Elena A. Popova

Medicinal chemistry of tetrazoles

Properties of responsible for biological activity tetrazoles are considered. Examples are given of active pharmaceutical ingredients of modern drugs containing the tetrazole ring in the molecular structure. New publications on the synthesis and investigations of biological activity of promising tetrazole-containing compounds are cited.

Kinetics of azidation of isomeric benzenedicarbonitriles

Rate constants and activation parameters of two-step azidation of isomeric dicyanobenzenes with dimethylammonium azide in DMF at 70–100°C were determined. Tetrazole rings are formed from cyano groups in dicyanobenzenes in a stepwise mode following the 1,3-dipolar cycloaddition pattern. The rate of azidation of isomeric dicyanobenzenes is considerably higher than the rate of subsequent azidation of intermediate cyanophenyltetrazolides. The azidation rate constant decrease in going from m-dicyanobenzene to its para and ortho isomers.

Synthesis of tetrazol-1-yl analogs of L-lysine and L-ornithine

Tetrazole group is known to be a promising pharmacophore that is widely used in designing highly efficient drugs [1, 2]. Tetrazolyl analogs of amino acids exhibit versatile biologic activity, and some of them are known pharmaceuticals [3]. Compounds of this type may be utilized in development of radiopharmaceuticals for positron emission tomography [4]. We have formerly demonstrated that natural diamino monocarboxylic acids are convenient substrates for the synthesis of the corresponding tetrazolyl analogs [5].

Tetrazole Derivatives as Promising Anticancer Agents

Tetrazole cycle is a promising pharmacophore fragment frequently used in the development of novel drugs. This moiety is a stable, practically non-metabolized bioisosteric analog of carboxylic, cis-amide, and other functional groups. Over recent 10-15 years, various isomeric forms of tetrazole (NH-unsubstituted, 1H-1- substituted, and 2H-2-substituted tetrazoles) have been successfully used in the design of promising anticancer drugs. Coordination compounds of transition metals containing tetrazoles as ligands, semisynthetic tetrazolyl derivatives of natural compounds (biogenic acids, peptides, steroids, combretastatin, etc.), 5-oxo and 5- thiotetrazoles, and some other related compounds have been recognized as promising antineoplastic agents. This review presents a comprehensive analysis of modern approaches to synthesis of these tetrazole derivatives as well as their biological (anticancer) properties. The most promising structure types of tetrazoles to be used as anticancer agents have been picked out.

Synthesis of new tetrazolyl derivatives of L- and D-phenylalanine

New tetrazolyl derivatives of L- and D-phenylalanine were synthesized by azidation of n-propyl esters of (2S)- and (2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(4-aminophenyl)propionic acids and by a series of subsequent chemical transformations. The structure and individuality of the compounds obtained were confirmed by using a complex of spectral and chromatographic methods.

Kinetics and mechanism of 1-phenyl-5-methyltetrazole nitration in HNO3–H2SO4 system

At nitration of 1-phenyl-5-methyltetrazole with nitric acid in aqueous solutions of sulfuric acid of 84–96% concentration a mixture forms of 1-(4-nitrophenyl)- and 1-(3-nitrophenyl)-5-methyltetrazoles in a ratio 60: 40. According to kinetic data, the tetrazole ring in the substrate is present in a protonated form. The protonation constants of 1-(4-carboxyphenyl)-5-methyltetrazole at the tetrazole ring and the carboxy group were determined. The Hammet’s electronic constant of the protonated tetrazole ring was calculated.

Quantitative studies of DNA binding with trans complexes of PtII and PdII featuring tetrazolylacetic acids and their derivatives as ligands

The interaction of calf thymus DNA (CT DNA) with trans-[PtCl2L2] and trans-[PdCl2L2] complexes (L–5-methyl-1H-tetrazol-1-ylacetic acid and its ethyl, butyl, and isobutyl esters; ethyl esters of 2-R-2H-tetrazol-5-ylacetic acids, R = But, CH2CH2OH) have been quantitatively studied by a spectrophotometric method. The binding constants (Kb) of the tetrazolecontaining coordination compounds with CT DNA at pH 7.2 and 298 K are in the range of (3.67–5.93)•105 mol L–1 for the PdII complexes and (7.82–13.30)•105 mol L–1 for and the PtII complexes, respectively. The Kb values, as well as negative values of ΔGb (–(31.7–34.9) kJ mol–1) indicate the effective binding between the studied complexes and CT DNA.

Enantioselectivity of the reaction of α-amino acids with sodium azide and triethyl orthoformate in the synthesis of tetrazoles

Tetrazolyl derivatives or analogs of amino acids are important pharmacophoric fragments in the design of new drugs [1, 2]. 1-Substituted 1H-tetrazoles can be synthesized by heterocyclization of primary amines with sodium azide and ortho esters [1, 3–6]. We previously reported the synthesis of natural amino acid analogs containing a 1H-tetrazol-1-yl fragment in the side chain at a considerable distance from the asymmetric carbon atom, so that their optical purity was retained [7, 8]. Such compounds were used, e.g., in the synthesis of peptidomimetics [8]. Voitekhovich et al. [9] described a procedure for the synthesis of tetrazol-1-ylacetic acid derivatives via reaction of α-amino acids with sodium azide and triethyl orthoformate. However, the optical purity of the products was not discussed. Taking into account that the amino group in α-amino acids is directly linked to the asymmetric carbon atom, the problem of enantioselectivity of such reactions remains unresolved. In this work we used enantiomerically pure Land D-amino acids and their benzyl esters 1a–1g to synthesize the corresponding 2-(1H-tetrazol-1-yl)acetic acids 2a–2g. The substrates were amino acids of different natures, including aliphatic and aromatic amino acids, amino dicarboxylic acid benzyl esters, and those containing an ester group in the side chain. The reactions were carried out by heating a mixture of amino acid derivative 1a–1g with sodium azide and triethyl orthoformate in glacial acetic acid at 55°C. All compounds 2, except for tryptophan analog 2g, were isolated in good yields. The product structure was confirmed by H and C NMR and mass spectra, and their enantiomeric purity was determined by HPLC. In the H NMR spectra of 2a–2g, the 5-H proton of the tetrazole ring resonated as a downfield singlet at δ 9.1–9.4 ppm, and the corresponding carbon signal was observed in the C NMR spectra at δC 144– ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 12, pp. 1863–1865.