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., Biochemistry1998, 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)