title: Design, synthesis, and DNA binding characteristics of a group of orthogonally positioned diamino, N-formamido, pyrrole- and imidazole-containing polyamides.
abstract: Orthogonally positioned diamino/dicationic polyamides (PAs) have good water solubility and enhanced binding affinity, whilst retaining DNA minor groove and sequence specificity compared to their monoamino/monocationic counterparts. The synthesis and DNA binding properties of the following diamino PAs: f-IPI (3a), f-IPP (4), f-PIP (5), and f-PPP (6) are described. P denotes the site where a 1-propylamino group is attached to the N1-position of the heterocycle. Binding of the diamino PAs to DNA was assessed by DNase I footprinting, thermal denaturation, circular dichroism titration, biosensor surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) studies. According to SPR studies, f-IPI (3a) bound more strongly (K(eq)=2.4×10(8) M(-1)) and with comparable sequence selectivity to its cognate sequence 5'-ACGCGT-3' when compared to its monoamino analog f-IPI (1). The binding of f-IPI (3a) to 5'-ACGCGT-3' via the stacked dimer motif was balanced between enthalpy and entropy, and that was quite different from the enthalpy-driven binding of its monoamino parent f-IPI (1). f-IPP (4) also bound more strongly to its cognate sequence 5'-ATGCAT-3' (K(eq)=7.4×10(6) M(-1)) via the side-by-side stacked motif than its monoamino analog f-IPP (2a). Although f-PPP (6) bound via a 1:1 motif, it bound strongly to its cognate sequence 5'-AAATTT-3' (K(eq)=4.8×10(7) M(-1)), 15-times higher than the binding of its monoamino analog f-PPP (2c), albeit f-PPP bound via the stacked motif. Finally, f-PIP (5) bound to its target sequence 5'-ATCGAT-3' as a stacked dimer and it has the lowest affinity among the diamino PAs tested (Keq <1×10(5) M(-1)). This was about two times lower in affinity than the binding of its monoamino analog f-PIP (2b). The results further demonstrated that the 'core rules' of DNA recognition by monoamino PAs also apply to their diamino analogs. Specifically, PAs that contain a stacked IP core structure bind most strongly (highest binding constants) to their cognate GC doublet, followed by the binding of PAs with a stacked PP structure to two degenerate AT base pairs, and finally the binding of PAs with a PI core to their cognate CG doublet.
authors: Division of Natural and Applied Sciences and Department of Chemistry, Hope College, Holland, MI 49423, USA.
authors: Sameer
authors: S
authors: Chavda
authors: Balaji
authors: B
authors: Babu
authors: Pravin
authors: P
authors: Patil
authors: Adam
authors: A
authors: Plaunt
authors: Amanda
authors: A
authors: Ferguson
authors: Megan
authors: M
authors: Lee
authors: Samuel
authors: S
authors: Tzou
authors: Robert
authors: R
authors: Sjoholm
authors: Toni
authors: T
authors: Rice
authors: Hilary
authors: H
authors: Mackay
authors: Joseph
authors: J
authors: Ramos
authors: Shuo
authors: S
authors: Wang
authors: Shicai
authors: S
authors: Lin
authors: Konstantinos
authors: K
authors: Kiakos
authors: W David
authors: WD
authors: Wilson
authors: John A
authors: JA
authors: Hartley
authors: Moses
authors: M
authors: Lee
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D018983:DNA Footprinting; D015195:Drug Design; D005559:Formamides / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D005559:Formamides; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA