In the search for new anticancer drugs. 29. A study on the correlation of lipophilicities, ionization constants and anticancer activities of 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 between about 4.0 and 6.3. It was shown using the Henderson-Hasselbalch equation that at physiological pH, arbitrarily chosen 6, 7 and 8, the amine derivatives would exist mainly in the protonated form, whereas the hydroxylamine derivatives would be expected to be mainly in the unprotonated 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 results, it was hypothesized that the alkylating anticancer drugs of TEPA (N,N:N',N':N ",N "-tri-1,2-ethanediylphosphoric triamide) type, containing sterically hindered carrier moieties, would be expected to permeate across cell membranes, and, consequently, exhibit anticancer activities according to the following sequence: spin-labeled drugs containing 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 partition coefficients. The conclusion was reiterated that, in the quest for a rational design of anticancer drugs, the aim should be to construct agents with partition coefficients approaching the logarithm of zero, either from the negative or positive side, and pKa values as low as practically possible and applicable.