Metallointercalators

Metallointercalators, Organic Intercalators and Modified Bases as Probes... 

Redox participants are chosen to facilitate spectroscopic, biochemical and electrochemical probing of DNA CT. These include metallointercalators, organic intercalators, and modified bases that possess useful, well-described, and varied redox, photophysical and photochemical properties (Table 1). Our probes are readily incorporated into DNA assemblies where CT distances ranging from 3.4 to 200 A and driving forces spanning over two volts can be modulated with certainty. Most importantly, all redox probes which afford fast and/or efficient CT through DNA are well-coupled to the 7r-stack. 

Fig. 4 Coupling of the redox participants to the DNA w-stack is requisite to DNA-mediated charge transport. Rapid (>109 s 1) photoinduced electron transfer occurs between the metallointercalators, [Ru(phen)2dppz]2+ and [Rh(phi) 2phen]3+, when they are tethered to opposite ends of a DNA duplex over 40 A apart. Conversely, electron transfer does not occur between non-intercalated Ru(II) and Rh(III) complexes tethered to DNA...

However, careful kinetic measurements on related systems showed the invalidity of wire-type behavior [41]. Furthermore, Sen and coworkers [42] recently showed that the appearance of rapid, long-distance charge transfer for metallointercalators may be an artifact caused by the formation of aggregates. Currently, there are no data that clearly support the existence of a coherent transfer process in DNA over a distance greater than one or two base pairs [43, 44]. 

The first examples of DNA metallointercalators containing a 1,2- or 1,7-carborane thiolato ligand have been reported.349 For example, treatment of [Pt(OTf)(terpy)]+ (terpy = 2,2 6, 2 -terpyr-idine) with l-HSCH2-l,2-C2B10Hii leads to the formation of [Pt(l-SCH2-l,2-C2BioHn)(terpy)]+ (143). The DNA-binding properties of several complexes have also been described. 

Arkin MR, Stemp EDA, Elolmlin RE, Barton JK, Elormann A, Olson EJC, Barbara PF (1996) Rates of DNA-mediated electron transfer between metallointercalators. Science 273 475-480 ArmitageB (1998) Photocleavage of nucleic acids. Chem Rev 98 1171-1200... 

Dandliker PJ, Nunez ME, Barton JK (1998) Oxidative charge transfer to repair thymine dimers and damage guanine bases in DNA assemblies containing tethered metallointercalators. Biochemistry 37 6491-6502... 

Overlap Geometry A schematic representation of the proposed overlap geometry for proflavine intercalated into a deoxy pyrimidine(3 -5 )purine site is presented below with the (o) symbols representing the location of the phenanthridine ring protons. The mutual overlap of the two base pairs at the intercalation site involves features observed in the crystal structures of a platinum metallointercalator miniature dC-dG duplex complex (55) and the more recent proflavine miniature dC-dG duplex complex (48), as well as features derived in a linked-atom conformational calculation of the intercalation site in the proflavine DNA complex (51). [4]... 

ErkkUa KE, Odom DT, Barton JK. Recognition and reaction of metallointercalators. Chem Rev 1999 99 2777-95. 

Nunez ME, Barton JK. Probing DNA charge transport with metallointercalators. Curr Opin Chem Biol 2000 4 199-206. 

Arkin MR, Stemp EDA, Holmlin RE, et al. Rates of DNA-mediated electron transfer between metallointercalators. Science 1996 273 475-80. 

Odom DT, Parker CS, Barton JK. Site-specific inhibition of transcription factor binding to DNA by a metallointercalator. Biochemistry 1999 38 5155-63. 

Studies of metallointercalation agents [99-101] in the presence of dsDNA have been done with solutions containing the redox complexes... 

A doubly metallated 15 base-pair double helix containing ruthenium and rhodium at each end of the strands [106] showed the efficiency of DNA for coupling electron donors and acceptors over a very long range, greater than 40 A. The DNA double helix was found to behave like a piece of molecular wire with fast electron-transfer rates (>1010 s l) for the photoinduced electron transfer between the metallointercalators [107-109] and semiempirical Hartree-Fock calculations of HAB for DNA mediated electron transfer [110] were described. 

METALLOINTERCALATION REAGENTS THIOLATO COMPLEXES OF (2, 2 6, 2"-TERPYRIDINE)PLATINUM(II)... 

The metallointercalation reagents are a class of heavy metal derivatives that bind to double-stranded polynucleotides by inserting between adjacent base pairs in the helix.1 2 Prototype members of this class of intercalators are (2,2 6, 2"-terpyridine)(thiolato)platinum(II) complexes.3 These may be synthesized from chloro(2,2 6, 2"- terpyridine)platinum(II), which can both intercalate and bind covalently by losing chloride ion. Covalent binding of the thiolato complexes is much slower owing to the more inert character of the Pt—S bond. Metallointercalation reagents also have the potential to bind to proteins that have natural receptor sites for nucleic acid bases. They may therefore also be used to provide isomorphous heavy atom derivatives for X-ray analysis. 

To probe more effectively the role of the DNA 7r-way in mediating electron-transfer reactions, we now focus on avid metallointercalators with binding constants for intercalation of >107 M-1. The strong preference of these molecules to intercalate rather than groove-bind clarifies the relationship of the donor and acceptor to the DNA medium. 

Figure 2. Structures of donor and acceptor metallointercalators. The pho-toexcited donor [Ru(phen) 2(dppz)]2+ is shown on the left, and the acceptor [Rh(phi) 2(phen)]3+ is pictured on the right.

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