Design, Synthesis, And Dna Binding Characteristics Of A Group Of Orthogonally Positioned Diamino, N-formamido, Pyrrole- And Imidazole-containing Polyamides
Bioorganic and Medicinal Chemistry
Elsevier Science BV
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-I (P) under barI (3a), f-I (P) under barP (4), f-(P) under bar IP (5), and f-P (P) under barP (6) are described. (P) under bar denotes the site where a 1-propylamino group is attached to the NI-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-I (P) under barI (3a) bound more strongly (K-eq = 2.4 x 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-I (P) under barI (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-I (P) under barP (4) also bound more strongly to its cognate sequence 5'-ATGCAT-3' (K-eq = 7.4 x 10(6) M-1) via the side-by-side stacked motif than its monoamino analog f-IPP (2a). Although f-P (P) under barP (6) bound via a 1:1 motif, it bound strongly to its cognate sequence 5'-AAATTT-3' (K-eq = 4.8 x 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-(P) under bar IP (5) bound to its target sequence 5'-ATCGAT-3' as a stacked dimer and it has the lowest affinity among the diamino PAs tested (K-eq10(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. (C) 2013 Elsevier Ltd. All rights reserved.
Author Keywords: Polyamides; Diamino; Minor groove; Sequence specificity; Core rules KeyWords Plus: II-ALPHA PROMOTER; CELL-CYCLE BOX; MINOR-GROOVE; MOLECULAR RECOGNITION; SEQUENCE SPECIFICITY; NUCLEAR-LOCALIZATION; BASE-PAIRS; TARGET 5'-ACGCGT-3'; F-IMPYIM; T-G
Chavda, Sameer, Balaji Babu, Pravin Patil, Adam Plaunt, Amanda Ferguson, Megan Lee, Samuel Tzou, Robert Sjoholm, Toni Rice, Hilary Mackay, Joseph Ramos, Shuo Wang, Shicai Lin, Konstantikos Kiakos, W. David Wilson, John A. Hartley and Moses Lee. "Design, Synthesis, and Dna Binding Characteristics of a Group of Orthogonally Positioned Diamino, N-Formamido, Pyrrole- and Imidazole-Containing Polyamides." Bioorganic and Medicinal Chemistry 21, no. 13 (2013): 3907-3918.