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(12) United States Patent (10) Patent No.: US 7,713,701 B2 Dervan Et Al

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(12) United States Patent (10) Patent No.: US 7,713,701 B2 Dervan Et Al USOO7713701 B2 (12) United States Patent (10) Patent No.: US 7,713,701 B2 DerVan et al. (45) Date of Patent: May 11, 2010 (54) DNA-BINDING POLYMERS 4,452,775 A 6, 1984 Kent 4.675, 189 A 6, 1987 Kent et al. (75) Inventors: Peter B. Dervan, San Marino, CA (US); 5,075,109 A 12/1991 Tice et al. Shane Foister, risely (US); 5,133,974 A 7/1992 Paradissis et al. Raymond Doss, Clark, NJ (US); 5,407,686 A 4, 1995 Patel et al. Michael A. Marques, San Mateo, CA 5,624,898 A 4/1997 Frey, II 5,736,152 A 4/1998 Dunn (73) Assignee: California Institute of Technology, 6,180,603 B1 1/2001 Frey, II Pasadena, CA (US) (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Arcamone, et al., “Structure and Synthesis of Distamycin A' Nature (21) Appl. No.: 12/238,167 203-1064-1065Baird and Dervan, (1964). “Solid Phase Synthesis of Polyamides Containing (22) Filed:1-1. Sep. 25, 2008 6146Imidazole (1996). and Pyrrole Amino Acids' J. Am. Chem. Soc. 118:6141 (65) Prior Publication Data Behrens, et al., “Synthesis of a Hoechst 32258 Analogue Amino Acid Building Block for Direct Incorporation of a Fluorescent, High US 2009/O1552O2A1 Jun. 18, 2009 Affinity DNA Binding Motif into Peptides' Bioconjugate Chem. 12:1021-1027 (2001). Related U.S. Application Data d Continue (62) Division of application No. 11/038,506, filed on Jan. ( ) 18, 2005, now Pat. No. 7,452,730. Primary Examiner Jezia Riley (60) Provisional application No. 60/536,919, filed on Jan. (74)74). AttAttorney, Agent, or FirmFirm—Foley Foley & LardneraCe LLP 16, 2004. (57) ABSTRACT (51) Int. Cl. EK. '', 3.08: Methods and compositions are provided for forming com GOIN 33/566 (2006.015 plexes between dsDNA and novel DNA-binding polymers CO7H 2 1/02 (200 6. 01) comprising N-terminal thiophene-containing moieties which 52) U.S. C 435/6: 43.5/5:435/7.1 exhibit selectivity for T-A base pairs. By appropriate choice (52) U.S. Cl. "/7 2: 536,23 1. 436/50 of target sequences and DNA-binding polymers, complexes • 1s • us comprising polymer-DNA are obtained with high association (58) Field of Classification Search ..................... 435/5, constants. The formation of complexes can be used for iden S licati ni, 6, ise E. 1: 436/501 tification of specific dsDNA sequences, for inhibiting gene ee application file for complete search history. transcription, and as a therapeutic for inhibiting proliferation (56) References Cited of undesired cells or modulation of expression of specific genes. U.S. PATENT DOCUMENTS 3,854,480 A 12/1974 Zaffaroni 21 Claims, 6 Drawing Sheets US 7,713,701 B2 Page 2 OTHER PUBLICATIONS Marques, et al., “Toward an Understanding of the Chemical Etiology for DNA Minor-Groove Recognition by Polyamides' Helvetica Briehn, et al., “Alternative Heterocycles for DNA Recognition: The Chimica Acta 85:4485-4517 (2002). Benzimidazole/Imidazole Pair’ Chem. Eur: J. 9:21 10-2122 (2003). Matsuba, et al., “A Novel Synthetic DNA Minor Groove Binder, Church, et al., “N-(2-Chloroethyl)-N-Nitrosoureas Covalently MS-247: Antitumor Activity and Cytotoxic Mechanism” Cancer Bound to Nonionic and Monocationic Lexitropsin Dipeptides. Syn Chemother; Pharmacol. 46: 1-9 (2000). thesis, DNA Affinity Binding Characteristics, and Reactions with Minehan, et al., “Molecular Recognition of DNA by Hoechst P-End-Labeled DNA” Biochemistry 29:6827-6838 (1990). Benzimidazoles: Exploring Beyond the Pyrrole-Imidazole Clanton, et al., “Novel Sulfonated and Phosphonated Analogs of Hydroxypyrrole Polyamide-Pairing Code' Helvetica Chimica Acta Distamycin Which Inhibit he Replication of HIV” Antiviral Res. 83:21.97-2213 (2000). 27:335-354 (1995). Pelton and Wemmer, “Structural Characterization of a 2:1 Dervan, et al., “Sequence-Specific DNA Recognition by Distamycin Ad(CGCAAATTGGC) Complex by Two-Dimensional Polyamides' Current Opinion in Chemical Biology, 3:688-693 NMR Proc Natl AcadSci USA 86:5723-5727 (1989). (1999). Pura, et al., “Binding of Hoechst 33258 to the Minor Groove of Ellervik et al., “Hydroxybenzamide/Pyrrole Pair Distinguishes TA B-DNA” J. Mol. Biol. 197:257-271 (1987). from AT Base Pairs in the Minor Groove of DNA 122:9354-9360 Renneberg and Dervan, "Imidazopyridine/Pyrrole and (2000). Hydroxybenzimidazole Pyrrole Pairs for DNA Minor Groove Rec Gottesfeld, et al., “Regulation of Gene Expression by Small Mol ognition”JACS 125:5707-5716 (2003). ecules' Nature 387:202-205 (1997). Satz and Bruice, “Recognition of Nine Base Pairs in the Minor Graham, et al., “Manipulation of Adenovirus Vectors' Methods in Groove of DNA by a Tripyrrole Peptide-Hoechst Conjugate” J. Am. Molecular Biology 7: 109-128 (1991). Chem. Soc. 123:2469-2477 (2001) He, et al., “Microgonotropens and Their Interactions with DNA. 1. Taylor and Zhou, "A Facile Synthesis of 3-Fluorothiophene-2- Synthesis of the Tripyrrole Peptides Dien-Microgonotropen-a, -b, Carboxylic Acid' 29:221-223 (1997). and-c and Characterization of Their Interactions with dsDNA.J. Am. Teng, et al., “The Molecular Structure of the Complex of Hoechst Chem. Soc. 115:7061-7071 (1993). 33258 and the DNA Dodecamer d(CGCGAATTCGCG)” Nucleic Ji, et al., “Tris-Benzimidazole Derivatives: Design, Synthesis and Acids Res. 16:2671-2690 (1988). DNA Sequence Recognition” Bioorg. Med. Chem. 9:2905-2919 Trauger, and Dervan, “Footprinting Methods for Analysis of Pyrrole (2001). Imidazole Polyamide/DNA Complexes” Methods Enzymol. Kielkopf, et al., “Structural Basis for GC Recognition in the DNA 340:450-466 (2001). Minor Groove” Nature Struct. Biol. 5:104-109 (1998). Wang, et al., “Evaluation of the Influence of Compound Structure on Kielkopfet al., “A Structural Basis for Recognition of AT and TA Stacked-Dimer Formation in the DNA Minor Groove' Biochemistry Base Pairs in the Minor Groove of B-DNA Science 282:111-115 40:251 1-2521 (2001). (1998). White, et al., “On the Pairing Rules for Recognition in the Minor Kumar, et al., “Sequence Specific Molecular Recognition and Bind Groove of DNA by Pyrrole-Imidazole Polyamides' Chemistry & ing by a GC Recognizing Hoechst 33258 Analogue to the Biology 4:569-578 (1997). Decadeoxynbonucleotide d-ICATGGCCATG: Structural and White et al., “Recognition of the Four Watson-Crick Base Pairs in the Dynamic Aspects Deduced from High Field H-NMR Studies' J. DNA Minor Groove by Synthetic Ligands' Nature 391:468-471 Biomol. Struct. Dyn. 8:331-357 (1990). (1998). Lewin, B., “Promoters for RNA Polymerase II Have Short Sequence Yamamoto, et al., “Synthesis and DNA Binding Properties of Amide Elements' Genes 831-835 (1997). Bond-Modified Analogues Related to Distamycin’ Tetrahedron Let Lombardy, et al., “Synthesis and DNA Interactions of Benzimidazole ters 37:7801-7804 (1996). Dications Which Have Activity Against Opportunistic Infections”.J. Zhang, et al., “A Novel Dicationic Polyamide Ligand Binds in the Med. Chem. 39: 1452-1462 (1996). DNA Minor Groove as a Dimer” FEBS Lett. 509:85-89, (2001). U.S. Patent May 11, 2010 Sheet 1 of 6 US 7,713,701 B2 FIG. Ia (a) (b) FIG. Ib U.S. Patent May 11, 2010 Sheet 2 of 6 US 7,713,701 B2 pCW15 ECOR At TA cG Gc PVIII 5'- C A TXT A C A T A - 3' s 3' - G T A YA T G T A T - 5' O (S) = S R = H 1 NHAC 4 7 \ 0 CH, 2 OH 5 CI 8 R NH 3 OCH 6 S.N-f) & \ N / 9 10 FIG 2 U.S. Patent May 11, 2010 Sheet 3 of 6 US 7,713,701 B2 (a) O O S S 1 O 1 - "i, "ii -- K S J1 OH NH2 NHBoc (b) O O kroS 1. -iii, iv & S r OH 2 OH 13 1. (C) O O S V, vi S FIG. 3 U.S. Patent May 11, 2010 Sheet 4 of 6 US 7,713,701 B2 R = NHBOC iv NH R3 NHAC R4 vi - vii FIG. 4 U.S. Patent May 11, 2010 Sheet 5 of 6 US 7,713,701 B2 99.99g5 6 8 90 2 a it is - - - - a a s so - - - - - - a - --i-ii- is is is:a XY 8 iiitiii.3st is - g c - is a 3 a 84 ma W led 2a : gigis J AT - - - - se - - : ora --------g4, 5 6 8 Se s - s as: . as e - wa? w: - - - as a had be w X.Y s ... -----us-SE - CG . :: see p r s r se - it is...}is " " s - - - as is rew we as are g g g g -- a se - w as is air us U.S. Patent May 11, 2010 Sheet 6 of 6 US 7,713,701 B2 US 7,713,701 B2 1. 2 DNA-BINDING POLYMERS recognition of hundreds of predetermined DNA sequences by polyamide oligomers. Listed below in Table 1 are represen CROSS-REFERENCE TO RELATED PATENT tative polyamide pairs offive-membered heterocycles and the APPLICATIONS DNA pairs that they preferentially bind to, referred to herein as the “pairing rules.” This application is a Divisional Application of U.S. Non provisional application Ser. No. 11/038,506, filed Jan. 18. TABLE 1 2005 which is a Continuation in Part of U.S. Provisional Application 60/536,919, filed Jan. 16, 2004, the entire con Pairing Rules for Five-Membered Heterocyles 10 tents of which are incorporated herein by reference. This DNA base pair application also incorporates by reference the entire contents Polyamide Pair recognition of U.S. Nonprovisional application Ser. No. 10/794,584 filed Im/Py GOC Mar. 4, 2004. Py/Im COG Hp/Py ToA STATEMENT OF GOVERNMENT SUPPORT 15 Py/Hip AOT The U.S.
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