Preferred orientation in an angled intercalation site of a chloro-substituted Λ -[Ru(TAP) ₂ (dppz)] ²⁺ complex bound to d(TCGGCGCCGA) ₂

Abstract

The crystal structure of the ruthenium DNA ‘light-switch’ complex Λ -[Ru(TAP) 2 (11-Cl-dppz)] 2+ (TAP=tetraazaphenanthrene, dppz=dipyrido[3,2- a ′:2′,3′- c ]phenazine) bound to the oligonucleotide duplex d(TCGGCGCCGA) 2 is reported. The synthesis of the racemic ruthenium complex is described for the first time, and the racemate was used in this study. The crystal structure, at atomic resolution (1.0 Å), shows one ligand as a wedge in the minor groove, resulting in the 51 ° kinking of the double helix, as with the parent Λ -[Ru(TAP) 2 (dppz)] 2+ . Each complex binds to one duplex by intercalation of the dppz ligand and also by semi-intercalation of one of the orthogonal TAP ligands into a second symmetrically equivalent duplex. The 11-chloro substituent binds with the major component (66%) oriented with the 11-chloro substituent on the purine side of the terminal step of the duplex.

X‐ray Crystal Structures Show DNA Stacking Advantage of Terminal Nitrile Substitution in Ru‐dppz Complexes

“…The structureo btained ( Figure 3e)w as isomorphoust ot hat seen with the L-11-Cl analogue with af lipped-out A10 stacked on as ymmetry equivalent dppz ligand and 2:1d isorder of the 11-Br-dppz ligand. [30] The major Br orientation is on the "purines ide" of the open intercalation cavity.U nlike the effect of 11-CN substitution,t here is no water network around the Br positions, despite the high data resolution and the location of 88 water molecules per DNA strand ( Figures S7 and S8). The Br atom projects directly into the disordered part of the solvents pace.…”

“…Ta ble 1c ompares the dihedrala ngles derivedi nt he present work for the T1C2/G9A10s tep with those from our previous work on -Cl and -Me substitution, which in every case gave g dihedrala ngles in the gauche range of 57-608 on the pyrimidine side. [30,35] In all these cases the cavity was incomplete. Interestingly,f or the first time with the 11-Br substitution we see a gauche dihedral angle at the purine G9ÀA10 as well, which on closer inspection reveals that, what in the other structures is an unfavourable interaction, may insteadb ea na ttractive interaction between the C3'ÀOH and the bromine atom, with an O3'ÀBr separation of 4.2 .…”

“…The major orientation of the 11-CN substituent, shown in both Figure 3a nd Figure 5, and for the 11-Br substituent in Figure 3, corresponds to that previously seen for 11-Me and 11-Cl substitution. [30,35] The effect on the water structure is different, however.H ere we observe direct hydrogen bonding to the nitrile Na tom when bound to DNA ( Figure S4), also present with the 11,12-diCN ligand ( Figure S10), creatinga dditional water ordering. Strikingly,t he methyl group substitution seen with the asymmetric1 0-Me-, 11-Me-and 10,12-Me 2 -dppz [35] are the most strongly directional (where total ordering was seen with X-ray data to 0.9 resolution in each of these cases),a nd here the ordered water creates ac age around the ligand,b ut there is no ordered water structurea roundt he methyl groups in the major groove ( Figure S11).…”

Delta chirality ruthenium ‘light-switch’ complexes can bind in the minor groove of DNA with five different binding modes

“…In contrast to this, the interaction of the Λ enantiomer appears relatively straightforward: Λ-[Ru(phen) 2 (dppz)] 2+ has been shown to intercalate into well-matched DNA and, both it and the isostructural Λ-[Ru(TAP) 2 (dppz)] 2+ , bind selectively to 5′-TA-3′ steps and not 5′-AT-3′ in both the crystal state and solution (15). The effects of introducing methyl (16) and chloro (17) substitutions onto the dppz group have also been examined, and the resulting DNA structures were isomorphous with those reported for the parent compound, while displaying site preferences for asymmetric substitution.…”

Ruthenium Complex “Light Switches” that are Selective for Different G‐Quadruplex Structures

“…[16] In contrast, the parent complex, L-[Ru(TAP) 2 dppz] 2 + ,c an intercalate more symmetrically, preventing any partial water occupancy. [16] As association between water molecules and one or more of the phenazine nitrogen atoms results in population of the "dark" state, [17] the interaction of aw ater molecule with the Cl-substituted ligand would be expected to result in reduced luminescence when the complex is bound to duplex DNA. [18] Given the binding orientation of the dppz-Cl ligand in duplex DNA, we hypothesized as imilars ubstitution would induce ac omparable binding mode.…”