DNA RECOGNITION BY RHODIUM(III) POLYAMINE INTERCALATORS - CONSIDERATIONS OF HYDROGEN-BONDING AND VANDERWAALS INTERACTIONS

A series of 9,10-phenanthrenequinone diimine (phi) complexes of rhodium have been prepared so as to systematically explore contributions of hydrogen bonding and van der Waals interactions to DNA site specificity. The novel, synthetic complexes LAMBDA- and DELTA-[Rh(en)2phi]3+ (2), as well as the analogs [Rh(NH3)4phi]3+ (1), [Rh([12]aneN4)-phi]3+ (3), and [Rh([12]aneS4)phi]3+ (4) (en = ethylenediamine, [12]aneN4 = 1,4,7,10-tetraazacyclododecane, [12]-aneS4 = 1,4,7, 10-tetrathiacyclododecane) bind in the major groove of DNA via intercalation and promote DNA strand cleavage upon activation with UV light. Complexes 1, DELTA-2, and 3, all of which contain axial amines, display a high sequence preference for 5'-GC-3' steps which is not observed for 4. The 5'-GC-3' preference is attributed to the hydrogen-bonding interactions between the amine ligands and the guanine O6 atoms in the major groove. Complex 4, which lacks hydrogen bond donating groups in the axial positions, shows instead a high degree of specificity for a 5'-ATG-3' site which is best explained by shape selection. LAMBDA-2 cleaves DNA with lower sequence selectivity but cleaves enantioselectively at 5'-TX-3' steps. Photocleavage of an oligonucleotide containing the substitution of 5'-UA-3' for 5'-TA-3' shows no similar enantioselectivity, and hence chiral recognition of the 5'-TA-3' step is attributed to van der Waals interactions between the methylene groups of the LAMBDA-isomer and the thymine methyl groups in the major groove of DNA. These results provide a first example of binding and photoactivated cleavage using saturated amines and macrocyclic thioethers as ancillary ligands in DNA recognition by metallointercalators and illustrate how discrete elements of molecular recognition may direct specificity for a DNA site.