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2.
Bioorg Khim ; 25(1): 3-7, 1999 Jan.
Article in Russian | MEDLINE | ID: mdl-10234439

ABSTRACT

The interaction kinetics of potential pesticides, O,O-dialkyl S-bromomethylthiophosphates (RO)2P(O) SCH2Br (R = Et, i-Pr, n-Pr, n-Bu, or n-Am) with acetylcholinesterase, butyryl cholinesterase, and carboxyl esterase from warm-blooded animals was studied. All the compounds irreversibly inhibit these esterases, with k1 (M-1 min-1) being 1.8 x 10(4) - 1.9 x 10(6) for acetylcholinesterase, 2.0 x 10(6) - 4.1 x 10(7) for the more sensitive butyryl cholinesterase, and 2.3 x 10(7) - 2.3 x 10(8) and higher for the most sensitive carboxyl esterase. By using the Hansch and Kubinyi technique of multiple regression analysis, we quantitatively analyzed the relationship between the structure and inhibiting activity of these substances toward acetylcholinesterase and butyryl cholinesterase. Hydrophobic interactions were found to be important for the inhibition of both enzymes but are more pronounced in the case of butyryl cholinesterase. On the other hand, steric factors were much more significant in the inhibition of acetylcholinesterase. For both enzymes, the steric hindrances affect the phosphorylation stage of the enzyme.


Subject(s)
Carboxylic Ester Hydrolases/antagonists & inhibitors , Cholinesterase Inhibitors/chemistry , Enzyme Inhibitors/chemistry , Insecticides/chemistry , Organothiophosphorus Compounds , Animals , Carboxylesterase , Horses , Humans , Kinetics , Structure-Activity Relationship , Swine
3.
Bioorg Khim ; 25(1): 8-13, 1999 Jan.
Article in Russian | MEDLINE | ID: mdl-10234440

ABSTRACT

The interaction of potential pesticides, O,O-dialkyl S-ethoxycarbonylbromomethylthiophosphates (RO)2P(O)SCH(Br)COOC2H5 (R = Et, i-Pr, n-Pr, n-Bu, n-Am, or n-Hx) with the esterases of warm-blooded animals [acetylcholinesterase (ACE), butyryl cholinesterase (BCE), and carboxyl esterase (CE)] was studied. The acute toxicities of these compounds for mice were determined. All the compounds were non-hydrolyzable by CE and capable of irreversible inhibition of all these esterases with ki (M-1 min-1) of 1.2 x 10(5)-6 x 10(6), 2.0 x 10(6)-1.5 x 10(8), and 2.0 x 10(8), respectively. By using multiple regression analysis, we found that the steric factor plays a significant role in the inhibition of ACE, with the steric hindrances manifesting themselves even at the sorption stage. On the other hand, hydrophobic interactions predominate in the case of BCE, while steric properties of its substituents exert a markedly weaker effect and manifest themselves at the phosphorylation stage. We suggested the presence of an electrophilic region in the active site of ACE, which can interact with the ethoxycarbonyl group of the thiophosphates under study. The decrease in toxicities and the affinities to BCE and CE were found to correlate with an increase in the length of n-alkyl substituents of the compounds studied. This suggests that the unspecific esterases play a significant role as a buffer system in the exhibition of toxic effects by the thiophosphates under consideration.


Subject(s)
Cholinesterase Inhibitors/toxicity , Insecticides/toxicity , Organothiophosphorus Compounds , Animals , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Horses , Humans , Insecticides/chemical synthesis , Insecticides/chemistry , Lethal Dose 50 , Mice , Structure-Activity Relationship
5.
Izv Akad Nauk SSSR Biol ; (6): 831-7, 1989.
Article in Russian | MEDLINE | ID: mdl-2621279

ABSTRACT

The effect of exchange of 15-hydroxyl for fluor on biological activity of PGF2 alpha and PGE2 on isolated smooth muscles of different organs has been studied. The exchange leads to significant increase in contractile (100-fold) and relaxation (1000-fold) activity of PGF2 alpha on smooth respiratory muscles. At the same time, the effect of 15-fluor-15-deoxyprostaglandin F2 alpha on smooth muscles of intestinal and vascular tracts did not differ from that of PGF2 alpha. Similar modification of PGE2 led to the decrease (10-fold) both in contractile and relaxation activity on all studied types of smooth muscles. The data obtained have been discussed within the boundaries of prostanoid receptor classification (Kennedy, 1982). Fluor derivative of PGF2 alpha may be used for pharmacological differentiation of EP-receptors.


Subject(s)
Dinoprost/analogs & derivatives , Dinoprostone/analogs & derivatives , Muscle, Smooth/drug effects , Animals , Cricetinae , Dinoprost/pharmacology , Dinoprostone/pharmacology , Dose-Response Relationship, Drug , Guinea Pigs , In Vitro Techniques , Male , Mesocricetus , Muscle Contraction/drug effects , Rats , Structure-Activity Relationship
6.
Bioorg Khim ; 15(7): 987-9, 1989 Jul.
Article in Russian | MEDLINE | ID: mdl-2510738

ABSTRACT

Influence of O,O,-diethyl-1-(N-alpha-hydrohexafluoroisobutyryl)amino-1- methylpropylphosphonate and O,O-diisobutyl-1-[2-(ethoxycarbonyl)aminoperfluoroprop-2-yl] -1- methylpropylphosphonate on the level of production of human proinsulin secreted by a genetically engineered culture Bacillus subtilis AJ 73 (pBINS1.0.) has been studied. The above phosphonates, being non-toxic for microorganisms, reduced degradation of proinsulin by serine proteinases.


Subject(s)
Bacillus subtilis/metabolism , Proinsulin/biosynthesis , Protease Inhibitors/pharmacology , Animals , Genetic Engineering , Humans , Insulin Antagonists , Recombinant Proteins/biosynthesis , Swine
8.
Bioorg Khim ; 13(1): 33-7, 1987 Jan.
Article in Russian | MEDLINE | ID: mdl-3566818

ABSTRACT

The interaction of dialkyl (alpha-carbometoxy-beta,beta,beta-trifluoroethyl) phosphates (RO)2P(O) . OCH(CF3)COOMe (R = Me, Et, Pr, Pri, Bu, Bui, Am, Hex) (I-VIII) with human erythrocyte acetylcholinesterase, horse serum butyrylcholinesterase, pig liver carboxylesterase was studied and acute toxicity in mice was estimated. Compounds (I)-(VIII) were not hydrolyzed by carboxylesterase, slowly and irreversibly inhibited acetylcholinesterase (kII = 10(2)-10(4) M-1 X min-1) and more efficiently inhibited butyrylcholinesterase and carboxylesterase (kII = 10(3)-10(7) M-1 X min-1). The structure--antienzymatic activity relationships were investigated. With increasing of hydrophobicity of alkoxy groups, antienzymatic activity to butyrylcholinesterase and carboxylesterase ("sites of loss") rises equally and more significantly, than antiacetylcholinesterase activity (delta lg kII 1.0 and 2.4 for R = CH3 and C5H11 resp.). Branching at the alpha-position of alkoxy groups leads to sharp reducing of acetylcholinesterase and butyrylcholinesterase inhibition constants, the carboxylesterase inhibition mechanism becoming reversible. Multiple regression analysis (the Kubinyi model) showed that influence of steric hindrances is revealed at the phosphorylation stage. It was found that phosphates (I)-(VIII) possess low acute toxicity in mice (900-2000 mg/kg). The toxicity of this homologous series appears to be independent of the hydrophobicity. Role of esterases in toxicological effect of compounds (I)-(VIII) is discussed.


Subject(s)
Cholinesterase Inhibitors , Organophosphorus Compounds/pharmacology , Acetylcholinesterase/metabolism , Animals , Carboxylesterase , Carboxylic Ester Hydrolases/metabolism , Cholinesterase Inhibitors/metabolism , Cholinesterase Inhibitors/toxicity , Cholinesterases/metabolism , Erythrocytes/enzymology , Horses , Humans , Hydrolysis , In Vitro Techniques , Kinetics , Lethal Dose 50 , Liver/enzymology , Mice , Organophosphorus Compounds/metabolism , Organophosphorus Compounds/toxicity , Swine
9.
Bioorg Khim ; 10(10): 1347-52, 1984 Oct.
Article in Russian | MEDLINE | ID: mdl-6517964

ABSTRACT

The interaction of human erythrocyte acetylcholinesterase, horse serum butyrylcholinesterase and rat liver carboxylesterase with insecticides (RO)2P(O)SCH(COOEt)SP(O)(OR)2 (I) and (RO)2P(O)SCH(COOEt)OP(S)(OR)2 (II) was studied. The type I and II compounds were not hydrolyzed by carboxylesterase and inhibited the esterases irreversibly. A complex pattern of inhibition of acetylcholinesterase and butyrylcholinesterase by these compounds was caused by kinetically-manifested formation of an enzyme-inhibitor complex. The compounds I and II were more selective towards butyrylcholinesterase than towards acetylcholinesterase and carboxylesterase (kII two orders of magnitude higher) because of effective binding in the butyrylcholinesterase active center (K alpha 10(-8)--10(-9) M) due to hydrophobic interaction. An important role of the thion-phosphoryl-containing fragment in the interaction of type II compounds with hydrophobic sites of butyrylcholinesterase and carboxylesterase active centers was established.


Subject(s)
Cholinesterase Inhibitors/chemical synthesis , Insecticides/chemical synthesis , Organothiophosphorus Compounds , Acetylcholinesterase/blood , Animals , Butyrylcholinesterase/blood , Carboxylic Ester Hydrolases/antagonists & inhibitors , Chemical Phenomena , Chemistry , Cholinesterase Inhibitors/pharmacology , Erythrocytes/enzymology , Horses , Humans , Insecticides/pharmacology , Kinetics , Liver/enzymology , Rats
10.
Bioorg Khim ; 10(10): 1353-8, 1984 Oct.
Article in Russian | MEDLINE | ID: mdl-6517965

ABSTRACT

The dependence of antiesteratic activity on the structure of insecticides (RO)2P(O)SCH(COOEt)SP(O)(OR)2 (I) and (RO)2P(O)SCH(COOEt)OP(S)(OR)2 (II) was examined. Nonlinear regression equations (parabolic and bilinear) "hydrophobicity-antiesteratic activity" were derived. Basing on the studies of the relationships between hydrophobicity and individual constants, the detailed mechanisms were proposed for the interaction of type (I) and (II) compounds with the esterase active centers. The mechanisms implicate different kinds of sorbtion for compounds of type I and II. Applicability of bilinear models, similar to that of Kubinyi type, for analyzing the structure-antienzyme activity dependences was demonstrated. Thus, several equations were obtained starting from the literature data on inhibition of esterases with diverse organophosphorus compounds.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Organophosphorus Compounds/pharmacology , Acetylcholinesterase/blood , Animals , Butyrylcholinesterase/blood , Carboxylesterase , Carboxylic Ester Hydrolases/antagonists & inhibitors , Chemical Phenomena , Chemistry, Physical , Erythrocytes/enzymology , Horses , Humans , Kinetics , Liver/enzymology , Models, Biological , Rats
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