T. I. Osipova

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.

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.

Crystal structure of mutant form Cys115His of Citrobacter freundii methionine γ-lyase complexed with l-norleucine

The mutant form of Citrobacter freundii methionine γ-lyase with the replacement of active site Cys115 for His has been found to be inactive in the γ-elimination reaction of methionine while fully active in the γ-elimination reaction of O-acetyl-l-homoserine and in the β-elimination reaction of S-alk(en)yl-substituted cysteines. In this work, the crystal structure of the mutant enzyme complexed with competitive inhibitor, l-norleucine was determined at 1.45Å resolution. At the enzyme active site the inhibitor proved to be bound both noncovalently and covalently, which corresponds to the two intermediates of the γ- and β-elimination reactions, Michaelis complex and the external aldimine. Analysis of the structure allowed us to suggest the possible reason for the inability of the mutant enzyme to catalyze the physiological reaction.

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.