Yu. N. Zhukov

Inhibition of pigeon breast muscle α-ketoglutarate dehydrogenase by phosphonate analogues of α-ketoglutarate

Succinylphosphonate (SP) is a powerful inhibitor or α‐ketoglutarate dehydrogenase (KGD). Methylation of the phosphonate reduces its inhibitory effect. The complex of KGD with SP undergoes a kinetically slow transition similar to the process observed during catalysis. α‐Ketoglutarate binds to the enzyme—inhibitor complex, preventing its isomerisation.

Succinyl phosphonate inhibits α-ketoglutarate oxidative decarboxylation, catalyzed by α-ketoglutarate dehydrogenase complexes from E. coli and pigeon breast muscle

Effects of a set of α‐ketoglutarate phosphoanalogues on the activity of α‐ketoglutarate dehydrogenase (EC 1.2.4.2) complexes from E. coli and pigeon breast muscle, as well as on α‐ketoglutarate dehydrogenase isolated from the pigeon breast muscle, have been studied. α‐Ketoglutarate phosphoanalogues (succinyl phosphonate and its monomethyl ester) were found to be effective inhibitors of α‐ketoglutarate oxidative decarboxylation, catalyzed by both muscle and bacterial α‐ketoglutarate dehydrogenase complexes, as well as muscle α‐ketoglutarate dehydrogenase. The ability of glutamate phosphoanalogues to inhibit α‐ketoglutarate oxidative decarboxylation has been shown in E. coli extract and a model system.

Synthesis of (α-substituted α-aminophosphinic and α-aminophosphonic acids

The reaction of ketoximes with hypophosphorous acid resulted in previously unknown α-substituted-α-aminophosphinic acids, which were oxidized into the corresponding α-substituted-α-aminophosphonic acids.

Synthesis of phosphinic and phosphonic analogs of aromatic amino acids

The reaction of aryl and aralkyl aldoximes with hypophosphorous acid resulted in aminophosphinic acids, which were oxidized into the corresponding aminophosphonic acids.

Organophosphorus analogs of biologically active compounds

Conclusions1.A new method has been proposed for the synthesis of α-amino- and α-alkylaminophosphonic acids.2.N-formyl, N-trifluoroacetyl, and N-carbobenzoxy derivatives of α-aminophosphonic acids were synthesized.3.Methods were developed for obtaining monoesters of α-aminophosphonic acids.4.Formation of pyridoxamine from pyridoxal and α-aminoisobutylphosphonic acid was not found under conditions for nonenzymatic transamination.

Aminoalkythiophosphonates: a new type of biologically active compounds.

The broad family of natural and synthetic organophosphorous analogues of amino acids includes a large group of compounds classified with phosphinic 1 and phosphonic 2 acids (scheme 1 ), whose diverse physiological activity is determined by their effect on amino acid exchange and depends on the structure of the phosphorus-containing fragment. For example, substitution of the monobasic carboxyl group of an amino acid with the monobasic P(O)(OH)H group does not qualitatively affect the affinity of aminoalkylphosphinates 1 for enzymes involved in amino acid exchange and the ability of these isosteres of amino acids for substrate transformations, as well as does not prevent their permeation across microbial cell walls [1]. In aminoalkylphosphonates 2 , the dibasic phosphonate group significantly differs in size, molecular geometry, and acidity from the carboxyl group of amino acids, making the concept of the direct structural similarity between phosphonates 2 and amino acids fairly formal [2]. However, the structure of phosphonates 2 allows them to be considered as stable analogues of labile transient states or intermediate compounds in enzymatic transformations of amino acids [3, 4]. This led to occurrence of novel inhibitors of enzymes involved in amino acid exchange and haptens for designing catalytic antibodies. Thus, modification of the phosphorus-containing fragment may induce changes in the basic biochemical characteristics of phosphorous analogues, as is observed in the case of phosphinates 1 and phosphonates 2 .

Synthesis of phosphinic and phosphonic analogs of homoserine

A convenient procedure for the synthesis of 1-amino-3-hydroxypropylphosphinic and -phosphonic acids (analogs of homoserine) was developed. The procedure involves the reaction of salts of phosphinic and phosphonic analogs of S-methylmethionine with AcONa/AcOH followed by hydrolysis.

Aminoalkylphosphinates Are New Effective Inhibitors of Melanogenesis and Fungicides

Phytopathogenic fungi exhibit high resistance to extremal environmental conditions, which is largely determined by protective properties of high-molecularweight pigments of different composition contained in them. Melanin of cell walls of the pathogen Magnaporthe grisea that causes blast disease of rise is classified in the widespread type of pigments; it represents a colored polymer of 1,8-dihydroxynaphthalene, the biosynthesis of which depends on acetyl-CoA (the pentaketide pathway) [1]. Analysis of the strains of this fungus defective in pigmentation, which were obtained by induced mutagenesis, showed that blockade of the biosynthesis of melanin attenuates the ability of the fungus to penetrate into leaf tissues and prevents excrescence of the mycelium in the plant, thereby suppressing its pathogenicity [2]. One of the most effective preparations that are used for fighting against blast disease of rice, tricyclazole 1 (Scheme 1), is classified with a small group of fungicides of similar structure, the effect of which is related to selective blockade of the synthesis of the pigment [1]. Another type of inhibitors, which has been represented so far only by the organophosphorous analogue of alanine 2.1 , suppresses the biosynthesis of not only melanin but also other metabolites of the polyketide pathway (including phytotoxins) and exhibits fungitoxicity [3]. In contrast to tricyclazole, which is effective per se , analogue 2.1 is the precursor of the active compound, pyruvate analogue 3.1 , which suppresses the synthesis of acetyl-CoA and melanin (Scheme 2) [4]. A similar mechanism was suggested for the blockade with analogue 2.1 of formation of plant polyketide pigment [5].

SYNTHESIS OF α‐KETOPHOSPHONIC ACIDS

1. α-Ketophosphonic acids are synthesized by hydrogenation of their benzyl esters. 2. The possibility of nonenzymatic transamination of α-ketophosphonic acids without rupure of the C-P bond is shown.

Fungicidal Activity of Phosphinic Analogues of Amino Acids Involved in Methionine Metabolism

In medicine and agriculture, the necessity of rationally planning attempts to find for new biologically active chemical compounds because of a tendency towards a reduction in the rate of the introduction of new products [1]. The conventional approach, based on accidental discovery of new preparations with their subsequent chemical optimization, has proven to be inefficient. With respect to pesticides, it implies synthesis and testing of 10000–15000 compounds in order to develop a single valuable preparation, i.e., this approach is time-consuming and expensive. Using the example of a new kind of fungicide, we have shown in this study that a rational search for biologically active compounds may be based on a system of chemical regulators of certain metabolic pathways. This new approach is much more efficient.