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.

The interaction of native calf thymus DNA with FeIII-dipyrido[3,2-a:2′,3′-c]phenazine

“…In the last decades the synthesis of transition metal complexes that interact with DNA has attracted wide interest for their potential applications as diagnostic probes, anticancer or therapeutics agents and in genomic research [1][2][3]. Transition metal complexes present different advantages as DNA-binding agents.…”

“…Transition metal complexes present different advantages as DNA-binding agents. The metal center offers in fact the possibility of a facile interchange of ligands as well as unique photophysical and electrochemical properties [2]. In this context, particular attention has been devoted to the interaction of DNA with chiral octahedral MðdiimineÞ nþ 3 type complexes [4], in particular with the heteroleptic [M(phen) 2 dppz] 2+/3+ complexes (M = Ru 2+ , Co 3+ , Cr 3+ , Fe 2+ , Os 2+ , Ni 2+ , phen = 1,10-phenantroline, dppz = dipyrido[3,2-a:2 0 ,3 0 -c]phenazine) [3,[5][6][7][8].…”

“…The metal center offers in fact the possibility of a facile interchange of ligands as well as unique photophysical and electrochemical properties [2]. In this context, particular attention has been devoted to the interaction of DNA with chiral octahedral MðdiimineÞ nþ 3 type complexes [4], in particular with the heteroleptic [M(phen) 2 dppz] 2+/3+ complexes (M = Ru 2+ , Co 3+ , Cr 3+ , Fe 2+ , Os 2+ , Ni 2+ , phen = 1,10-phenantroline, dppz = dipyrido[3,2-a:2 0 ,3 0 -c]phenazine) [3,[5][6][7][8]. Barton and coworkers have shown that the dppz ligand (Scheme 1) in such tris-chelates of metal ions displays significant DNA intercalating ability, preferentially at the major groove side, because of its extended aromatic moiety, while the phenanthroline ligands prefer to bind at the minor groove of DNA [2].…”

“…The latter property has been in fact observed, for example, in [Au(dppz) 2 ]Cl 3 [9], [Cu(dppz)(NO 3 )](NO 3 ) [10], [Cu(dppz) 2 -(NO 3 )](NO 3 ) [10], [Ru(NH 3 ) 4 dppz] 2+ [11], [Ru(L) 4 dppz] 2+ (L = imidazole (Im) or 1-methylimidazole (MeIm)) [12], [Cr(dppz) 2 Cl 2 ] + [13]. Nevertheless, due to the limited number of investigations and with the possible sole exception of ruthenium-dppz complexes, detailed information is lacking on the influence of non-chelating ancillary ligands on the stability and optical properties of dppz transition metal complexes and on their DNA-binding modes.…”

“…Concerning the properties of mono-dppz ruthenium complexes with non-chelating ancillary ligands, it has been reported that both complexes [Ru(NH 3 ) 4 dppz] [11] and [Ru(CN) 4 dppz] [15] show different DNA-binding mode or optical properties compared to the related complex [Ru(bpy) 2 dppz] and to the widely studied [Ru(phen) 2 dppz]. On the other hand, (ImH)[trans-RuCl 4 (DMSO-S)(Im)] (known as Ru-NAMI-A) has successfully completed Phase I clinical trials as anticancer agent [16] and, interestingly, it has been recently inferred that its hydrolysis is a crucial step for the mechanism of its anticancer activity [17].…”