IN THE SEARCH FOR NEW ANTICANCER DRUGS - 29 - A STUDY ON THE CORRELATION OF LIPOPHILICITIES, IONIZATION-CONSTANTS AND ANTICANCER ACTIVITIESOF AMINOXYL LABELED TEPA CONGENERS

Ionization constants for a series of sterically hindered pyrrolidine, pyrroline and piperidine derivatives were determined by potentiometric titrations. The pKa values for the secondary amines as a group ranged from about 7.7 to 11.7, whereby the ring size had no decisive effect on the values. The corresponding hydroxylamine derivatives as a group had distinctly lower pKa values than the amine derivatives ranging bet ween about 4.0 and 6.3. It was shown using the Henderson-Hasselbalch e quation that at physiological pH, arbitrarily chosen 6, 7 and 8, the a mine derivatives would exist mainly in the protonated form, whereas th e hydroxylamine derivatives would be expected to be mainly in the unpr otonated form. In contrast, the 4-hydroxy-2,2,6,6-tetramethylpiperdin- 1-oxyl radical, under analogous conditions, was a neutral species, i.e . it could not be titrated in aqueous media. On the basis of these res ults, it was hypothesized that the alkylating anticancer drugs of TEPA (N,N:N',N':N '',N ''-tri-1,2-ethanediylphosphoric triamide) type, con taining sterically hindered carrier moieties, would be expected to per meate across cell membranes, and, consequently, exhibit anticancer act ivities according to the following sequence: spin-labeled drugs contai ning no titratable components > hydroxylamine derivatives > secondary amine congeners. This assumption is confirmed by good correlations of anticancer activities of these drugs with their pKa values, and the pa rtition coefficients. The conclusion was reiterated that, in the quest for a rational design of anticancer drugs, the aim should be to const ruct agents with partition coefficients approaching the logarithm of z ero, either from the negative or positive side, and pKa values as low as practically possible and applicable.