Thermally Inert Metal Ammines as Light-Inducible DNA-Targeted Agents. Synthesis, Photochemistry, and Photobiology of a Prototypical Rhodium(III)−Intercalator Conjugate

• Published in: Inorganic chemistry 2002-12, Vol.41 (26), p.7159-7169
• Main Authors: Barry, Colin G, Turney, Elizabeth C, Day, Cynthia S, Saluta, Gilda, Kucera, Gregory L, Bierbach, Ulrich
• Format: Article
• Language: English
• Subjects: Acridines - chemical synthesis; Acridines - chemistry; Acridines - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cattle; Chemical Phenomena; Chemistry; DNA - chemistry; DNA - drug effects; DNA - metabolism; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Electrophoresis, Agar Gel; Escherichia coli; Humans; Intercalating Agents - chemical synthesis; Intercalating Agents - chemistry; Intercalating Agents - pharmacology; Magnetic Resonance Spectroscopy; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Photochemistry; Rhodium - chemistry; Structure-Activity Relationship; Thiourea - chemical synthesis; Thiourea - chemistry; Thiourea - pharmacology; Tumor Cells, Cultured - drug effects
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic025744n

The recent discovery of the promising tumor cell kill by a novel platinum−acridine conjugate [Martins, E. T.; et al. J. Med. Chem. 2001, 44, 4492] has prompted us to explore the utility of analogous light-activatable rhodium(III) compounds as photocytotoxic agents. Here, the design and synthesis of [Rh(NH3)5L] n + complexes are described with L = 1,1,3,3-tetramethylthiourea (tmtu) or 1-[2-(acridin-9-ylamino)ethyl]-1,3,3-trimethylthiourea (2). The intercalator-based DNA-affinic carrier ligand 2 was synthesized from N-acridin-9-yl-N‘-methylethane-1,2-diamine and dimethylthiocarbamoyl chloride and isolated as the hydrotriflate salt 2(CF3SO3). [Rh(NH3)5(tmtu)]3+ (1) and [Rh(NH3)5(2)]4+ (3) were obtained from the reactions of the trifluoromethanesulfonato complex [Rh(NH3)5(OSO2CF3)](CF3SO3)2 with the appropriate thiourea in noncoordinating solvents. All compounds were characterized by 1H NMR and UV−vis spectroscopies and by elemental analyses. The single-crystal X-ray structures of 1(CF3SO3)3·2MeOH, 2(CF3SO3), and 3(CF3SO3)4·H2O have been determined. Ligand-field photolysis of thermally inert 1 (λmax = 378 nm) resulted in the aquation of 2 equiv of ammine ligand without noticeable release of sulfur-bound tmtu (1H NMR spectroscopy, NH3-sensitive electrode measurements). This was confirmed by 15N{1H} NMR spectroscopy using 15N-labeled [Rh(15NH3)5(tmtu)]3+ (1*), which also indicated photoisomerization of the [RhN5S] moiety. Despite greatly accelerated ligand exchange, rhodium in 1 and 3 did not show light-enhanced formation of covalent adducts in calf thymus DNA. “Dark binding” levels of 3 in native DNA were slightly higher than for nontargeted 1, but significantly lower than those observed for analogous platinum−acridine. Agarose gel electrophoresis revealed photocleavage of supercoiled pUC19 plasmid DNA in the presence of hybrid 3 and its individual constituents 1 and 2. Simple 1 induced single-strand breaks while 3 produced complete degradation of the DNA after 24 h of continuous irradiation. Acridine 2 alone produced double-strand breaks. The extent of DNA damage observed for 1 − 3 correlates with the photocytotoxicity of the compounds in human leukemia cells, suggesting that DNA might be the cellular target of these agents.