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Influence of the Linker Length on the Cytotoxicity of Homobinuclear Ruthenium(II) and Gold(I) Complexes

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Batchelor Lucinda K., Păunescu Emilia, Soudani Mylène, Scopelliti Rosario, Dyson Paul J.,
Project Modulation of the site specificity of binding of metal-based drugs to chromatin
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Original article (peer-reviewed)

Journal Inorganic Chemistry
Volume (Issue) 56(16)
Page(s) 9617 - 9633
Title of proceedings Inorganic Chemistry
DOI 10.1021/acs.inorgchem.7b01082

Abstract

The clinical success of cisplatin resulted in considerable efforts being directed toward the development of other platinum- based therapeutics.1 However, the need to overcome the adverse side effects and intrinsic or acquired resistance to these compounds led to the investigation of alternative metals for their therapeutic potential.2 Ruthenium(III) complexes imida- zolium [trans-tetrachloro(1H-imidazole)(S-dimethyl sulfoxide)- ruthenate(III)]3 and indazolium trans-[tetrachlorobis(1H- indazole)ruthanate(III)] (KP1019)4−6 and its sodium analogue (NKP1339)7 have completed phase I and I/II clinical trials. Ruthenium(II) organometallic compounds have also attracted attention because they exhibit a number of promising pharmacological properties.8−10 For example, the so-called RAPTA complexes (Figure 1),11 of the general formula [Ru(η6- arene)(PTA)X2] (PTA = 1,3,5-triaza-7-phosphaadamantane), and the RAED complexes, [Ru(η6-arene)(en)Cl]+ (en = ethylenediamine),12 have been particularly well studied for their anticancer properties. RAPTA-C13 and RAED-C,14 (where C = p-cymene) along with their derivatives exhibit an array of promising in vitro and in vivo properties.9,12,13,15−19 Interestingly, crystallographic studies on the nucleosome core particle have shown that the choice of ligand strongly influences the biomolecular target of ruthenium(II) arene complexes with RAED-C preferentially binding to DNA and RAPTA-C binding to the histone proteins.20,21 Mononuclear gold(I) phosphine complexes have been evaluated for anticancer properties and exhibit promising activity.22−25 Auranofin (1-thio-β-D-glucopyr- anose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold(I) (Figure 1), which is used clinically for the treatment of rheumatoid arthritis,25,26 is currently being repositioned as an anticancer drug.27−32 Similar to RAPTA complexes,33,34 auranofin preferentially binds to cysteine-rich proteins such as thioredox- in reductase (TrX).35−37 Multinuclearity, i.e., covalently connecting two or more metal centers via an appropriate linker, emerged as an approach to introducing new modes of action to overcome resistance in chemoresistant cancers.38 The trinuclear platinum compound [{trans-PtCl(NH3)2}2-μ-(trans-Pt(NH3)2{H2N(CH2)6- NH2}2]4+] (BBR3464; Figure 1) can overcome cisplatin resistance, and it exhibits a profile of antitumor efficacy distinct from that of cisplatin in a number of preclinical models.39 However, despite successfully passing phase I clinical trials, BBR3464 failed a phase II evaluation, with only a minor response observed in small lung cancer and gastric/gastro- esophageal adenocarcinoma.40,41 A growing number of multinuclear ruthenium(II) and gold(I) complexes have also been reported.38 Interest in homobimetallic ruthenium(II) complexes has focused on the structure−reactivity investigations and the use of bioactive bridging ligands such as thiosemicarbazones.42,43 The influence of the spacer length on in vitro anticancer activity has previously been explored using bis(pyridinone)alkane linkers (η6-p-cymene)Ru(O,O-C6H5O2N(CH2)nNC6H5O2-O,O)Ru- (η6-p-cymene) (RU1, with n = 3, 6, 12; Figure 1), where the cytotoxicity correlates to the lipophilicity, which increases with increasing linker length.44 Both proteins and DNA were identified as possible targets for the dinuclear ruthenium(II) complexes, which hydrolyze rapidly to form active diaqua
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