Gold(III) complexes with bipyridyl ligands: solution chemistry, cytotoxicity, and DNA binding properties.
Gold(III) compounds generally exhibit significant cytotoxic effects on cancer cell lines and are of potential interest as antitumor drugs. We report here on the solution chemistry, the cytotoxicity, and the DNA binding properties of two new bipyridyl gold(III) compounds: [Au(bipy)(OH)(2)][PF(6)] (1) and the organometallic compound [Au(bipy(c)-H)(OH)][PF(6)] (2) (bipy(c) = 6-(1,1-dimethylbenzyl)-2,2'-bipyridine). Both compounds are sufficiently soluble, and stable for hours, within a physiological buffer at 37 degrees C; [Au(bipy)(OH)(2)][PF(6)], at variance with [Au(bipy(c)-H)(OH)][PF(6)], is quickly and quantitatively reduced by ascorbate. Both compounds showed relevant cytotoxic effects toward the A2780S, A2780R, and SKOV3 tumor cell lines; lower effects were detected on the CCRF-CEM/S and CCRF-CEM/R lines. In most cases the mechanisms of resistance to CDDP are only marginally effective against these gold(III) complexes. The interactions of [Au(bipy)(OH)(2)][PF(6)] and [Au(bipy(c)-H)(OH)][PF(6)] with calf thymus DNA were investigated in vitro by various techniques to establish whether DNA represents a primary target for these compounds. Addition of saturating amounts of DNA did not affect appreciably the visible spectra of these gold(III) complexes. Some slight modifications of the CD spectra of calf thymus DNA and of the DNA melting parameters were observed; in any case, ultrafiltration experiments showed that binding of these gold(III) complexes to DNA is weak and reversible. The mechanistic implications of these findings are discussed.
Marcon
Giordana
G
CIRCMSB, local Unit of Florence, University of Florence, Florence, Italy.
Carotti
Stefania
S
Coronnello
Marcella
M
Messori
Luigi
L
Mini
Enrico
E
Orioli
Pierluigi
P
Mazzei
Teresita
T
Cinellu
Maria Agostina
MA
Minghetti
Giovanni
G
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D003956:Dialysis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006046:Gold; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; C453479:dihydroxo(bipyridine)gold(III); C453480:hydroxo(6-(1,1-dimethylbenzyl)-2,2'-bipyridine)gold(III); D015082:2,2'-Dipyridyl; D006046:Gold; D004247:DNA; D002945:Cisplatin