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Interrelationships of Some Chemical, Physicochemical, and Biological Activities of Several 1-(2-Haloethyl)-1-nitrosoureas¹

Biochemistry Department and Chemotherapy Department, Southern Research Institute, Birmingham, Alabama 35205

Biological, chemical, and physicochemical data for a number of nitrosoureas have been subjected to a computer analysis to seek the relative roles of carbamoylating activity, alkylating activity, and oil solubility (octanol/water) in determining the activities of the compounds against i.p. implanted leukemia L1210. All of the compounds included in the study have some antileukemia activity, and their octanol/water distribution coefficients fall within the range designated by Hansch et al. as necessary for activity. The conclusions are as follows.

Carbamoylating activity, alkylating activity, and solubility are all important in determining the degree of antileukemia activity.

Perhaps a dominant role of carbamyolating activity is in determining the toxicity, as reflected in the dose (mmoles/kg) causing death of 10% of the mice when administered i.p. as a single dose and in the therapeutic indexes.

Alkylating activity (which may reflect in an inverse manner the chemical half-life of the nitrosourea) is a relatively greater factor in determining the single i.p. dose (mmoles/kg) killing 99% of the leukemic L1210 cells after i.p. inoculation of 10⁵ cells and the single i.p. dose (mmoles/kg) producing 50% 45-day survivors in a group of mice inoculated i.p. with 10⁵ L1210 cells than in determining the dose (mmoles/kg) causing death of 10% of the mice when administered i.p. as a single dose, and it is also important in yielding desirable therapeutic indexes.

The solubility (as reflected in the octanol/water distribution coefficient) is a major factor in determining the toxicity and hence the therapeutic indexes, perhaps because of the essentiality that the agents reach the critical anatomical sites for causation of toxicity.

Consideration of the data leads to the suggestion that a nitrosourea having optimal therapeutic properties will have low carbamoylating activity, relatively low chemical stability, high alkylating activity, and a distribution coefficient falling at the upper end of the range for the compounds included in this study.

¹ This work was performed under Contract PH-43-66-29, Division of Cancer Treatment, National Cancer Institute, NIH.

Received 6/27/73. Accepted 10/18/73.

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