Inhibition of transcription in vitro by anticancer active dirhodium(II) complexes.
The DNA binding and inhibition of transcription in vitro by neutral Rh(2)(mu-O(2)CCH(3))(4) and cationic cis-[Rh(2)(mu-O(2)CCH(3))(2)(phen)(2)](2+) complexes were investigated. The binding constants of the two complexes to calf-thymus DNA were estimated from absorption titrations to be 4.6 x 10(2) M(-)(1) and 1.7 x 10(4) M(-)(1) for Rh(2)(mu-O(2)CCH(3))(4) and cis-[Rh(2)(mu-O(2)CCH(3))(2)(phen)(2)](2+), respectively. The shift to higher energies of the low-energy absorption of the complexes upon addition of DNA is consistent with axial binding of the complexes to duplex DNA. The relative concentrations, [complex]/[DNA], of Rh(2)(mu-O(2)CCH(3))(4) and cis-[Rh(2)(mu-O(2)CCH(3))(2)(phen)(2)](2+) at which 50% of the transcription is inhibited (R(inh)(50)), are 0.0031 and 0.0011, respectively. These concentrations are significantly lower than that required for activated cisplatin, cis-[Pt(NH(3))(2)(H(2)O)(2)](2+), with R(inh)(50) = 0.0085 under similar experimental conditions. Upon incubation of cis-[Pt(NH(3))(2)(H(2)O)(2)](2+) with the template DNA prior to the addition of the enzyme and nucleobases necessary for the transcription reaction for 30 min at 37 degrees C, significantly lower concentrations of the complex were required to attain 50% inhibition. In contrast, similar incubation of the DNA with the dirhodium complexes did not result in better transcription inhibition. Experiments designed to elucidate the mechanism of the observed inhibition indicate that, unlike cis-[Pt(NH(3))(2)(H(2)O)(2)](2+), Rh(2)(mu-O(2)CCH(3))(4) and cis-[Rh(2)(mu-O(2)CCH(3))(2)(phen)(2)](2+) appear to interact directly with the enzyme T7-RNA polymerase as their mode of inhibition.
Sorasaenee
Karn
K
Department of Chemistry, Texas A&M University, College Station, Texas 77843, USA.
Fu
Patty K-L
PK
Angeles-Boza
Alfredo M
AM
Dunbar
Kim R
KR
Turro
Claudia
C
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004587:Electrophoresis, Agar Gel; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy / Q000295:instrumentation / Q000379:methods; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012313:RNA / Q000187:drug effects; D012238:Rhodium / Q000737:chemistry*; D013237:Stereoisomerism; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014764:Viral Proteins
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D014764:Viral Proteins; D012313:RNA; D004247:DNA; C427203:calf thymus DNA; D012238:Rhodium; C062210:bacteriophage T7 RNA polymerase; D012321:DNA-Directed RNA Polymerases; D002945:Cisplatin