Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity

نویسندگان

  • Zenita Adhireksan
  • Gabriela E. Davey
  • Pablo Campomanes
  • Michael Groessl
  • Catherine M. Clavel
  • Haojie Yu
  • Alexey A. Nazarov
  • Charmian Hui Fang Yeo
  • Wee Han Ang
  • Peter Dröge
  • Ursula Rothlisberger
  • Paul J. Dyson
  • Curt A. Davey
چکیده

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents-the cytotoxic antiprimary tumour compound [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]-and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel 'atom-to-cell' approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Physicochemical Studies and Anticancer Potency of Ruthenium η6-p-Cymene Complexes Containing Antibacterial Quinolones

With the aim of exploring the anticancer properties of organometallic compounds with bioactive ligands, Ru(arene) compounds of the antibacterial quinolones nalidixic acid (2) and cinoxacin (3) were synthesized, and their physicochemical properties were compared to those of chlorido(η(6)-p-cymene)(ofloxacinato-κ(2)O,O)ruthenium(II) (1). All compounds undergo a rapid ligand exchange reaction from...

متن کامل

Maltol-derived ruthenium-cymene complexes with tumor inhibiting properties: the impact of ligand-metal bond stability on anticancer activity in vitro.

Organometallic ruthenium-arene compounds bearing a maltol ligand have been shown to be nearly inactive in in vitro anticancer assays, presumably due to the formation of dimeric Ru(II) species in aqueous solutions. In an attempt to stabilize such complexes, [Ru(eta(6)-p-cymene)(XY)Cl] (XY=pyrones or thiopyrones) complexes with different substitution pattern of the (thio)pyrone ligands have been ...

متن کامل

Solution Equilibrium Studies of Anticancer Ruthenium(II)--p-cymene Complexes of Pyridinecarboxylic Acids

Stoichiometry and stability of antitumor ruthenium(II)-η-p-cymene complexes of picolinic acid and its 6-methyl and 6-carboxylic acid derivatives were determined by pHpotentiometry, H NMR spectroscopy and UV/Vis spectrophotometry in aqueous solution in the presence or absence of coordinating chloride ions. The picolinates form exclusively monoligand complexes in which they can coordinate via the...

متن کامل

Influence of the Arene Ligand, the Number and Type of Metal Centers, and the Leaving Group on the in Vitro Antitumor Activity of Polynuclear Organometallic Compounds

Dinuclear ruthenium complexes were shown to exhibit strong antiproliferative properties in human tumor cell lines. In order to extend the structure-activity relationships (SARs), a series of new Ru(arene)X complexes (X = Cl, Br, I) linked by pyridinone-based spacers were synthesized and assayed for their in vitro antineoplastic effect. The SARs were established in terms of the arene ligand, the...

متن کامل

Ruthenium based catalysts for olefin hydrosilylation: dichloro(p-cymene)ruthenium and related complexes.

We report our third and final investigation into the use of ruthenium based compounds for catalyzing the hydrosilylation of methylvinyldimethoxysilane with methyldimethoxysilane. The catalytic mechanism of dichloro(p-cymene)ruthenium(II) (B1) is examined and compared to that of previously studied, less active catalysts. Density functional theory (DFT) has been applied to explore the possibility...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 5  شماره 

صفحات  -

تاریخ انتشار 2014