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A rational approach to the synthesis of template inhibitory antitumor drugs
Author(s) -
Gabbay Edmond J.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560100722
Subject(s) - in vitro , anthracycline , in vivo , dna , chemistry , pharmacology , dna synthesis , biochemistry , biology , cancer , genetics , breast cancer
A rational synthesis of template inhibitory antitumor drugs (that is, the anthracyclines) is described which is based on the results of ( a ) in vitro studies (the interaction specificities of the drugs with template DNA), ( b ) pharmacological properties of the anthracyclines, and ( c ) the known differential physical properties of cancer versus normal cells. It appears that for most cases the in vitro studies of ( a ) the rates of dissociation of DNA‐drug complexes, ( b ) the extent of inhibition of DNA‐dependent RNA polymerase, and ( c ) the determination of the distribution coefficients of the drugs (a measure of cellular permeability) provide a fairly reliable and rapid estimate of the in vivo biological activity of the anthracycline. This conclusion is based on the comparison of the in vitro data with the results obtained from the antitumor activity of anthracycline analogs against the P‐388 mouse lymphocytic tumor. In addition, it is found that enhanced chemotherapeutic indexes of the anthracyclines are obtained when administered in the form of a DNA complex. However, it is not possible to conclude that a lysosomotropic principle (as postulated by Trouet and coworkers [3‐5]) is the mechanism responsible for this effect.