Crystallographic and NMR evidence of the unusual N6,N7-didentate chelation of 3-methyladenine coordinated to the cytotoxic α-dichlorobis(2-phenylazopyridine)ruthenium(ii) complex

Abstract

Adenine bases have recently been found to coordinate to the cytotoxic alpha isomer of dichlorobis(2-phenylazopyridine)ruthenium(II) complexes in the rare imine form, stabilised by N6,N7-didentate coordination, which is now proven by X-ray structure determination of the compound -[Ru(azpy) 2 (3-MeAde ؊H )]PF 6 (azpy ‫؍‬ 2-phenyl-azopyridine, 3-MeAde ؊H ‫؍‬ deprotonated 3-methyladenine).Ruthenium complexes have attracted much attention in the search for new anticancer agents.1 The so-called α-isomer of the dichlorobis(2-phenylazopyridine)ruthenium() complexes, 2 α-[Ru(azpy) 2 Cl 2 ] (α corresponds to the isomer in which the coordination pairs Cl, N(py), and N(azo) are cis, trans and cis, respectively) shows remarkably high cytotoxicity against a series of human tumour cell lines.3 It is generally accepted that DNA might be the ultimate target for antitumour-active ruthenium complexes, 1 as in the case of antitumour-active platinum complexes.4 Therefore, the interaction of the cytotoxic α-[Ru(azpy) 2 Cl 2 ] with DNA-model bases has been studied. With 9-ethylguanine (9-EtGua) the monofunctional adduct α-[Ru(azpy) 2 (9-EtGua)(H 2 O)](PF 6 ) 2 is formed, fully characterised by NMR spectroscopy.5 The coordination of adenine bases to the α-[Ru(azpy) 2 ] moiety results in didentate coordination via the N6 and N7 atoms as concluded from NMR data 6 of α-[Ru(azpy) 2 (9-MeAde)](PF 6 ) 2 , and shown in the X-ray structure of α-[Ru(azpy) 2 (3-MeAde ϪH )](PF 6 ) 2 reported here. The single-crystal structure determination of α-[Ru(azpy) 2 -(3-MeAde ϪH )]PF 6 , 1, ‡ is the first crystallographic evidence of a mononuclear ruthenium() complex in which an adenine model base is present in the imine form and stabilised by chelating coordination via both its N7 and N6 atoms. There are some differences between 9-MeAde and 3-MeAde like the increased ligating power of 3-alkylated 6-aminopurines over the 9-alkylated 6-aminopurines 7 and tautomeric structures 8 (Fig. 1). Nevertheless, the coordination mode of 9-MeAde and Another example is a rhodium complex with a bridging 3-MeAde ligand (via the N7 and N6 sites). 10The molecular structure of 1 (Fig. 2) shows the 3-MeAde base coordinated in a didentate fashion via its N6 and N7 atoms. In fact the 3-MeAde ligand is found to be disordered over two positions, related by a two-fold rotation around the axis bisecting the angle N8-Ru-N28 (see Fig. S1, ESI). Since bond distances and valence angles of both components are linked, only geometric parameters for the major component are listed. The Ru-N6 distance of 2.215(10) Å and Ru-N7 distance of 2.033(11) Å are comparable to those in the polynuclear ruthenium structures [{Ru(ade)(η3ϩ (9-EtAde ϪH = deprotonated 9-ethyladenine) and [{Ru(5-AMP)(η 6 -p-MeC 6 -H 4 Pr)} 3 ]ؒ7.5H 2 O (5Ј-AMP = adenosine 5Ј-monophosphate) in which the adenine derivatives also coordinate in a N6,N7-didentate fashion.11 In contrast to 1, these complexes are polynuclear: the adenine derivatives function as bridging ligands via the N1 or N9 sites.The 3-MeAde ligand in 1 sho...

Head‐to‐Head Right‐Handed Cross‐Links of the Antitumor‐Active Bis(μ‐N,N′‐di‐p‐tolylformamidinato)dirhodium(II,II) Unit with the Dinucleotides d(GpA) and d(ApG)

“…Similar changes to the chemical shifts of the aromatic proton resonances of metalated adenine rings have been previously recorded in the literature 47. 48 Additionally, downfield shifts of the guanine H8 proton indicate metal binding to site N7 of the base 22. 23, 59…”

“…Metal binding to the exocyclic amino group N6, howA C H T U N G T R E N N U N G ever, may be accompanied by a concomitant shift of the amino proton to site N1, thus generating a metalated form of the rare adenine imino tautomer. [25,[44][45][46][47][48][49] The unprecedented binding modes and conformational characteristics encountered in the homopurine adducts [24] and [ [25] led us to undertake structural characterization of the mixed purine complexes…”

Chlorido-, aqua-, 9-ethylguanine- and 9-ethyladenine-adducts of cytotoxic ruthenium arene complexes containing O,O-chelating ligands

“…The complexes studied previously were Ru II arenes with 2 or 3 reactive sites and formation of tri-and tetranuclear species via bridging adenine derivatives appeared to be prevalent. Other reported ruthenium-containing structures have included chelated [45,46] and N7-coordinated [47] adenine derivatives.…”

Solution, solid state and biological characterization of ruthenium(III)-DMSO complexes with purine base derivatives

“…When N(9) is blocked, N(7) is the site of coordination and there are only few exceptions that violate these general guidelines [1]. The interactions of various ruthenium compounds with purine base derivatives have also attracted much attention [5][6][7][8][9][10][11][12][13][14]. One of the main goals of these studies with DNA model bases was to determine if and how ruthenium compounds would bind to DNA.…”