Bifunctional Rhodium Intercalator Conjugates as Mismatch-Directing DNA Alkylating Agents

Abstract

A conjugate of a DNA mismatch-specific rhodium intercalator, containing the bulky chrysenediimine ligand, and an aniline mustard has been prepared, and targeting of mismatches in DNA by this conjugate has been examined. The preferential alkylation of mismatched over fully matched DNA is found by a mobility shift assay at concentrations where untethered organic mustards show little reaction. The binding site of the Rh intercalator was determined by DNA photocleavage, and the position of covalent modification was established on the basis of the enhanced depurination associated with N-alkylation. The site-selective alkylation at mismatched DNA renders these conjugates useful tools for the covalent tagging of DNA base pair mismatches and new chemotherapeutic design.

DNA Strand Cleavage near a CC Mismatch Directed by a Metalloinsertor

“…[12][13][14] Studies of these conjugates demonstrate that the Rh moiety tunes the reactivity of the agent linked to the metalloinsertor. Figure 1) promotes lightindependent DNA backbone cleavage showing more localized cleavage sites than those generated by [Fe(EDTA)] 2−.15-17 The complex Cu tethered to various DNA-binding moieties exhibits efficient DNA scission.…”

“…The Rh complex [Rh (bpy) 2 (chrysi)] 3+ in Rh+Cu ( Figure 1) was synthesized as described. 18 For the conjugate Rh −Cu, we prepared its 12 with the modified phen ligand (phen' = 5-(1,10-phenanthrolin-5-ylamino)-5-oxopentanoic acid), 19 as described in Scheme 1 and Supporting Information. Copper coordination was accomplished in situ (vide infra), affording the conjugate Rh−Cu.…”

2D NMR Spectroscopic Evidence for Unprecedented Interactions of cis‐[Rh2(dap)(μ‐O2CCH3)2(η1‐O2CCH3)(CH3OH)](O2CCH3) with a DNA Oligonucleotide: Combination of Intercalative and Coordinative Binding

“…The assignment of the N7 atom of residue A6 as the binding site of the dirhodium complex, instead of the N7 atom of residue A7, is mainly due to the downfield chemical shift of the H8 proton of A6 (Dd = 0.14 ppm) in contrast to the upfield shift (Dd = À0.12 ppm) of the H8 proton of the A7 residue. The downfield shift of A6H8 is rather small when compared with the dirhodium adduct from the reaction of Rh 2 (O 2 CCH 3 ) 4 with the same AA12 mer (Dd = 0.55 ppm) [29] in which the dirhodium unit binds to the N7 atom of the A6 residue. In the present case, however, the change in chemical shift for A6H8 reflects both the downfield shift induced by the coordinative binding of the metal on the protons near the metal-binding site (inductive effect) [30] and the upfield shift induced by the intercalation effect on the protons located above or below the intercalator, due to the ring current of the aromatic group.…”

Erzwingung oder Erkennung einer dreiarmigen DNA‐Kreuzung: Metall‐Tripelhelicat trifft Doppelhelix

“…[15] Selbst die Erkennung von Basenfehlpaarungen mittels intercalierender Metallkomplexe ist möglich; [16] die Kombination alkylierender Seitengruppen mit intercalierenden Einheiten in entsprechenden Konjugaten ermöglicht die kovalente Markierung fehlgepaarter DNA-Basen und weist Wege zu neuen chemotherapeutischen Wirkstoffen. [17] Allerdings geht nicht jeder Komplex, der aufgrund planarer aromatischer Liganden theoretisch intercalieren kann, auch diese Art der Bindung ein. So wurde für einige Beispiele eine Abhängigkeit der Art der Bindung von Faktoren wie der DNA-Basensequenz, dem Substitutionsmuster des aromatischen Liganden und der relativen Konzentration von DNA und Metallkomplex postuliert.…”