STRUCTURE-ACTIVITY STUDY OF 7 NEW WATER-SOLUBLE NITROSOUREAS

The in vitro alkylating activity, carbamoylating activity, decomposition rates and octanol-water partition coefficients (Log P) of seven water soluble chloroethylnitrosourea antitumor agents and a reference lipid soluble analog were correlated with their biological activities in mice. The alkylating activity of each compound demonstrated a significant inverse linear correlation with both the decomposition rate in 0.1 M sodium phosphate buffer. pH 7.4 (r = -0.92, P < 0.01), and the molar ld10 dose (r = -0.87, P < 0.01). A direct relationship was found between the Log P values and both the alkylating activity (r = -0.86. P < 0.01) and the molar ld10 dose (r = 0.77, P < 0.025). However, the addition of the variable. Log P, in multiple regression analysis did not contribute significantly to any of the direct correlations of chemical parameters with biological variables. In comparison, carbamoylating activity did not function as an independent variable for the relative myelotoxicity or lethality of each compound. All water soluble drugs except for chlorozotocin and 1-(2 chloroethyl)-3-(β-d-glucopyranosyl)-1-nitrosourea, the two analogs with glucose carriers, produced a significant reduction in circulating neutrophils at their respective ld10 doses. There was no correlation between relative myelotoxicity and alkylating activity, carbamoylating activity or Log P. The glucose moiety appears to function as an independent variable for reducing nitrosourea cytotoxicity to bone marrow cells without significantly altering antitumor activity. © 1979.