engleski

Novel diazenedicarboxamides as potential anticancer agents

During the last ten years, we have synthesized and screened the cytotoxic activity of a number of compounds from diazene family. We have shown that these compounds have antiproliferative activity against different tumor cell lines. If diazenecarboxamides were administered in combination with cisplatin, one of the most commonly used anti-cancer drug for the treatment of various solid tumors, synergistic effect was detected on several tumor cells from different origins, as well as the reversion of cisplatin resistance and vincristine. Moreover, it was shown that antiproliferative activity of selected diazenecarboxamides against tumor cells was significantly higher in comparison to the normal cells. Although diazenecarboxamides possess several desired characteristics, their main disadvantage in view of potential clinical application is low solubility in aqueous media. Therefore the aim of the present study was to synthesize new diazenedicarboxamides, with improved solubility and a good cytotoxicity. Here we report the synthesis and biological evaluation of new N, N’-disubstituted diazenedicarboxamides. Aryl isocyanates reacted with methyl carbazate to give the corresponding 1, 4-disubstituted semicarbazides. The latter compounds were oxidized to diazenes and finally transformed into six new diazene¬dicarboxamides employing the appropriate picolylamine as a nucleophile. The cytotoxic activity of new compounds was determined by spectrophotometric MTT assay using different tumor cell lines. We have shown that all new diazenedicarboxamides are cytotoxic against several human carcinoma cell lines. Among the analogues, having the same aryl group, the compounds bearing 3-picolyl functionality are more cytotoxic than those possessing either 2-picolyl or 4-picolyl substituent. For the diazenedicarboxamides with 4-alkylphenyl group at one of the amide nitrogen atom an increased bulkiness of the alkyl chain resulted in decreased cytotoxicity. From the series compounds examined, diazene N1-(4-methoxyphenyl)-N2-(pyridin-3-ylmethyl)diazene-1, 2-dicarboxamide (JV-158) was found to be the most biologically active. Its cytotoxic effect depends on the origin of the tumor cells, being highly cytotoxic against cervical carcinoma HeLa and laryngeal HEp-2 cells, and half as active to carboplatin and curcumin resistant sublines of HEp-2 cells. On the other hand, this compound had very low effect to the lung adenocarcinoma H460 and particularly to the colorectal carcinoma HCT-116 cells. Using specific inhibitor of glutathione synthesis, buthionine sulfoximine, we have shown that glutathione is not involved in cell response to compound JV-158. In addition, this diazene induced necrosis in the treated cells. Our results indicate that the diazenedicarboxamide JV-158 could be considered as a new potential anticancer agent, especially for the tumors of cervical and head and neck origin.

Diazenedicarboxamides; tumor cells; anticancer drugs

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