Pathways and kinetics of aqueous decomposition and carbamoylating activity of new anticancer nitroimidazole-linked 2-chloroethylnitrosoureas

Add time:07/31/2019    Source:sciencedirect.com

The products of decomposition in anaerobic aqueous solution at pH 7.1 and 37° were determined for two series of novel anticancer agents incorporating both nitroimidazole and 2-chloroethylnitrosourea moieties (NI-CENUs) and examples of which exhibit preferential hypoxic toxicity against HeLa-MR cells. The decomposition products identified were vinyl chloride, acetaldehyde, 2-chloroethanol, ethylene glycol and imidazole-bearing compounds of the type including oxazolidinone, ethylamine or urea moieties. Series A NI-CENUs, which contain a 2-hydroxypropyl unit, gave rise to the oxazolidinone intramolecularly compared with the series B agents which gave rise to the imidazole-ethylamine and ureas. The half-lives of the B series agents were comparable with those of 1, 3-bis(2-chloroethyl) nitrosourea (BCNU), 2-cyclohexyl-1-(2-chloroethyl)-1-nitrosourea (CCNU) and streptozotocin. The carbamoylation activity of the series B agents was approximately ten times that of series A compounds. This latter property may be related to the greater potency of series B than series A NICENUs against Mer+ HeLa-S3 cells via inhibition of relevant repair enzymes.

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