I. V. Martynov

Esterase profile and analysis of structure-inhibitor selectivity relationships for homologous phosphorylated 1-hydroperfluoroisopropanols

352 Organophosphorous compounds (OPCs) are widely used not only in agrochemical practice but are also cited in pharmacopoeias of many countries as drugs for treating schistosomiasis, glaucoma, and Alzheimer’s disease [1]. The physiological effect of such compounds is based on competitive interaction with serine esterases including the primary biological targets, such as acetylcholinesterase (AChE) [2], the target enzyme for the acute toxic effect of antiacetylcholinesterase compounds, and the neuropathy target esterase (NTE) [3], the target enzyme for organophosphate-induced delayed neurotoxicity, as well as the secondary biological targets, such as butyrylcholinesterase (BChE) and carboxylesterase (CaE). BChE and CaE are stoichiometric scavengers, interaction with which reduces the content of active phosphoryl compound at the toxicokinetic stage of development of biological response [4, 5]. The preferential binding of anticholinesterase compounds with one or another target esterase largely determines the resultant therapeutic or toxic effect of a given compound as well as the character and degree of expression of this effect.

Fluorinated α-aminophosphonates—a new type of irreversible inhibitors of serine hydrolases

The structural analogs of α -aminoacids, α -aminophosphonic acids and their esters, are widely studied as biologically active substances [1]. At the same time, among the numerous publications of the last twenty years there are only a few communications devoted to biological activity of fluorinated α -aminophosphonates, although it is well known that inclusion of fluorine atoms and fluorine-containing substituents into molecules of organic substances results in profound changes of chemical and physicochemical properties and, consequently, the biological activity of these substances. In particular, it was shown that some fluorinated esters and phosphin-oxides inhibited cholinesterases [2, 3] and thrombin [4], in contrast to their nonfluorinated analogues. In this paper, the results of studies of interaction of fluorinated α -aminophosphonates (FAPs, 3a ‐ 3h ) with four serine hydrolases are presented. Compounds 3a ‐ 3h were synthesized according to the scheme shown below:

Reactions of methyl trifluoropyruvate 2-pyridylimines with trimethyl phosphite

Reactions of methyl trifluoropyruvate 2-pyridylimines with trimethyl phosphite afford methyl 3-fluoroimidazo [1, 2-a]pyridine-2-carboxylates.

Fluorination of phosphorus(+3) derivatives by xenon difluoride

Abstract Xenon difluoride, XeF 2 , effectively fluorinates various phosphorous acid derivatives as well as hydrophosphoryl compounds. Arbuzov rearrangement is followed by i-Bu → t-Bu isomerization in the case of i-Bu OPF 2 .

Acylimines of hexafluoroacetone and methyl trifluoropyruvate in cyclocondensation with 2-aminothiazolines

Reactions of acylimines of hexafluoroacetone and methyl trifluoropyruvate with 2-aminothiazolines afforded fluorine-containing heterocycles of two structural types: 6,7-dihydro-2H-thiazolo[3,2-a][1,3,5]triazines and 2,3,5,6-tetrahydroimidazo[2,1-b]thiazoles.

Esterase profile of O-phosphorylated ethyltrifluorolactates in prediction of their therapeutic and toxic effects

81 The use of anticholinesterase compounds in medi cine, veterinary practice and agricultural chemistry is based on their common mechanism of action, which is determined by the inhibition of acetylcholinesterase (EC 3.1.1.7, AChE) [1]. Many cholinesterase inhibi tors, in addition to AChE, interact with other serine esterases, that can lead to both toxic and therapeutic effects [2]. Toxic and therapeutic effects resulting from the inhibition by organophosphorus compounds (OPCs) of four serine esterases—acetylcholinest erase, neuropathy target esterase (EC 3.1.1.5, NTE), butyrylcholinesterase (EC 3.1.1.7, BChE), and car boxylesterase (EC 3.1.1.1, CaE)—are shown in Scheme 1, where the effects that determine the toxic action of OPCs are shown in italic.

Arenesulfonylimines of methyl trifluoropyruvate in the cyclocondensation reactions with 1,3-C,N-and-N,N-binucleophiles

Reaction of arenesulfonylimines of methyl trifluoropyruvate with 1,3-C,N-and-N,N-binucleophiles led to a variety of N-sulfonylated fluorine-containing heterocycles, including the fused ones.

Acylimines of methyl trifluoropyruvate in cyclocondensation with C,N-bisnucleophiles

Reactions of acylimines of methyl trifluoropyruvate with C,N-bisnucleophiles gave fluoro-containing heterocycles including the 5-oxo-4,5-dihydro-1H-pyrrole fragment.

Reaction of 6-amino-1,3-dimethyluracil with hexafluoroacetone and ethyl trifluoropyruvate benzoylimines

Heating of 6-amino-1,3-dimethyluracil with hexafluoroacetone and ethyl trifluoropyruvate benzoylimines in DMF in the presence of Et3N results in 1,3-dimethyl-7-phenyl-5,5-bis(trifluoromethyl)-1,2,3,4,5,8-hexahydropyrimido[4,5-d]pyrimidine-2,4-dione and 5-benzoylamido-1,3-dimethyl-5-trifluoromethyl-1,2,3,4,5,6-hexahydropyrrolo[2,3-d]pyrimidine-2,4,6-trione, respectively.

A New Selective Inhibitor of Mouse Blood Plasma Carboxylesterase

1) are enzymes with a broad substrate specificity that catalyze hydroll ysis and esterification of a wide spectrum of structurr ally different exogenous and endogenous substances [1]. These enzymes play an important role in the metabolism of numerous therapeutically important compounds containing ester or amide groups. This accounts for therapeutic significance of CaE inhibii tors that influence the rate of hydrolysis of drugs behaving as CaE substrates and thereby determine the rate of drug conversion into active substance or proo long the halfflife of the latter in the body [2, 3]. Investigations of pharmacologically active preparaa tions, including preclinical trials, are conducted on rodents, which, unlike humans, have a high level of blood plasma CaE [4, 5]. Consequently, preparations with ester or amide groups are rapidly hydrolyzed in the rodent plasma, which decreases their effective concentration and creates difficulties in studying their pharmacological and toxicological properties as well in extrapolating the results of these studies to humans [6, 7]. Thus, it is a relevant task to search for comm pounds capable of inhibiting rodent plasma CaE in vivo and in vitro, having more prolonged effect irree versible inhibitors are more preferred. Low acute toxx icity of CaE inhibitors is also an important requiree ment when using in vivo. Application of such inhibii tors will make it possible to create an adequate rodent model for preclinical trials of pharmacological prepaa rations subject to hydrolysis by CaE [6]. Today, only one selective and irreversible CaE inhibitor, bissp nitrophenyl phosphate, is used both in tests on prepaa rations of rodent blood plasma and, in some cases, in experiments on rodents in vivo [8, 9]. Our previous kinetic studies with commercial prepaa rations of human red blood cells acetylcholinesterase (AChE, EC 3.1.1.7), horse serum butyrylcholinestt erase (BChE, EC 3.1.1.8), and porcine liver CaE showed that fluorineecontaining phosphates with a general formula of (AlkO) 2 P(O)OCH(CF 3) 2 had a selective effect on CaE, compared to AChE and BChE [10]. The leader compound (О,Оdibutyl))О 11trifluoromethyll2,2,22trifluoroethyl phosphate (nnС 4 H 9 O) 2 P(O)OCH(CF 3) 2 (DBFP) was irreversible effective and selective inhibitor of CaE: k i (CaE) = posed that DBFP may be effective as a selective inhibb itor of plasma CaE both in experiments with mouse blood preparations in vitro and upon systemic adminn istration in vivo. The purpose of this study was to test the potential of DBFP as an effective and selective …