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(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.