Continuing our research in the field of new heterocyclic compounds, herein we report on the synthesis and antitumor activity of new amino derivatives of pyrido[3′,2′:4,5](furo)thieno[3,2-d]pyrimidines as well as of two new heterocyclic systems: furo[2–e]imidazo[1,2-c]pyrimidine and furo[2,3-e]pyrimido[1,2-c]pyrimidine. Thus, by refluxing the 8-chloro derivatives of pyrido[3′,2′:4,5]thieno(furo)[3,2-d]pyrimidines with various amines, the relevant pyrido[3′,2′:4,5]thieno(furo)[3,2-d]pyrimidin-8-amines were obtained. Further, the cyclization of some amines under the action of phosphorus oxychloride led to the formation of new heterorings: imidazo[1,2-c]pyrimidine and pyrimido[1,2-c]pyrimidine. The possible antitumor activity of the newly synthesized compounds was evaluated in vitro. The biological tests evidenced that some of them showed pronounced antitumor activity. A study of the structure–activity relationships revealed that the compound activity depended mostly on the nature of the amine fragments. A docking analysis was also performed for the most active compounds.

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Unlike now widely used traditional methods of treatment of tumors by means of ionizing radiation and the chemotherapy, the method of the use of low intensity electromagnetic fields (EMF) is non-ionizing and noninvasive and hence is completely deprived of any harmful side effects. The present study was undertaken to investigate whether low-intensity EMFs can suppress tumoral cells growth in vivo without cytostatic agents. The course of influence of EMFs started 3 days before transplantation in order to raise activity of the animals' immune system. On the fourth day animals were injected by sarcoma-37 and daily exposure was continued during 15 days. For study of the effect of irradiation on the secondary structure of DNA, in the experiments DNA isolated from the liver of healthy mice (hDNA) as well as from the tumor sarcoma 37 (tDNA) was used. After 15 sessions of exposure without cytostatic drugs, at animals of the irradiated 0,5 hour was observed an inhibition of tumor growth by 33.5% compared with a control group and a sharp suppression of the level of DNA-methylation in 2.1 times. The tDNA has the high level of methylation (4.7 mol%), which after 0.5 hour daily exposure becomes (2.2 mol%) close to the corresponding value for hDNA (1.9 mol%). Differential melting curves (DMC) of tDNA are shifted relatively DMC of the hDNA to lower temperatures, and in the DMC of tDNA the additional peaks in the 52-60ºC range are appeared, which are absent for DMC of liver hDNA. The obtained results are correlated with the spectrophotometric data. Under the influence of EMFs the values of temperature and interval of melting of tDNA are changed and approach to the corresponding values of hDNA. Presented preliminary results have demonstrated the potential clinical application of low power EMFs for clinical oncology in the treatment of malignancies. The changes of physical-chemical properties of tumoral and healthy DNA under amplitude modulated radiation at 64.5 GHz and possible mechanisms of these changes have been investigated and discussed.

Abstract-Violations of the process of methylation reveal itself at the early stages of malignant transformation of cells, and the content of 5-methylcytosine can serve as a diagnostic test for tumor formation and treatment of disease. The carried out studies revealed the correlation of antitumor activity of MM-therapy (the use of coherent millimeter electromagnetic waves of low intensity for therapy) with inhibition of methylation of tumor DNA in vivo. It is revealed in our experiments that an half-hour exposure of MM-radiation results in the tumor growth inhibition by 33.5% and a sharp suppression of the level of DNA-methylation 2.5 times. The results obtained in this experiment indicate the prospects of working out the MM-therapy for clinical oncology in the treatment of malignant neoplasms.

A series of new 3,4,5-substituted 1,2,4-triazoles were synthesized. Their SH-alkylation by various alkylating compounds and aminomethylation leading to the formation of Mannich bases were studied. The influence of the synthesized compounds on the level of DNA methylation and their antitumor and antibacterial properties were investigated. Several compounds with pronounced demethylation and weak antitumor and antibacterial activities were identified. Correlations among the investigated biological properties were not found.In continuation of research on the search for biologically active 1,2,4-triazole derivatives [1 -5], herein the synthesis and several transformations of new 3,4,5-substituted 1,2,4-triazoles with a 4-chlorophenoxymethyl group in the heterocycle 3-position, in contrast with the previous compounds, were reported. The previously synthesized analogs with a 4-bromophenyl or 4-bromophenoxymethylene substituent in this position exhibited moderate experimental antitumor activity [4]. It seemed interesting to study the effect of the new triazole derivatives on the level of tumor DNA methylation and to find a possible correlation between the ability to inhibit DNA methylation and the antitumor activity. The series of synthesized compounds were also tested for antibacterial activity based on published reports of the antibacterial properties of 1,2,4-triazole derivatives [6,7].Scheme 1 illustrates the syntheses of the 1,2,4-triazoles.The starting compounds were 1,4-substituted thiosemicarbazides that were prepared by reacting 4-chlorophenoxyacetic acid hydrazide with allyl-, phenyl-, benzyl-, 3-bromo-4-methoxybenzyl-, and cyclohexylisothiocyanates in EtOH [3,4]. Alkaline cyclization of thiosemicarbazides I yielded 3,4-substituted 5-thio-1,2,4-triazoles II -VI, which were stable crystalline compounds. Halides of certain structures, i.e., aliphatic and unsaturated acid chlorides or bromides or their esters and amides, were selected for alkylation of the 5-thio group of triazoles II -VI. The alkylation was performed using the methods developed previously by us, i.e., refluxing the triazoles with the appropriate halides in EtOH or H 2 O in the presence of a certain amount of KOH [4]. As a result, a series of new 3,4,5-substituted triazoles (VII -XXV) were synthesized as colorless crystalline compounds.Aminomethylation of triazoles II -VI to give the corresponding Mannich bases was carried out in MeOH with an excess of secondary amine and formalin at room (20 -25°C) temperature. The obtained 1-N-morpholinomethylene-1,2,4-triazolinethiones-5 (XXVI -XXX) were slightly yellowish stable crystalline compounds. Only starting triazole IV was isolated after an attempt to synthesize the corresponding thiazolino-1,2,4-triazole via bromination in CHCl 3 of 4-allyl-5-thio-1,2,4-triazole (IV) by the literature method [8]. The intended reaction product was obtained via bromination of IV in anhydrous EtOH at room temperature followed by refluxing for 4 h.