NHBzl抑制组织蛋白酶L的酶促水解，其浓度顺序为10 μ <-6>M-10 μ <-7>M。

项目成果

Yoshimitsu Nagao: "New Intramolecular Spiro-Endo-Mode Ring Closure of Allenyl (Methoxy-Substituted Phenyl) alkyl Ketones" Tetrahedron Letters. 36. 2799-2802 (1995)

Yoshimitsu Nagao：“烯基（甲氧基取代的苯基）烷基酮的新型分子内螺内模式闭环”四面体字母。

Yoshimitsu Nagao: "New Intramolecular Five-Endo-Mode Cyclization of Allenyl Aryl Ketones" Chemistry Letters. 389-392 (1994)

Yoshimitsu Nagao：“烯基芳基酮的新分子内五内模式环化”化学快报。

Yoshimitsu Nagao: "New Six-toEight-Membered-Ring Formation Based on the Intramolecular Endo-Mode Ring Closure of Allenyl Ketones" Chemistry Letters. 597-600 (1994)

Yoshimitsu Nagao：“基于烯基酮分子内模式环闭合的新六至八元环形成”化学快报。

Yoshimitsu Nagao: "A New Ring Enlargement Reaction of gamma-Lactones to Seven-Membered Cyclic Ethers via Intramolecular Cyclisation of omega-Hydroxy Allenyl Ketone Intermediates in situ" J.Chem.Soc., Chemical. Communications. 19-20 (1996)

Yoshimitsu Nagao：“通过 omega-羟基烯基酮中间体的分子内环化将 γ-内酯原位扩环为七元环醚”J.Chem.Soc.，Chemical。

Yoshimitsu Nagao: "A New Ring Enlargement Reaction of γ-Lactones to Seven-Membered Cyclic Ethers via Intramolecular Cyclisation of ω-Hydroxy Alleyl Ketone Intermediates in situ" J. Chem. Soc., Chemical Communications. 19-20 (1996)

Yoshimitsu Nagao：“通过 ω-羟基烯基酮中间体原位分子内环化将 γ-内酯扩大到七元环醚”J. Chem.，化学通讯。