title: Biophysical and biological evaluation of porphyrin-bisacridine conjugates.
abstract: 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 have been subjected to biophysical and biological evaluation. The interactions of the conjugates with calf thymus DNA were evaluated using viscometric, 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 time on DNA relative to the parent acridine ligand. Their biological activity in vitro was studied against the C6 rat glioma, MCF-7, GBM and A431 cell lines. Both conjugates were cytotoxic to all four cell lines. The ID50 (C6 glioma) was essentially the same as that of the parent acridine for one conjugate, but was increased 20-fold for the other, while both conjugates were approximately 10-fold more cytotoxic than the parent porphyrin component. The tissue distribution of the two conjugates was assessed in nude mice xenografted with a human small cell lung carcinoma (POVD). There were large differences in the tissue distribution of the two conjugates, with conjugate 2 localizing 8-fold more in the tumour than conjugate 1.
authors.affiliation: Department of Chemistry, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Karagianis
authors.forename: J A
authors.initials: JA
authors.lastname: Reiss
authors.forename: R
authors.initials: R
authors.lastname: Marchesini
authors.forename: M
authors.initials: M
authors.lastname: De Cesare
authors.forename: F
authors.initials: F
authors.lastname: Zunino
authors.forename: D R
authors.initials: DR
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy; D004247:DNA / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D011166:Porphyrins / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013053:Spectrophotometry; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy; D014783:Viscosity
chemical_list: C099903:2,18-bis(((3-(9-acridinylamino)propyl)aminocarbonyl)ethyl)-7,12-bis(1-((2-(dimethylamino)ethyl)thio)ethyl)-3,8,13,17-tetramethylporphine; C099904:2,18-bis(2-((3-((4-(2-dimethylaminoethyl)carbamoyl)-9-acridinylamino)propyl)aminocarbonyl)ethyl)-7,12-bis(1-((2-(dimethylamino)ethyl)thio)ethyl)-3,8,13,17-tetramethylporphine; D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; D004247:DNA