Inhibition of Transcription in Vitro by Anticancer Active Dirhodium(II) Complexes

Abstract

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.

Glutathione binding to dirhodium tetraacetate: a spectroscopic, mass spectral and computational study of an anti-tumour compound

“…Such interactions likely reduce the efficacy of these metallodrugs. Dirhodium(II) carboxylates and their derivatives are an emerging class of anti-tumour compounds that are described as exhibiting greater potency than cisplatin in vitro [32][33][34][35][36][37][38] . However, significantly, with respect to possible cellular chemistry, rhodium(II) carboxylates bind strongly to sulfur containing compounds 32,33,35,37,[39][40][41] .…”

“…Indeed, the propensity for these rhodium complexes to deplete intracellular thiols makes them especially useful as radiosensitizers 42,43 . Other classes of dirhodium carboxylates, such as the Rh2(O2CR)4 (R = Me, Et, Pr), display potent anti-tumour activity that stems from their ability to inhibit enzymes with sulfylhydryl groups in their active sites 33,34,44 . Dirhodium(II) tetraacetate (Rh2(OAc)4) is a bimetallic complex with four bridging acetate ligands bound in an octahedral geometry, with an empty axial site usually coordinated by solvent.…”

“…Dirhodium(II) tetraacetate (Rh2(OAc)4) is a bimetallic complex with four bridging acetate ligands bound in an octahedral geometry, with an empty axial site usually coordinated by solvent. This complex is capable of inhibiting DNA polymerase I and RNA polymerase, showing cytotoxic behaviour in vivo against L1210 tumours, Ehrlich ascites, and the sarcoma 180 and P388 tumour lines, as well as exhibiting DNA-binding in a manner similar to that of cisplatin 34,35,45,46 . However, because of the strong, sulfur-binding properties of dirhodium(II) carboxylates, intracellular thiols like glutathione may prevent these rhodium-based therapeutics from reaching their intended target unchanged, especially with the Rh axial bioactive site remaining available.…”

Rhenium–platinum antitumor systems

“…An important paradigm for the development of new antitumor pharmaceuticals is represented by dinuclear carboxylate complexes of rhodium, ruthenium and rhenium with so-called 'chinese lantern' structure [8][9][10]. It was postulated that such species could bind to DNA, inhibit DNA replication and protein synthesis [11,12] in a manner similar to cisplatin [4,13,14]. Among this group, the dirhenium(III) compounds may be recognized as especially promi sing candidates for clinical development due to their very low toxicity [15].…”

Interactions of Metal—Metal‐Bonded Antitumor Active Complexes with DNA Fragments and DNA

“…Studies of the biological activity of dirhodium complexes conducted in the 1970s support the conclusion that tetracarboxylate compounds Rh 2 (µ-O 2 CR) 4 (R ) Me, Et, Pr) exhibit significant in vivo antitumor activity against L1210 tumors, 10 Ehrlich ascites, 8,9,11,12 sarcoma 180, and P388 tumor lines. 4 Although the precise antitumor mechanism of dirhodium carboxylate compounds has not been elucidated, it is known that they bind to DNA 8,9,13-15 and inhibit DNA replication and protein synthesis [16][17][18] in a manner akin to cisplatin.…”