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(111) compounds as photocytotoxic agents. Here, the design and synthesis of [Rh(NH3)(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(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 H-1 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 (lambda(max) = 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 N-15{H-1} NMR spectroscopy using N-15-labeled [Rh((NH3)-N-15)(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.