Relationships between physicochemical and biological properties in a series of oxazolopyridocarbazole derivatives (OPCd); comparison with related anti-tumor agents.

Oxazolopyridocarbazole derivatives (OPCd) are intercalating polycyclic molecules related to the anti-tumor drug 9-hydroxyellipticinium (Celiptium). From a pharmacological point of view, OPCd compounds are highly cytotoxic to malignant cultured cells but inactive or only weakly active against experimental tumors in vivo. Extensive physicochemical and biological investigations have been performed in this series including the determination of hydrophobic properties, interaction parameters with DNA and polynucleotides, interaction with DNA topoisomerase II in vitro, diffusion through cell membranes, accessibility to genomic DNA in cells and in chromatin preparations and finally, cytotoxic and anti-tumor activities. Establishment of relationships between physicochemical data and biological properties have been attempted. The results show that all the OPCd compounds display favorable parameters in terms of association constant values to DNA, accessibility to DNA in chromatin structure and permeation through cellular membranes. However, in contrast with intercalating drugs such as m-AMSA, adriamycin and 9-hydroxyellipticinium, OPCd compounds are not able to generate cleavable complexes in DNA through the interaction with topoisomerase II. With respect to design of anti-tumor drugs, these findings indicate that a high association constant value to DNA, the ability to intercalate between DNA base pairs without causing physical damage and an efficient diffusion through cell membranes are not by themselves sufficient for the expression of anti-tumor activity.