Bis- and Tris-DNA Intercalating Porphyrins Designed to Target the Major Groove: Synthesis of Acridylbis-arginyl-porphyrins, Molecular Modelling of Their DNA Complexes, and Experimental Tests

In order to increase the DNA binding affinity of a bis‐arginyl‐porphyrin which has been previously shown to bind preferentially in the major groove of the d(GGCGCC)2 sequence (Mohammadi et al., Biochemistry 1998, 37, 9165), we have synthesized bis‐ and tris‐intercalating derivatives in which one or both arginyl arms are connected through a flexible chain to an acridine ring. We report here the synthesis of these two molecules along with the molecular modelling of their complexes with a GC‐rich oligonucleotide encompassing the central d(GGCGCC)2 hexamer. The modelling computations showed that when the porphyrin was intercalated into the central d(CpG)2 site with both arginyl side‐chains bonded to the guanines flanking the intercalation site, the acridine ring(s) could intercalate immediately upstream from the central hexamer, but at the cost of substantial DNA conformational energy. A significant preference for major‐groove binding over minor‐groove binding was found. The results of circular dichroism studies and topoisomerase I‐unwinding experiments supported the bis‐ and tris‐intercalation of these derivatives. The bis‐acridyl derivative provided, as expected, greater stabilization against thermal denaturation than the mono‐acridyl and the parent bis‐arginyl‐porphyrin compounds. Based on the modelling results, the structures of derivatives can be tailored to facilitate tris‐intercalation in rigid GC‐rich sequences, and thereby enhance the selective targeting of GC base pairs by the arginyl side‐chains, by lengthening the porphyrin‐acridine connectors. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)