Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) represents an attractive polyfunctional skeleton for development of biologically active compounds. The authors prepared a great variety of kojic acid derivatives and selected biological properties have been studied. Thus, kojic acid derivatives are promising compounds that might advantageously be used in human and/or veterinary medicine and also in preparation of new, even more biologically active preparations.

Some new pyridone aminophosphonic acids were synthesized from pyridone aldimines and tris(trimethylsilyl)phosphite. It was found that the obtained aminophosphonic acids 2 were cleaved in mineral acid solutions to form the corresponding amines 3 and phosphoric acid. Preliminary kinetic measurements were performed.

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) and analogues have been reported as biologically active compounds. Four kojic acid thiocyanato- and selenocyanatoanalogues have been prepared in order to investigate them for antineoplastic effects.

The stability of the new antileukemic kojic acid derivative, 5-benzyloxy-2-thiocyanatomethyl-4-pyranone (BTMP) was investigated. The degradation of BTMP was studied using specific and reproducible HPLC and LC-MS methods. Accelerated stability studies of BTMP were conducted in 0.1 M hydrochloric acid solution, physiological phosphate buffer solution (pH 7.5) and basic phosphate buffer solution (pH 9.0) at 30, 40 and 60 degrees C, respectively. The degradation of BTMP was found to follow pseudo-first order kinetics. In basic solution (pH 9.0) BTMP underwent rapid hydrolysis at a degradation rate constant (0.183-0.638 h-1) and degradation half-life (3.67-1.06 h) depending on the temperature setting. On the other hand, BTMP was significantly stable in 0.1 M hydrochloric acid solution (kdeg: 0.0017-0.0052 h-1; degradation half-life t1/2: 408.6-135.7 h), whereas in physiological phosphate buffer solution (pH 7.5), BTMP was only moderately stable (kdeg: 0.006-0.231 h-1; degradation half-life: 117.7-3.0 h). Arrhenius plots were constructed to predict the degradation kinetic parameters of BTMP at 25 degrees C and 4 degrees C. LC-MS analyses confirmed the degradation of BTMP in basic solutions and indicated at least two degradation products; namely 5-benzyloxypyran-2-ol-4-one (m/z 217.8) and 2-thiocyanatomethylpyran-5-ol-4-one (m/z 181.6).

Heterocyclic derivatives of aminomethylphosphonic acid were obtained in a one-pot procedure, by treatment of the corresponding heterocyclic aldimines with a mixture of trimethyl phosphite and bromotrimethylsilane (BrTMS). A reagent for phosphorylation of the imines in this case was the tris(trimethylsilyl)phosphite, formed in Sial in a reaction mixture. The silylated esters formed were hydrolyzed to the final aminophosphonic acids.

The present study was undertaken to investigate the effects of eight halogen derivatives of 5-hydroxy-2-hydroxymethyl-4-pyranone on a) neoplastic cell growth, b) DNA, RNA, and protein synthesis c) cytoplasmic phosphorylation, and d) cAMP accumulation in culture medium. Two neoplastic cell lines (the murine leukemia L1210 and the rat pituitary GH(4)C(1) were used in the present study. The inhibitory effects of the halogen derivatives on GH(4)C(1) cell division when compared to L1210 cells were found to be almost equal. Two halogen derivatives (2-chloromethyl-5-hydroxy-4-pyranone and 6-bromo-5-hydroxy-2-hydroxymethyl-4-pyranone) were found to inhibit DNA, RNA and protein synthesis. Moreover, the electrophoretic profile of low molecular mass cytoplasmic proteins was markedly influenced by certain halogen derivatives of 5-hydroxy-hydroxymethyl-4-pyranone in L1210 cells.

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The previously published model of the model-based quantitative structure-time-activity relationship (QSTAR) for growth inhibitory activity of nonionizable series of kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyrane-4-one) derivatives against Escherichia coli has been extended for the complete set consisting of 21 nonionizable and 14 ionizable compounds. The inhibitory activity has been characterized by the isoeffective concentrations causing 50%-decrease in the specific growth rate in comparison with the untreated control after the five exposure periods in 7 media differing in their pH values (pH 5.6-8.0). For an acceptable fit of the model to the data the receptor binding of both ionized and nonionized molecules had to be considered and the model modified accordingly. The model describes the toxicity of the tested compounds as an explicit non-linear function of hydrophobicity, pKa values, the size of the substituent in the position 2, the pH values of the external media, and the time of exposure. The results can be interpreted as follows. Elimination as well as binding to the receptor have been positively influenced by both size of the molecules and ionization. The ionized molecules exhibit about 2.6 x 10(3) stronger binding to the receptors than their nonionized counterparts. The QSTAR model can be used for rational development of more effective derivatives.

The present study was undertaken to prepare a novel 4-pyranone compound 5-benzylaxy-2-thiocyanatomethyl-4-pyranone as well as to investigate its effects on neoplastic cell growth. Three cell lines (murine leukemia L1210, human leukemia K562 and rat pituitary GH4C1 cells) were used in our experiments. The cell growth, DNA, RNA, protein synthesis, and cytoplasmatic protein phosphorylation after the treatment of GH4C1 cells with 5-benzyloxy-2-thiocyanatomethyl-4-pyranone were investigated. We found that the above new 4-pyranone derivative at 2.6 microM significantly (p < 0.05) inhibits neoplastic cell growth, and inhibits (p < 0.05) DNA synthesis.

Several 1,2-disubstituted gamma-pyridone derivatives have been synthesized by reaction of kojic acid and its derivatives with primary amines and amino acids. The synthesis of tricyclic compounds 2-alkoxy-5H-benzo[e]pyrido[2,1-c][1,4]oxazepine-3,7-diones and 3-alkoxypyrido[1,2-a]indole-2,10-diones is described. H-1 and C-13 NMR, IR, UV, and mass spectra are presented.

A number of heterocyclic aldehydes were transformed via their NN-dimethythydrazones to nitriles in high yields using a one-pot procedure.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Polarographic properties of kojic acid [5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one] and 10 of their synthetic derivatives were investigated. It was shown that these compounds are reduced in anhydrous conditions, usually in one two-electron step or in two one-electron steps. The presence of some substituents may change the course of reduction process. The polarography of these compounds in the presence of alpha-lipoic acid showed the kojic acid analog-alpha-lipoic acid complex formation. The determined potential carcinogenic activity of these compounds expressed as a parameter tg alpha is not substantial.

A semi-empirical model for quantitative structure-time-activity relationships (QSTAR) has been applied to the data on inhibition of Escherichia call in a batch culture in seven media of different acidity (pH 5.6-8.0) by twenty one nonionizable derivatives of kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyrane-4-one). The antibacterial potency of individual derivatives was characterized by the equieffective concentrations causing the 50%-decrease in the specific growth rate in comparison with the untreated control. The QSTAR models satisfactorily describe toxicity of the studied compounds as a model-based non-linear function of hydrophobicity, the size of the substituents in the position 2, and the time of exposure. The dependence of the antibacterial activity on hydrophobicity at a fixed exposure time exhibits a broad maximum: the decrease for hydrophilic compounds is caused by their diminished ability for binding to the receptors and that for hydrophobic compounds is elicited by their lower concentrations in the aqueous phases and their slower inactivation. Inactivation is probably enzymatic because its rate depends on the size of the molecules. The size has a positive effect also on the binding to the receptor.

It has been revealed that N,N-dimethylhydrazones (1a-c, 3a,b) derived from kojic acid analogs, such as substituted furans (3a,b), 4-pyrones (1a,b) and 4-pyridine (1c), on oxididation with 3-chloroperoxybenzoic acid afford the corresponding nitriles (2a-c, 4a,b). The method has preparative value. The mechanism of the reaction is presented.

In this contribution there is described the reaction of 2-chloromethyl-5-hydroxy-4H-pyran-4-one with secondary amines. Apart from the products of nucleophilic substitution, e.g. 2-aminomethyl derivatives of kojic acid and also 2-amino-6-methyl derivatives of the same compound were obtained. In the case when hydroxylic group in the position 5 was substituted, the result of the reaction was only 2-aminomethyl derivative.

In a search for new compounds possessing antitumor activity, we examined the effects of a group of oxygen containing heterocyclic derivatives on L1210 murine leukemia cell growth. Several 5-hydroxy-2-hydroxymethyl-4-pyranone derivatives were tested in a growth assay employing a human leukemia K562 cells line. IC50 was extrapolated from the growth inhibition curves at compound concentrations ranging from 0.1 to 100 microM. The halogen derivatives of 5-hydroxy-2-hydroxymethyl-4-pyranone inhibited L1210 cell growth in suspension culture after 96 hr incubation in the following order: 5-hydroxy-2-iodomethyl-4-pyranone (IC50 3.15 microM) > 6-bromo-2-bromomethyl-5-hydroxy-4-pyranone (IC50 3.40 microM) > 6-bromo-5-hydroxy-2-hydroxy-methyl-4-pyranone (IC50 3.75 microM) > 2-bromomethyl-5-hydroxy-4-pyranone (IC50 4.30 microM) > 5-benzyloxy-2-chloromethyl-4-pyranone (IC50 5 microM) > 6-bromo-2-chloromethyl-4-pyranone (IC50 13.50 microM) > 6-chloro-2-chloromethyl-5-hydroxy-4-pyranone (IC50 18 microM) > 2-chloromethyl-5-hydroxy-4-pyranone (IC50 20 microM). The compound, 5-hydroxy-2-hydroxymethyl-4-pyranone has no effect on L1210 cell growth. These results suggest that 5-hydroxy-2-hydroxymethyl-4-pyranone derivatives might represent a new class of compounds with antileukemic activity.

The paper presents a study of oxidations of the primary alcohol group in position 2 of 5-substituted 4-oxo-4H-pyran ring. Some reactions of created carboxylic acids were investigated as well.

Synthesis of new 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one (kojic acid) via reaction of its 2-halomethyl derivatives with salts of N,N-dialkyldithiocarbamic acid, O-alkyl esters, and O,S-dialkyl esters of dithiophosphoric acid is described. Biological screening of synthesized compounds was performed.