Enhancement of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) toxicity by acetohydroxamic acid analogues of 3-nitropyrazole in vitro

Abstract

A series of acetohydroxamic acid derivatives of 3-nitropyrazole were synthesized and evaluated for their ability to potentiate (chemosensitization) the activity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) against EMT-6 mouse mammary tumor cells in vitro. The compounds were designed to test the hypothesis that the chemosensitizing activity of the analogues would be proportional to the rate of isocyanate formation via a Lossen rearrangement, in part a function of the leaving group at the N terminus of each acetohydroxamate. Substitution of acetohydroxamic acid side chains at the N-1 position of the parent 3-nitropyrazole resulted in compounds which were preferentially toxic to cells treated under hypoxic conditions, and which were capable of enhancing the toxicity of CCNU in hypoxia. As was observed for cytotoxicity, the enhancement of CCNU toxicity by these sensitizing agents was significantly reduced under aerobic treatment conditions. A strong correlation was established between hypoxic toxicity and chemosensitizing potency. The activity of the analogue, however, was not proportional to their excepted rates of Lossen rearrangement. Nevertheless, several potent chemosensitizing compounds were identified; some of which were 10-50 X's more potent on a molar basis than Misonidazole, the reference chemosensitizing compound.

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…The chemopotentiation of nitrosoureas by other nitroheterocycles was also investigated. , Thus, the toxicity of CCNU ( 137b ) against EMT-69 mouse mammary cancer cells in vitro was enhanced 271 by a series of acetohydroxamic acid derivatives of 3-nitropyrazole 303 (Chart ). Under appropriate conditions these compounds should undergo a Lossen rearrangement to give isocyanates (Scheme ) …”

“…Under appropriate conditions these compounds should undergo a Lossen rearrangement to give isocyanates (Scheme 39). 271 While the anticancer activity of these analogs was not found to be proportional to the rate of the Lossen rearrangement, a strong correlation was established 271 between hypoxic toxicity and chemosensitizing potency. The 2-nitroimidazole acridines 304a,b (Chart 9) were synthesized and shown 272 to be potentiators of the toxicity of CCNU (137b) under hypoxic conditions.…”