IN THE SEARCH FOR NEW ANTICANCER DRUGS - 29 - A STUDY ON THE CORRELATION OF LIPOPHILICITIES, IONIZATION-CONSTANTS AND ANTICANCER ACTIVITIESOF AMINOXYL LABELED TEPA CONGENERS
G. Sosnovsky et P. Bell, IN THE SEARCH FOR NEW ANTICANCER DRUGS - 29 - A STUDY ON THE CORRELATION OF LIPOPHILICITIES, IONIZATION-CONSTANTS AND ANTICANCER ACTIVITIESOF AMINOXYL LABELED TEPA CONGENERS, Life sciences, 62(7), 1998, pp. 639-648
Citations number
29
Categorie Soggetti
Biology,"Medicine, Research & Experimental","Pharmacology & Pharmacy
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.