S. P. Ivanov

Physicochemical Properties and Pharmacological Activity of Mn(II), Fe(II), Co(II), Cu(II), AND Zn(II) Gluconates

The well-known antitumor drugs suppress the immune system to different degrees [1]. It is therefore important to find substances possessing, in addition to antitumor activity, immunotropic properties. Of special interest in this respect are compounds of d-elements, an imbalance of which is known to accompany various pathological processes, including tumor growth [2 – 4]. The coordination compounds of these metals possess both immunomodulant properties [5 – 7] and cytotoxic activity [8 – 10]. It was reported that 3d-metal gluconates are effective correctors in some pathological states [11 – 14]. For this reason, we have synthesized gluconates of Mn, Fe, Co, Cu, and Zn (compounds I – V, respectively), determined some physicochemical properties of these compounds, and evaluated their cytotoxic and immunotropic activity. The compositions of gluconates I – V correspond to the general formula M(C6H11O7)2 2H2O, where M = Mn(II), Fe(II), Co(II), Cu(II), and Zn(II). The synthesized compounds were characterized by spectroscopic methods, thermogravimetric (TGA) and elemental analyses, and conductivity measurements in aqueous solutions. The IR absorption spectra of the synthesized compounds were analyzed in comparison to the spectra of the initial reagent, gluconic acid (VI), and the reference drug – calcium gluconate (VII). The IR spectra of metal gluconates display a strong absorption band at 1600 – 1588 cm – 1 and a medium-intensity band 1400 – 1420 cm – , corresponding to the antisymmetric and symmetric stretching vibrations of the carboxylate ion, respectively. In contrast, the spectrum of acid VI exhibits an absorption band at 1740 cm – , assigned to C=O of the COOH group. The formation of metal gluconates is always accompanied by almost complete vanishing of the absorption band at 1190 cm – 1 belonging to bending vibrations of the carboxy (C–O) group [15]. The absorption bands of bending vibrations of the secondary hydroxy groups OH, which are observed at 1220 – 1300 cm – 1 in the spectrum of calcium gluconate, shift to 1350 – 1400 cm – 1 in the spectra of compounds I – V. Significant differences between the IR spectra of gluconates and the spectra of gluconic acid and calcium gluconate are also observed for C–O of the secondary carboxy groups in the region of 1080 – 1135 cm – 1 and for their skeletal vibrations at 1000 – 1080 cm – 1 (Fig. 1). These distinctions indicate that these groups are involved in the formation of donor – acceptor groups with d-metal ions. Larsson [16] explained the observed character of absorption in this region by the formation of a chelate ring upon the complexation of d-elements with oxy acids. The results of C NMR measurements showed (Table 1) that this binding is mediated by the oxygen atom of a hydroxy group at the third carbon atom. This conclusion is confirmed by stereochemical considerations. Calculations by the AMPAK program using the AM-1 method, as well as the published data [17], indicate that the structure of molecule VI contains a fragment convenient for the formation of a six-member chelate cycle involving oxygen atoms of the carboxy group and the hydroxy group at the third carbon atom.

Synthesis of Methyl-Substituted Derivatives of 5-Hydroxy-6-methyluracil

Abstract5-Hydroxy-3,6-dimethyluracil, 5-methoxy-1,3,6-trimethyluracil, earlier unknown 5-methoxy-6- methyluracil, 5-methoxy-1,6-dimethyluracil, and 5-methoxy-3,6-dimethyluracil have been synthesized via alkylation of 5-hydroxy-6-methyluracil with dimethylsulfate in aqueous-alkaline media. The obtained compounds have been identified using 1Н, 13С, and 15N NMR spectroscopy.

Synthesis, Biological Activity, and Mechanism of Action of Mono-Substituted 5-Halouracil Salts

Mono-substituted sodium salts of 5-fluoro-, 5-chloro-, 5-bromo-, and 5-iodouracil were synthesized. The toxicity and effect of the synthesized compounds on the DNA-binding activity of transcription factors CREB, NFAT, NF-κB, p53, STAT1, GAS, VDR, HSF1, and HIF1á were studied. It was found that the sodium salts of 5-chloro-, 5-bromo-, and 5-iodouracil did not exhibit cytotoxicity comparable with that of the sodium salt of 5-fluorouracil.

Acid-Base Equilibrium of 5-Methoxy-6-methyluracil in Solutions: Evaluation of Content of Anionic Forms in Aqueous Alkaline Solution

Dissociation constants of 5-methoxy-6-methyluracil, 5-methoxy-1,6-dimethyluracil and 5-methoxy-3,6-dimethyluracil in water are determined. Basing on the obtained рKа1 values, the content of anions in aqueous alkaline solution of 5-methoxy-6-methyluracil was calculated. The results were confirmed by the use of model compounds: 5-methoxy-1,6-dimethyluracil and 5-methoxy-3,6-dimethyluracil using the NMR spectroscopy.