Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/71200
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dc.contributor.authorLin, G.L.en_US
dc.contributor.authorLiu, Y.C.en_US
dc.contributor.authorWu, Y.G.en_US
dc.contributor.authorLee, Y.R.en_US
dc.date2003zh_TW
dc.date.accessioned2014-06-11T06:01:01Z-
dc.date.available2014-06-11T06:01:01Z-
dc.identifier.issn1611-020Xzh_TW
dc.identifier.urihttp://hdl.handle.net/11455/71200-
dc.description.abstractOrtho-substituted phenyl-N-butyl carbamates (1-11) are synthesized and evaluated for their inhibition effects on Pseudomonas species lipase. Carbamates 1-11 are characterized as pseudo-substrate inhibitors of the enzyme. The logarithms of dissociation constant (K-i), carbamylation constant (k(2)), and bimolecular inhibition constant (k(i)) multiply linearly correlate with Hammett substituent constant (sigma), Taft-Kutter-Hansch ortho steric constant (E-S), and Swan-Lupton field constant (F). For - logK(i)-, logk(2)-, and logk(i)-correlations, values of rho, delta, f rho(XR) are 0.2, -0.06, -1.7, 0.8; 0.0, 0.0, 1.0, -0.07; and -1.8, 7, 0.6, 5; respectively. The enzyme inhibition mechanism is composed of four steps: 1) the first step which is protonation of carbamates 1 - 11, 2) the second step (Ki,) which involves in the proton 1,3-shift of protonated carbamates 1-11 then the pseudo-trans to cis conformational change, 3) the third step (K-i2) which is formation of a negative charged enzyme-inhibitor tetrahedral intermediate, and 4) the fourth step (k(2)) which is the carbamylation step. The former three steps are likely composed of the K-i step. There is little ortho steric enhancement effect in the K-i step. From cross-interaction correlations, distance between carbamate and phenyl substituents in transition state for the K-i step is relatively short due to a large rho(XR) value of 7. The k(2) step is insensitive to ortho steric effect. The k(2) step involves in departure of leaving group, substituted phenol in which is protonated from the proton 1,3-shift but not from the active site histidine of the enzyme. From cross-interaction correlations, the distance between carbamate and phenyl substituents in transition state for the k(2) step is relatively long due to a small rho(XR) value of 0.6.en_US
dc.language.isoen_USzh_TW
dc.relationQsar & Combinatorial Scienceen_US
dc.relation.ispartofseriesQsar & Combinatorial Science, Volume 22, Issue 8, Page(s) 852-858.en_US
dc.relation.urihttp://dx.doi.org/10.1002/qsar.200330827en_US
dc.subjectQSARen_US
dc.subjectortho effectsen_US
dc.subjectcross-interactionsen_US
dc.subjectlipase inhibitionen_US
dc.subjectcarbamateen_US
dc.subjectinhibitorsen_US
dc.subjectstructure-reactivity relationshipsen_US
dc.subjectpancreatic cholesterol esteraseen_US
dc.subjectopen conformationen_US
dc.subjectbinding siteen_US
dc.subjectmechanismen_US
dc.subjectprobesen_US
dc.titleOrtho effects in quantitative structure activity relationships for lipase inhibition by aryl carbamatesen_US
dc.typeJournal Articlezh_TW
dc.identifier.doi10.1002/qsar.200330827zh_TW
item.languageiso639-1en_US-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.cerifentitytypePublications-
item.openairetypeJournal Article-
item.fulltextno fulltext-
item.grantfulltextnone-
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