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.

在半胱氨酸蛋白酶的生物有机化学的背景下，我们基于我们对B型二聚体和二蛋白的一系列研究和非酶促性手性诱导的研究，我们设想将Dietthl Alpha-Alpha-alpha-allpha-Altallynylmalonates（Dam）（DAM）作为新的COMPOUNDA，用于开发CatterepsIns insepsin insepsin insepsin ins ins ins ins ins ins insepsin。各种大坝衍生物的乙氧基辅酶基团的酶促（带有PLE）和碱性水解产生了相应的艾烯基酯，它们与ETSH化学选择性反应以产生硫醇加合物。正如我们预期的那样，这些大坝衍生物在其10^<-4> -10^<-5> m的浓度顺序中表现出明显的抑制作用，以在体外用calterpsins b和l进行水解。带有组织蛋白酶B-识别部分的DAM-NH-L-ile-Pro-CO_2H衍生物在其10^<-6> -6> -10^<-7> m浓度顺序中抑制酶水解。一种新的化合物吡咯蛋白-2-烯-NH-L-li-l-PRO-CO_2H衍生自相应的DAM-NH-L-li-l-Pro-CO_2H，在1^<-7> m处有选择性地抑制组织蛋白酶B的酶作用（91％抑制）。 DAM-NH-L-PHE-NHBZL和吡咯蛋白-2-nh-L-l-PHE-NHBZL在其10^<-6> -10^<-7> m浓度顺序中抑制酶水解的酶水解。

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 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: "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: "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。