Studies on the chemistry, antitumor activity, and pharmacology of ethyl Di‐(2,2 ‐dimethyl)ethylenamido phosphate (AB‐163)

Abstract

AB-163, a new alkylating agent containing the 2,2-&methylaziridine moiety, was found to be active against a number of transplanted and virus-induced tumor systems in mice. This compound hydrolyzes in water a t 37 C. The hydrolysis product was isolated and identified as ethanol and amino-tert-butyl phosphate. The compound was shown to react with the model nucleophile 4-(p-nitrobenzyl) pyridine (NBP) comparably to previously studied alkylating agents. The intravenous LD,, was 198 mg/kg and the intraperitoneal LD,,, was 159 mg/kg in ICR/Ha male mice. I n mice carrying Ehrlich ascites tumor (E-2), 30 mg/kg of AB-163 resulted in 95% tumor inhibition. I n Sarcoma-180 inoculated mice, 15 mg/kg caused a 20-30% apparent cure rate and a 62% tumor inhibition of the animals having tumors. Against Adenocarcinoma 755,40 mg/kg exhibited a 60% cure rate and 50% tumor inhibition of the animals with tumors. Leukemia LIZ10 treated on days 1-11 was cured in 20-30y0 of the animals receiving 30 mg/kg of AB-163 and there was a 76-170% increase in survival time in the remaining animals. In animals infected with Friend virus, a 40 mg/kg dose resulted in 65% reduction of splenic weight as compared to controls. Studies in dogs indicated that the main toxicity is hematopoietic depression. Terminally, depression of liver functions was observed. High doses produced central nervous system effects which manifested themselves in loss of appetite, vomiting, increased salivation, lethargy, and convulsions.

Reactions of 2,2‐Dimethylaziridine‐Type Alkylating Agents in Biological Systems II: Comparative Pharmacokinetics in Dogs

“…7) suggest that, given two drugs producing identical plasma concentrations a t equal doses or infusion rates, the agent that hydrolyzes more rapidly may be more effective against tumors of the peripheral compartment because more of the drug will be located in the tissues a t a given time. Although only limited data are available (1,2), 111 does seem to be more effective than I in this type of tumor.…”

“…EXPERIMENTAL Organic Synthesis-The chemical method used for isotopic labeling of I was derived from that of Piantadosi et al (1). Sodium (0.5 g) was dissolved in 12.5 ml of absolute ethanol, and the solution was cooled to room temperature.…”

Reactions of 2,2-dimethylaziridine-type Alkylating Agents in Biological Systems I: Colorimetric Estimation and Stability in Physiological Media

“…These results suggest continuing interest in the clinical study of this agent. In the meantime, several other compounds containing the 2,2-dimethylaziridine moiety were synthesized and found to be effective against a spectrum of transplanted tumors in rodents (21)(22)(23)(24)(25)(26). Two of these agents, ethyl bis(2,2-dimethyl-l-aziridinyl)phosphinate (11) (23,24) and tris(2,2-dimethyl-l-aziridinyl)phosphine oxide (111) (25), which showed particularly potent activities against leukemia L-1210 in mice, passed through the preclinical pharmacology stage (24) and are presently undergoing preliminary evaluation against solid tumors in man.…”