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Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole

Anthony, N.G. and Johnston, B.F. and Khalaf, A.I. and Mackay, S.P. and Parkinson, J.A. and Suckling, C.J. and Waigh, R.D. (2004) Short Lexitropsin that Recognizes the DNA Minor Groove at 5'-ACTAGT-3': Understanding the Role of Isopropyl-thiazole. Journal of the American Chemical Society, 126 (36). pp. 11338-11349. ISSN 0002-7863

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Abstract

Isopropyl-thiazole (iPrTh) represents a new addition to the building blocks of nucleic acid minor groove-binding molecules. The DNA decamer duplex d(CGACTAGTCG)2 is bound by a short lexitropsin of sequence formyl-PyPyiPrTh-Dp (where Py represents N-methyl pyrrole, iPrTh represents thiazole with an isopropyl group attached, and Dp represents dimethylaminopropyl). NMR data indicate ligand binding in the minor groove of DNA to the sequence 5'-ACT5AG7T-3' at a 2:1 ratio of ligand to DNA duplex. Ligand binding, assisted by the enhanced hydrophobicity of the iPrTh group, occurs in a head-to-tail fashion, the formyl headgroups being located toward the 5'-ends of the DNA sequence. Sequence reading is augmented through hydrogen bond formation between the exocyclic amine protons of G7 and the iPrTh nitrogen, which lies on the minor groove floor. The BI/BII DNA backbone equilibrium is altered at the T5 3'-phosphate position to accommodate a BII configuration. The ligands bind in a staggered mode with respect to one another creating a six base pair DNA reading frame. The introduction of a new DNA sequence-reading element into the recognition jigsaw, combined with an extended reading frame for a small lexitropsin with enhanced hydrophobicity, holds great promise in the development of new, potentially commercially viable drug lead candidates for gene targeting.