DNA sequence-selective binding of head-to-tail linked bis-lexitropsins: relation of phasing to cytotoxic potency.

A series of polymethylene, -(CH2)n-tether-linked head-to-tail bislexitropsins (n = 1-7) have been synthesized in order to assess the effect on DNA binding of phasing, that arises because of lack of dimensional correspondence between oligopeptides and oligonucleotides. Binding constants to poly(dA-dT), estimated from ethidium displacement, are from 0.55 to 16.66 x 10(8) M-1. Comparable Ka values for calf thymus DNA and for poly(dG-dC) are approximately 10(6) and approximately 10(5) M-1, respectively reflecting the anticipated AT preference. Sequence-selective binding was examined by reflecting the anticipated AT preference. Sequence-selective binding was examined by methylethidium propyl ethylenediamine tetraacetic acid (MPE) complementary strand footprinting on an EcoRI/HindIII restriction fragment of pBR322 DNA with r = 0.08 and 0.32. Ligands bearing N-methylpyrrole dipeptide moieties linked by -(CH2)n, where n = 2, 4 or 6, give evidence of bidentate binding in (AT)n-rich sequences from footprinting at r = 0.32. By contrast, those ligands linked by (CH2)n, where n = 1, 3, 5 or 7, bind in a predominantly monodentate fashion. Cystostatic activity against KB human nasopharyngeal cancer cells has shown enhanced potency, compared with distamycin, for those linked bis-lexitropsins with n = 2, 4 and 6. That the increased potency may be attributed to more effective DNA binding in the latter cases is indicated by the fact that the n = 1, 3, 5 and 7 ligand homologues do not exhibit comparable enhanced cytotoxic potency.