The theory of interceptor-protector action of DNA binding drugs

Abstract

The review discusses the theory of interceptor-protector action (the IPA theory) as the new selfconsistent biophysical theory establishing a quantitative interrelation between parameters measured in independent physico-chemical experiment and in vitro biological experiment for the class of DNA binding drugs. The elements of the theory provide complete algorithm of analysis, which may potentially be applied to any system of DNA targeting aromatic drugs. Such analytical schemes, apart from extension of current scientific knowledge, are important in the context of rational drug design for managing drug's response by changing the physico-chemical parameters of molecular complexation.

C60 Fullerene Clusters Stabilize the Biologically Inactive Form of Topotecan

“…It is seen that as the concentration of the added molecules increases, the HGQ value gradually shifts from a positive control to a negative one, indicating that the functional activity of the cell nuclei is restored. It means that the effect of the added molecules, having different chemical structures, on TPT interaction with nonproliferating cells is exerted generally in a similar way and corresponds well with the same studies reported before for C 60 /FMN/CAF introduced simultaneously with other aromatic biologically compounds (see ref and references therein).…”

“…However, stage 1 is assumed to be important only at low concentrations of C 60 fullerene, when the fraction of large clusters is too small to dominate in the net binding effect . Comparison of complexation of TPT with C 60 fullerene against the hetero-complexation of TPT with classical interceptor molecules, FMN and CAF, which are known to modulate the biological effect of TPT in vitro through hetero-association (see ref and references therein), showed a similar spectrophotometric manifestation of these complexations, even more pronounced for TPT-C 60 (if compared by values of equilibrium complexation constants). Taking all this into account, we can conclude that the noncovalent interaction (complexation) of TPT with fullerene clusters can be considered confirmed, thereby providing the physicochemical basis for further analysis of their biological interaction in vitro.…”

“…To estimate the importance of TPT-C 60 complexation, we have tested the interaction of TPT with two classical interceptor molecules, FMN and CAF, which are known to induce modulation of the TPT biological effect in vitro via formation of TPT-CAF/FMN noncovalent hetero-complexes (see ref and references therein). The changes in the spectrum of TPT on addition of caffeine (Figure A) and flavin mononucleotide (Figure B) differ from those described above.…”

“…Looking for additional validation of this result, we repeated the test with buccal epithelium for the interaction of caffeine and flavin mononucleotide molecules with TPT. Both caffeine and flavin mononucleotide are well known as interceptor molecules that act on aromatic drug molecules, including TPT, in a manner identical to that of C 60 fullerene (i.e., form noncovalent hetero-complexes with TPT , and display changes in the biological effect of various aromatic drugs because of complexation in either nonproliferating and proliferating in vitro tests (see ref for review). Figure B,C evidences the similar effect to C 60 fullerene in restoring of the functional activity of the cell when caffeine or flavin mononucleotide is added to the mixture with TPT.…”

“…Table outlines the existing qualitative information in the literature concerning the facts of confirmed influence of pristine C 60 fullerene on the biological effect in vitro of various aromatic biologically active molecules. We also appended this table with the information on the action of typical interceptor molecules (xanthines, riboflavin, chlorophyllin) on these drugs through noncovalent complexation recently reviewed . It can be seen that in the majority of cases (when data are available) the existence of drug–interceptor complexation correlates with the in vitro response of the biological system to the addition of the drug–interceptor mixture.…”