Four trimethoxy-and dimethoxyphenylamine-based Schiff base (L1−L4)-bearing Ru II −p-cymene complexes (1−4) of the chemical formula [Ru II (η 6 -p-cymene)(L)(Cl)] were synthesized, isolated in pure form, and structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The complexes showed excellent in vitro antiproliferative activity against *
Oxamusplatin shows enhanced selectivity towards cancer, targets cellular DNA, disrupts the microtubule network and strongly resists sequestration by deactivating agents, glutathione, ATP7B or phosphoglycoproteins.
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Ruthenium(II/III) complexes are predicted to be effcient alternatives to platinum drug-resistant cancers but have never been investigated for sequestration and efflux by Cu-ATPases (ATP7A or ATP7B) overexpressed in resistant cancer cells, although a major cause of platinum drug resistance is found to be sequestration of platinum chemotherapeutic agents by thiol donors glutathione (GSH) or the Cys−X−X−Cys (CXXC) motifs in the Cu-ATPases in cytosol. Here, we show for the first time that ATP7B effciently sequesters ruthenium(II) η 6-p-cymene complexes. We present seven complexes, [Ru II (η 6-p-cym)(L)X](PF 6) (1−7; L = L1−L3, X = Cl, Br, and I), out of which two resists deactivation by the cellular thiol, glutathione (GSH). The results show that Ru −I coordination and a moderate steric factor increase resistance to GSH and the CXXC motif. Ru II −I-coordinated 3 and 7 showed resistance to sequestration by ATP7B. 3 displays highest resistance against GSH and does not trigger ATP7B trafficking in the liver cancer cell line. It escapes ATP7B-mediated sequestration and triggers apoptosis. Thus, with a suitable bidentate ligand and iodido leaving group, Ru II (η 6-p-cym) complexes may display strong kinetic inertness to inhibit the ATP7B detoxification pathway. Inductively coupled plasma mass spectrometry data show higher retention of 3 and 7 inside the cell with time compared to 4, supporting ATP7B-mediated sequestration.
Mutation in ATP7B gene causes Wilson disease (WD) that is characterized by severe hepatic and neurological symptoms. ATP7B localizes at the trans-Golgi Network (TGN) transporting copper to copper-dependent enzymes and traffics in apically targeted vesicles upon intracellular copper elevation. To decode the cellular underpinnings of WD manifestation we investigated copper-responsive polarized trafficking and copper transport activity of 15 WD causing point mutations in ATP7B. Amino-terminal mutations Gly85Val, Leu168Pro, and Gly591Asp displayed TGN and subapical localization whereas, Leu492Ser mislocalized at the basolateral region. The actuator domain mutation Gly875Arg shows retention in the endoplasmic reticulum (ER), Ala874Val and Leu795Phe show partial targeting to TGN and post-Golgi vesicles. The nucleotide-binding domain mutations His1069Gln and Leu1083Phe also display impaired targeting. The C-terminal mutations Leu1373Pro/Arg is arrested at ER but Ser1423Asn shows TGN localization. Transmembrane mutant Arg778Leu resides in ER and TGN while Arg969Gln is exclusively ER localized. Cellular Cu level does not alter the targeting of any of the studied mutations. Mutants that traffic to TGN exhibits biosynthetic function. Finally, we correlated cellular phenotypes with the clinical manifestation of the two most prevalent mutations; the early onset and more aggressive WD caused by Arg778Leu and the milder form of WD caused by mutation His1069Gln.
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