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.
Barry
Colin G
CG
Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, USA.
Turney
Elizabeth C
EC
Day
Cynthia S
CS
Saluta
Gilda
G
Kucera
Gregory L
GL
Bierbach
Ulrich
U
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D004926:Escherichia coli; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010777:Photochemistry; D012238:Rhodium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000166:Acridines; D000970:Antineoplastic Agents; D007364:Intercalating Agents; D009942:Organometallic Compounds; D004247:DNA; D012238:Rhodium; D013890:Thiourea