title: Threading polyintercalators with extremely slow dissociation rates and extended DNA binding sites.
abstract: The development of small molecules that bind DNA sequence specifically has the potential to modulate gene expression in a general way. One mode of DNA binding is intercalation, or the insertion of molecules between DNA base pairs. We have developed a modular polyintercalation system in which intercalating naphthalene diimide (NDI) units are connected by flexible linkers that alternate between the minor and major grooves of DNA when bound. We recently reported a threading tetraintercalator with a dissociation half-life of 16 days, the longest reported to date, from its preferred 14 bp binding site. Herein, three new tetraintercalator derivatives were synthesized with one, two, and three additional methylene units in the central major groove-binding linker. These molecules displayed dissociation half-lives of 57, 27, and 18 days, respectively, from the 14 bp site. The optimal major groove-binding linker was used in the design of an NDI hexaintercalator that was analyzed by gel-shift assays, DNase I footprinting, and UV-vis spectroscopy. The hexaintercalator bound its entire 22 bp binding site, the longest reported specific binding site for a synthetic, non-nucleic acid-based DNA binding molecule, but with a significantly faster dissociation rate compared to the tetraintercalators.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Rhoden Smith
authors.forename: Brent L
authors.initials: BL
authors.lastname: Iverson
mesh_terms: D001665:Binding Sites; D004247:DNA / Q000737:chemistry*; D007094:Imides / Q000737:chemistry*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D007094:Imides; D009281:Naphthalenes; D011108:Polymers; C542131:naphthalenediimide; D004247:DNA
references.citation: Bioorg Med Chem. 2008 Apr 15;16(8):4390-400
references.pmid: 18329887
references.citation: Bioorg Med Chem Lett. 2005 May 2;15(9):2197-201
references.pmid: 15837293
references.citation: Biochemistry. 2012 Jun 5;51(22):4445-52
references.pmid: 22554127
references.citation: J Am Chem Soc. 2004 Nov 3;126(43):14036-42
references.pmid: 15506767
references.citation: J Am Chem Soc. 2002 Mar 27;124(12):2864-5
references.pmid: 11902864
references.citation: Chembiochem. 2010 Oct 18;11(15):2073-6
references.pmid: 20872391
references.citation: Methods. 2007 Jun;42(2):128-40
references.pmid: 17472895
references.citation: Bioorg Med Chem. 2001 Sep;9(9):2215-35
references.pmid: 11553460
references.citation: Bioorg Med Chem. 2001 May;9(5):1141-8
references.pmid: 11377172
references.citation: Nat Chem. 2011 Sep 25;3(11):875-81
references.pmid: 22024884
references.citation: Biochemistry. 2000 Sep 26;39(38):11742-7
references.pmid: 10995242
references.citation: Chembiochem. 2011 Sep 5;12(13):2001-6
references.pmid: 21739556
references.citation: Biochemistry. 1991 Feb 19;30(7):1813-9
references.pmid: 1993195
references.citation: Chemistry. 2008;14(11):3236-49
references.pmid: 18236477
references.citation: Chemistry. 2013 May 10;19(20):6246-56
references.pmid: 23576496
references.citation: J Am Chem Soc. 1995 Oct 1;117(42):10434-10442
references.pmid: 20882118
references.citation: Nucleic Acids Res. 2008 Sep;36(16):5123-38
references.pmid: 18676453
references.citation: Anal Sci. 2012;28(7):643-9
references.pmid: 22790364
references.citation: Analyst. 2002 Jul;127(7):886-8
references.pmid: 12173644
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2232-7
references.pmid: 15677315
references.citation: J Am Chem Soc. 2012 Oct 24;134(42):17814-22
references.pmid: 23013524
references.citation: Chem Biol. 2000 Jan;7(1):1-8
references.pmid: 10662682
references.citation: Biochemistry. 1982 Apr 27;21(9):2070-6
references.pmid: 7093231
references.citation: Biochemistry. 1985 Sep 24;24(20):5567-75
references.pmid: 2866796
references.citation: Chem Biol. 2001 May;8(5):415-25
references.pmid: 11358689
references.citation: Nucleic Acids Res. 1999 Feb 15;27(4):1176-81
references.pmid: 9927753
references.citation: Bioorg Med Chem. 2012 Jan 15;20(2):693-701
references.pmid: 22222156
references.citation: Nucleic Acids Res. 1987 Oct 12;15(19):7823-30
references.pmid: 3671067
references.citation: Analyst. 2005 Nov;130(11):1478-82
references.pmid: 16222367
references.citation: Bioorg Med Chem Lett. 2010 Dec 1;20(23):6956-9
references.pmid: 20980148