The Pyrimidinyl Hydrazones: Selective for anti-Cancer cytotoxicity.

Pyrimidinyl hydrazones (PH) can be prepared using simple procedures beginning with dichloropyrimidine. A total of 9 PH were synthesised and these compounds associated strongly with copper, iron and zinc ions both at physiological and mildly acidic pH. The PH were cytotoxic in vitro against cancer cell lines (compound 15 having IC50 values of 0.37, 0.11 and 1.09 μM against melanoma, ovarian cancer and pancreatic cancer cell lines respectively - these values being superior to known agents such as doxorubicin) and displayed only minimal toxicity against non-cancer cell lines (no toxicity at 25 μM against the non-cancer MRC-5 fibroblast). Copper complexes of the PH formed in situ showed cytotoxicity against cancer lines similar to that of the PH alone - albeit with substantial increases in toxicity against non-cancer cells. Association of PH with iron or zinc ions in situ did not generally result in enhanced potency - unlike related thiosemicarbazones. The cytotoxic potency of PH was comparable to that observed for thiosemicarbazones. The PH are likely to exert their cytotoxic action through a combination of metal mobilisation and reactive oxygen generation. The PH should be more extensively studied as a class of metal-chelating anti-cancer agents.