BIOPHYSICAL AND BIOLOGICAL EVALUATION OF PORPHYRIN-BISACRIDINE CONJUGATES

Two novel porphyrin-bisacridine conjugates (1 and 2) were designed as bifunctional antitumour agents to combine the DNA-binding character of the acridines and the photosensitizing capacity of porphyrin, and hav e been subjected to biophysical and biological evaluation. The interac tions of the conjugates with calf thymus DNA were evaluated using visc ometric, spectrophotometric and stopped-flow sodium dodecyl sulphate ( SDS) sequestration methods. Both conjugates acted as bis-intercalators via the two acridine chromophores and displayed a longer residence ti me on DNA relative to the parent acridine ligand. Their biological act ivity in vitro was studied against the C6 rat glioma, MCF-7, GEM and A 431 cell lines. Both conjugates were cytotoxic to all four cell lines. The ID50 (C6 glioma) was essentially the same as that of the parent a cridine for one conjugate, but was increased 20-fold for the other, wh ile both conjugates were similar to 10-fold more cytotoxic than the pa rent porphyrin component. The tissue distribution of the two conjugate s was assessed in nude mice xenografted with a human small cell lung c arcinoma (POVD). There were large differences in the tissue distributi on of the two conjugates, with conjugate 2 localizing 8-fold more in t he tumour than conjugate 1.