1995 Fiscal Year Final Research Report Summary
Development of New Cysteine Proteinase Inhibitors Involving the Generation of Conjugated Allenyl Esters as the Latent Active Species
| Project/Area Number |
06453215
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Bioorganic chemistry
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| Research Institution | The University of Tokushima |
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Principal Investigator |
NAGAO Yoshimitsu The University of Tokusima, Fac. of Pharm.Sci., Professor, 薬学部, 教授 (40027074)
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| Co-Investigator(Kenkyū-buntansha) |
SANO Shigeki The University of Tokushima, Fac. of Pharm. Sci., Research Associate, 薬学部, 助手 (20226038)
KIHARA Masaru The University of Tokushima, Fac. of Pharm.Sci., Associate Professor, 薬学部, 助教授 (80035550)
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| Project Period (FY) |
1994 – 1995
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| Keywords | cathepsin / enzymatic inhibitor / alkynylmalonate / allenyl ester / cysteine proteinase / pyrrolinone / biomimetic reaction / enzymatic hydrolysis |
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| Research Abstract |
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.
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