Replacement of the Bizelesin ureadiyl linkage by a guanidinium moiety retards translocation from monoalkylation to cross-linking sites on DNA

In this contribution we demonstrate that Bizelesin can translocate along the minor groove of DNA from a kinetically favored monoalkylation site to a thermodynamically favored cross-linking site. This translocation is prevented in compounds that have a charged guanidino linkage substituting for the ureadiyl linkage. Furthermore, the manipulative interplay of Bizelesin and the target sequence 5'-TAATTA (Seaman, F.C.; Chu, J.; Hurley, L.H. J. Am. Chem. Soc. 1996, 118, 5383-5395) that is required to produce a suitably rearranged product for cross-linking is prevented by the substitution of a guanidino for the ureadiyl linkage. A structural basis involving hydrogen bonding of the guanidino linkage with phosphates on the backbone of DNA is proposed to account for the absence of translocation, the slow conversion of monoalkylated to cross-linked species, and the non-rearranged cross-linked product.