Isoxazolidinyl polycyclic aromatic hydrocarbons as DNA-intercalating antitumor agents.
Rescifina A, Chiacchio U, Corsaro A, Piperno A, Romeo R.
The second generation and an isosteric series of isoxazolidinyl polycyclic aromatic hydrocarbons, as DNA-intercalator agents designed to act on remotely implanted tumors, have been synthesized in good yields according to the 1,3-dipolar cycloaddition methodology. The structure of the obtained cycloadducts has been determined by NOE experiments and supported by computational studies at PM3 level. The utility of this new template in the synthesis of structures designed to capitalize on its intercalative properties has been examined. All the obtained compounds have been tested for their in vitro cytotoxic activity and the most potent of them showed an IC(50) of 9 μM upon the human lung cancer (A-549) cell and a binding constant, for the intercalation with calf thymus DNA, of 9.6 × 10(4) M(-1). Biological and docking studies showed that these compounds complex exclusively by intercalation between base pairs, approaching the DNA from its minor groove, with a neat selectivity for the AT or GC nucleobases.