Ruthenium−Porphyrin Conjugates with Cytotoxic and Phototoxic Antitumor Activity

• Published in: Journal of medicinal chemistry 2010-06, Vol.53 (12), p.4678-4690
• Main Authors: Gianferrara, Teresa, Bergamo, Alberta, Bratsos, Ioannis, Milani, Barbara, Spagnul, Cinzia, Sava, Gianni, Alessio, Enzo
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Cell Line, Tumor; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Drug Screening Assays, Antitumor; Humans; Light; Photosensitizing Agents - chemical synthesis; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; Porphyrins - chemical synthesis; Porphyrins - chemistry; Porphyrins - pharmacology; Ruthenium; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1002588

We report here two novel “extended-arms” porphyrins, TetbpyPP and TedabpyPP, in which four peripheral bpy fragments are connected to the meso positions of the macrocycle through flexible linkers of different length and hydrophilicity. We describe also the new, water-soluble, tetracationic conjugate [TedabpyPP{Ru([9]aneS3)Cl}4][Cl]4 (6). Compound 6 belongs to the series of cationic Ru−porphyrin conjugates 1−5, each bearing four peripheral Ru(II) half-sandwich coordination compounds, that we recently prepared as potential photosensitizing chemotherapeutic agents. The in vitro cell growth inhibition of conjugates 1−6 toward MDA-MB-231 human breast cancer cells and HBL-100 human nontumorigenic epithelial cells are reported, together with the phototoxic effects of 1, 4, and 6 on MDA-MB-231 cells. All conjugates have IC50 values in the low micromolar range that decrease by 1 order of magnitude upon irradiation of cell cultures with visible light. The most promising compounds 1 and 6 are phototoxic at low light and drug doses.