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Synthesis and evaluation of diazenedicarboxamides as potential anticancer agents

To increase the effectiveness of cancer treatment, more effective anti-cancer drugs, as well as the new improved strategies of cancer treatment are urgently needed. Diazenes have already been recognized as selective oxidants for mild transformation of various thiols to the corresponding disulphides. They selectively interact under physio¬logical conditions with natural thiols, particularly with glutathione, the major antioxidant in cells, that is also involved in detoxification of toxic compounds, and which plays a central role in intracellular redox state balance. Our previous results have shown that diazenes are cytotoxic, and that they may revert the resistance to cisplatin and vincristine. In addition, we observed similar behavior for non-symmetrical diazene¬dicarboxamides SB-409 and SB-411 that also exhibited promising cytotoxicity. The aim of the present study was to synthesize new diazene¬dicarboxamides with acceptable solubility and 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 was determined by spectrophotometric MTT assay using different tumor cell lines. Our results show that a modification of either SB-409 or SB-411 led to more active compounds. The most effective was diazene¬dicarboxymide bearing 4-methoxy group on one amide functionality and 2-picolyl on the other one. Our results further indicate that diazenedicaboxamide JV-158 could be considered as new potential anticancer agents, specially for the tumors of head and neck origin.

Diazenedicarboxamides; anticancer drugs; cells

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