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.