Ruthenium(II) Diphosphine Complexes with Mercapto Ligands That Inhibit Topoisomerase IB and Suppress Tumor Growth In Vivo

Abstract

Ruthenium­(II) complexes (Ru1–Ru5), with the general formula [Ru­(N-S)­(dppe)2]­PF6, bearing two 1,2-bis(diphenylphosphino)­ethane (dppe) ligands and a series of mercapto ligands (N-S), have been developed. The combination of these ligands in the complexes endowed hydrophobic species with high cytotoxic activity against five cancer cell lines. For the A549 (lung) and MDA-MB-231 (breast) cancer cell lines, the IC50 values of the complexes were 288- to 14-fold lower when compared to cisplatin. Furthermore, the complexes were selective for the A549 and MDA-MB-231 cancer cell lines compared to the MRC-5 nontumor cell line. The multitarget character of the complexes was investigated by using calf thymus DNA (CT DNA), human serum albumin, and human topoisomerase IB (hTopIB). The complexes potently inhibited hTopIB. In particular, complex [Ru­(dmp)­(dppe)2]­PF6 (Ru3), bearing the 4,6-diamino-2-mercaptopyrimidine (dmp) ligand, effectively inhibited hTopIB by acting on both the cleavage and religation steps of the catalytic cycle of this enzyme. Molecular docking showed that the Ru1–Ru5 complexes have binding affinity by active sites on the hTopI and hTopI-DNA, mainly via π-alkyl and alkyl hydrophobic interactions, as well as through hydrogen bonds. Complex Ru3 displayed significant antitumor activity against murine melanoma in mouse xenograph models, but this complex did not damage DNA, as revealed by Ames and micronucleus tests.

Enantioselective Cytotoxicity of Chiral Diphosphine Ruthenium(II) Complexes Against Cancer Cells

“…It is worth pointing out that the arene ruthenium complexes which have been investigated as promising anticancer drugs [33–35] can be involved in the disruption of the cellular redox homeostasis via NADH transfer hydrogenation, as well as GSH metal thiol binding and oxidation [36] . Conversely, only few studies have been reported on the use of diphosphine ruthenium hydrogenation catalysts as efficient anticancer systems [37–40] …”

“…[36] Conversely, only few studies have been reported on the use of diphosphine ruthenium hydrogenation catalysts as efficient anticancer systems. [37][38][39][40] Herein we report the isolation of the cationic enantiomer complexes [RuX(CO)(PP)(phen)]Y (X, Y = carboxylates, thioacetate, PP = (R,R)-or (S,S)-Skewphos) [21] and their behaviour with (S)-cysteine and GSH via formation of aquo complexes. Remarkably different and very promising cytotoxic activity toward several cell lines has been observed for the couples of enantiomers.…”

Hyphenation of lipophilic ruthenium(ii)-diphosphine core with 5-fluorouracil: an effective metallodrug against glioblastoma brain cancer cells

“…2b); this was also reported earlier by Batista et al in [Ru(dppe) 2 (N–S)]PF 6 complexes, (where N–S = mercapto ligands). 22 Thus, the four P-atoms in two dppe ligands were chemically and magnetically non-equivalent in [Ru II (dppe) 2 (5-FU)](PF 6 ) ( Ru-DPPE-5FU ) as also evident from the crystal structure. A characteristic 31 P heptet signal around −143 ppm also confirmed the presence of PF 6 − as a counter anion.…”

New ruthenium(ii) complexes with cyclic thio- and semicarbazone: evaluation of cytotoxicity and effects on cell migration and apoptosis of lung cancer cells

“…Studies by Velozo-Sá et al 54 showed that ruthenium( ii ) complexes with the formula [Ru(pymS)(dppm) 2 ]PF 6 and [Ru(pymS)(dppe) 2 ]PF 6 , where pymS = 2-mercaptopyrimidine anion, were cytotoxic to both A549 and MDA-MB-231 tumor cells, with SI close to 5 and 10, respectively. Ribeiro et al 55 investigated ruthenium( ii ) complexes bearing five mercapto ligands with the general formula [Ru(N-S)(dppe) 2 ]PF 6 . Among the five cancer cells line examined by these authors, the complexes were selective toward the A549 and MDA-MB-231 cell lines when compared to MRC-5, a non-tumor cell line.…”