Pathways and kinetics of aqueous decomposition and carbamoylating activity of new anticancer nitroimidazole-linked 2-chloroethylnitrosoureas.
The products of decomposition in anaerobic aqueous solution at pH 7.1 and 37 degrees 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 NI-CENUs against Mer+ HeLa-S3 cells via inhibition of relevant repair enzymes.
Carminati
A
A
Laboratoire de Chimie Bio-Organique, U.A. 488 au C.N.R.S. USTL, Montpellier, France.
Barascut
J L
JL
Naghipur
A
A
Lown
J W
JW
Imbach
J L
JL
D000970:Antineoplastic Agents / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000378:metabolism; D007700:Kinetics; D009593:Nitroimidazoles / Q000378:metabolism*
D000970:Antineoplastic Agents; D009593:Nitroimidazoles; C017139:1-(2-chloroethyl)-1-nitrosourea; D005038:Ethylnitrosourea