Journal of Medicinal Chemistry @ Copyright 1971 b y the American Chemical Society
APRIL1971
VOLUME14, No. 4
Electronic Representation of the Lipophilic Parameter
T
ARTHURCAMMARATA* Temple University, School of Pharmacy, Philadelphia, Pennsylvania AND
19140
KENNETHS . ROGERS
Virginia Commonwealth University, Medical College of Virginia, Department of Biochemistry, Richmond, Virginia Received J u l y 24, 1970 We have shown recently that the logarithm of partition coefficients can be related to molecular electronic indexes which can be calculated for various chemical agents. According to a theoretical interpretation of biological linear free energy relationships, the lipophilic parameter x should be related to similar electronic indexes calculated only for the substituents of a congeneric series of molecules. I n this report it is shown that x values for benzoic acids can be correlated with appropriate electronic indexes calculated for the substituents of benzoic acid derivatives. These same electronic indexes are shown t o also be suitable for correlating the x values derived for phenoxyacetic acids. Biological activities which are found t o be linearly related to x can be related t o the calculated electronic substituent indexes.
often used in establishing tlie relative rates with which chemical substances penetrate lipoidal membranesg or participate in the formation of n hydrophobic bond. l o The most useful lipophilic indexes are the logarithm of the partition coefficient, log P , or in tlie case of congeneric series the substituent constant T ivhich is defined by
Considerable effort has been expended in attempting t o describe biochemical and pharmacological processes on a n clcctroiiic While notable insight into thc electronic factors controlling the chemical behavior of important biomolecules has been gained, there are few instances where electronic indexes have been related directly t o experimental measures of a biological responseS4 1:rom the results of extrathermodynamic correlaiive it is clear that attempts t o gain insight into the electronic nature of biological processes will require the lipophilicity or hydrophobicity of the substrates or drugs t o be taken into account. The intcraction bctween a substrate and a biomacromolecule may be dominated by electronic factors, but the accessibility of the substrate to the region of the biomwromolecule where the interaction occurs is governed by lipophilic factors. Similar lipopliilic factors also seem t o contributc toward the "hydrophobic bonding" tendencies for a substrate. Iipophilicity is a term commonly used to describe the tendency for u chemical agent t o partition itself between aqueous and organic biophases. Partition coefficients provide a convenient measure of lipophilicity and are
where P X and P H are, respectively, the partition coefficients for a substituted member and tlic parent member of a congeneric series. l 1 Experimental measures of lipophilicity linve been used in combination with tlie results of simple Huclrel calculations in correlating the analgesic activity of imidaxoliries12and the rates of acylation of substituted anilines by acetylt'ransferase. 'l'nlting lipophilicity into account in this may, however, is quasi-empirical since theoretically justifiable relatioris prescribed by quantum perturbation theory14 are blended with enipiricnl indexes having no demonstrated basis in theory. I n worlcirig toward a quantum chemical description of lipophilicity we have been investigating potential relationships between quantum chemical indexes and partition coefficients. Preliminary work has resulted in a
(1) D . Pullman and A . Pullman, "Quantum 13iocliemistry," Wiley-lnterscience, Ken. York, I". Y., 1963. (2) 13. Pullman, E d . , "Electronic .ispects of Biochemistry," .lcademic Press, N e w York, N. Y . , 1964. (3) 13. Pullman and M . \Veissblutli, Ed., ".Molecular I3iophysics." .\cademic Press, New York, N. Y . , 1965. (41 L. B. Kier, E d . , "Molecular Orbital Studies in Chemical Pliarmacology," Springer-Verlag, N e v York, N . Y., 1970. ( 5 ) C . Hansch, Annu. Rep. .Wed. Chem., 1966, 347 (1967). (6) C . Hansch, "Pliysico-Chemical .Ispects of Drug .tction," 13. J. Ariens, Ed., Pergamon Press, New I'ork, N. Y., 1968. ( 7 ) C. Hansch. Accounts Chem. Res., 2, 232 (1969). (8) C. Hansch, Fnrmaco &d. S c i . , 28, 293 (1968).
(9) H . Davson and J. F. Danielli, "The Permeability of Katural XIembranes," 2nd ed, Cambridge University Press, Cambridge, England, 1952. (IO) E. J. Cohn and J. T. Edsall. "Proteins, .imino .kcids a n d Peptides as Ions and Dipolar Ions," Reinhold, N e w York. N. Y., 1913. (11) T . Fujita, J. Iwasa, a n d C. Hansch. J . d m r r . C h e m . S o c . , 86, 517.5 (1964).
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