Thermally inert metal ammines as light-inducible DNA-targeted agents. Synthesis, photochemistry, and photobiology of a prototypical rhodium(III)-intercalator conjugate

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(NH(3))(5)L](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(CF(3)SO(3)). [Rh(NH(3))(5)(tmtu)](3+) (1) and [Rh(NH(3))(5)(2)](4+) (3) were obtained from the reactions of the trifluoromethanesulfonato complex [Rh(NH(3))(5)(OSO(2)CF(3))](CF(3)SO(3))(2) with the appropriate thiourea in noncoordinating solvents. All compounds were characterized by (1)H NMR and UV-vis spectroscopies and by elemental analyses. The single-crystal X-ray structures of 1(CF(3)SO(3))(3) x 2MeOH, 2(CF(3)SO(3)), and 3(CF(3)SO(3))(4) x H(2)O have been determined. Ligand-field photolysis of thermally inert 1 (lambda(max) = 378 nm) resulted in the aquation of 2 equiv of ammine ligand without noticeable release of sulfur-bound tmtu ((1)H NMR spectroscopy, NH(3)-sensitive electrode measurements). This was confirmed by (15)N[(1)H] NMR spectroscopy using (15)N-labeled [Rh((15)NH(3))(5)(tmtu)](3+) (1), which also indicated photoisomerization of the [RhN(5)S] 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.