Mechanism of degradation of the investigational cytotoxic agent, cyclodisone (NSC-348948)

Abstract

Cyclodisone (1,5,2,4-dioxadithiepane-2,2,4,4,-tetraoxide, NSC 348948) is a chemically unstable, poorly water soluble investigational cytotoxic agent. The aqueous degradation of cyclodisone at 25°C (ionic strength of 0.5, NaClO 4 and NaCl) as a function of pH, was investigated. In the presence of NaCl, the pH-rate profile could be described by, k obs = k 1[H +]/( K a + [H +]) + k 2 K a/( K a + [H +]), where k 1 equals 5.27 × 10 −4 min −1, k 2 equals 2.7 × 10 −5 min −1 and K a was 1 × 10 −10 (p K a of 10). In the presence of NaClO 4, k 2 was negligible and the data could be fit with a value of 3.10 × 10 −4 min −1 for k 1 and 8.56 × 10 −11 for K a (p K a of 10.06). The p K a in this case refers to the ionization of the methylene group between the two sulfur atoms. At both high and low pH values, the major degradation step appeared to be hydrolysis, via an early transition state Sn2 mechanism, of the ethylene-oxygen bond to produce the monohydroxyethyl ester of methane disulfonic acid. The primary decomposition product undergoes further hydrolysis to give the final products, ethylene glycol and methane disulfonic acid. The results from 18O-enriched water experiments clearly demonstrated the C-O bond cleavage occured in both steps of the degradation pathway. Buffer studies, effect of halide nucleophiles and deuterium solvent isotope studies were used to further characterize the mechanism and products.