DNA Binding, Solubility, and Partitioning Characteristics of Extended Lexitropsins

Abstract

Four new ligands that bind to the minor groove of DNA have been designed, synthesized, and evaluated by DNA footprinting. Two of the ligands are polyamides containing central regions with five or six N-methylpyrrole units, conferring hydrophobicity and good binding affinity but without retaining the correct spacing for hydrogen bonding in the base of the minor groove. The two remaining ligands have central regions which are head-to-head-linked polyamides, in which the linker is designed to improve the phasing of hydrogen bonding of the ligand with the floor of the minor groove. The highest affinity was obtained with the two polypyrroles without headgroup spacers, indicating that H-bond phasing is secondary in determining affinity compared to the major hydrophobic driving force. With a dimethylaminoalkyl group, representing a moiety with modest base strength, at both ends, water solubility is good and pH-partition theory predicts that penetration through lipid membranes will be enhanced, compared to strongly basic amidine analogues of the alkaloid precursors. All four compounds bind to DNA, with strong selectivity for AT sequences but some tolerance of GC base pairs and subtle individual preferences. The data show that very high affinities can be anticipated for future compounds in this series, but drug design must take account of overall physicochemical properties as well as the details of hydrogen bonding between ligands and the floor of the minor groove.

A novel dicationic polyamide ligand binds in the DNA minor groove as a dimer

“…1A ). Many head‐to‐head polyamide molecules have been shown to bind to the A/T rich minor groove [14,15]. It was shown that GL020924 specifically inhibited expression of an engineered cyclin D1 promoter in MCF7 breast cancer cells by competing for promoter binding of transcription factors [16].…”

Design of a Composite Ethidium–Netropsin–Anilinoacridine Molecule for DNA Recognition

“…The pentamethylenic carboxamido linker between the oligopyrrolecarboxamide and the phenanthridine moieties was introduced into the oligopyrrole before condensation with the two chromophores. The fully protected amino oligopyrrolecarboxamide ester 15 was obtained by peptide condensation of the amino ester 12 and 6‐ tert ‐butyloxycarbonylaminohexanoic acid ( 14 ), which were respectively synthesized by reduction of the nitro derivative 11 35 and acylation of the commercially available 6‐aminohexanoic acid ( 13 ). Saponification of the ester 15 afforded the acid 16 (Scheme ).…”

“…Ethyl 1‐methyl‐4‐[1‐methyl‐4‐[(5‐ tert ‐butyloxycarbonylaminopentyl)carboxamido]pyrrole‐2‐carboxamido]pyrrole‐2‐carboxylate (15) : A suspension of nitro compound 11 35 (2.08 g, 6.5 mmol) in MeOH (600 mL) was hydrogenated for 5 h at room temperature under a 5‐bar pressure in the presence of 5 % Pd on activated charcoal (1 g). The catalyst was then removed by filtration, and the MeOH eliminated under reduced pressure.…”

Polyamide-Scorpion Cyclam Lexitropsins Selectively Bind AT-Rich DNA Independently of the Nature of the Coordinated Metal

“…Many analogs are known in which this group has been replaced with related structures that modify binding affinities,[44], [99], [101]–[102] and significant changes in this region have been tolerated, for example some of the metal complex-lexitropsin conjugates described in the introduction [55], [60], [65], [72]. However, the reduction in binding affinity for Py-Py-Py (the lexitropsin scaffold of interest here) when the N -formamido moiety is removed is smaller than for other lexitropsins (one order of magnitude, from ca .…”