Dinuclear organoiridium(III) mono- and bis-intercalators with rigid bridging ligands: synthesis, cytotoxicity and DNA binding.
The DNA binding and in vitro cytotoxicity of the dinuclear Ir(III) polypyridyl complexes [{(eta(5)-C(5)Me(5))Ir(dppz)}(2)(mu-pyz)](CF(3)SO(3))(4)1 and [{(eta(5)-C(5)Me(5))Ir(pp)}(2)(mu-4,4'-bpy)](CF(3)SO(3))(4)2-4 (pp=dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), dipyrido[2,3-a:2',3'-c]phenazine (dppz), benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn)) with the rigid bridging ligands pyrazine (pyz) or 4,4'-bipyridine (4,4'-bpy) have been studied. Stable intercalative binding into CT DNA (calf thymus DNA) is indicated for the dppz complexes 1 and 3 by induced negative CD bands at about 300nm and large viscosity increases, with the individual measurements being in accordance with intrastrand bis-intercalation for 3 and mono-intercalation for 1. The observed interruption of specific interresidue NOE cross peaks from the relevant nucleobase H6/H8 protons to the sugar H2'/H2'' protons of the preceding nucleotide is in accordance with bis-intercalation of complex 3 between the C3G18 and G4C17 base pairs and the T5A16 and A6T15 base pairs of the decanucleotide d(5'-CGCGTAGGCC-3'). Complexes 1 and 3 exhibit a greatly improved uptake by HT-29 (colon carcinoma) cells and significantly improved in vitro IC(50) values of 1.8+/-0.1 and 3.8+/-0.1microM towards this cell line in comparison to the mononuclear complex [(eta(5)-C(5)Me(5))IrCl(dppz)](CF(3)SO(3)) (IC(50)=7.4+/-0.9microM).
Ali Nazif
Mhd
M
Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstr. 150, D-44780 Bochum, Germany.
Bangert
Jan-Amadé
JA
Ott
Ingo
I
Gust
Ronald
R
Stoll
Raphael
R
Sheldrick
William S
WS
D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007495:Iridium / Q000737:chemistry / Q000494:pharmacology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D003603:Cytotoxins; D007364:Intercalating Agents; D009942:Organometallic Compounds; D007495:Iridium; D004247:DNA; C427203:calf thymus DNA