Metallo-intercalators and metallo-insertors

Abstract

Since the elucidation of the structure of double helical DNA, the construction of small molecules that recognize and react at specific DNA sites has been an area of considerable interest. In particular, the study of transition metal complexes that bind DNA with specificity has been a burgeoning field. This growth has been due in large part to the useful properties of metal complexes, which possess a wide array of photophysical attributes and allow for the modular assembly of an ensemble of recognition elements. Here we review recent experiments in our laboratory aimed at the design and study of octahedral metal complexes that bind DNA non-covalently and target reactions to specific sites. Emphasis is placed both on the variety of methods employed to confer site-specificity and upon the many applications for these complexes. Particular attention is given to the family of complexes recently designed that target single base mismatches in duplex DNA through metallo-insertion.

Fig. 1

The three binding modes of metal complexes with DNA: (a) groove binding, (b) intercalation, and (c) insertion.

Fig. 2

Geometries of (a) groove binder, (b) metallointercalator, (c) metalloinsertor.

Fig. 3

Λ– and Δ-enantiomers of [Rh(phen)₃]³⁺.

Fig. 4

Chemical structure of two common metallointercalators: (a) Δ-[Rh(phen)₂phi]³⁺ and Δ-[Ru(bpy)₂dppz]²⁺. The intercalating ligands are highlighted in blue, the ancillary ligands in yellow.

Fig. 5

Crystal structure of the metallointercalator Δ–α-[Rh[(R,R)-Me₂trien]phi]³⁺ bound to its target sequence, 5′-TGCA-3′.

Fig. 6

The light-switch effect of dppz-based metallointercalators..

Fig. 7

Chemical structures of (a) an artificial nuclease and (b) a luminescent cross-linking agent.

Fig. 8

Sequence-specific metallointercalators and their target sequences. The intercalation sites are marked with grey ovals.

Fig. 9

Chemical structures of mismatch-specific metalloinsertors.

Fig. 10

Crystal structure of the metalloinsertor (red) bound to a target CA mismatch.

Fig. 11

Luminescent probes for mismatch detection.

Fig. 12

Single nucleotide polymorphism detection using mismatch-directed photocleavage.

Fig. 13

Mismatch-specific conjugates for therapeutic applications.

Fig. 14

A mismatch-specific conjugate for nuclear uptake.

Fig. 15

Confocal microscopy of HeLa cells incubated with Ru(DIP)₂dppz²⁺.