Advanced search
Publication Cover
Journal of Enzyme Inhibition and Medicinal Chemistry Volume 26, 2011 - Issue 2
Submit an article Journal homepage
527
Views
21
CrossRef citations to date
0
Altmetric
Short Communications

Dimeric bisbenzimidazoles inhibit the DNA methylation catalyzed by the murine Dnmt3a catalytic domain

N. A. CherepanovaChemistry Department, Moscow State University, Moscow, Russian Federation
,
A. A. IvanovEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
,
D. V. MaltsevaChemistry Department, Moscow State University, Moscow, Russian Federation
,
A. S. MineroChemistry Department, Moscow State University, Moscow, Russian Federation
,
A. V. GromykoEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
,
S. A. StreltsovEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
,
A. L. ZhuzeEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
&
E. S. GromovaChemistry Department, Moscow State University, Moscow, Russian FederationCorrespondence[email protected]
 show all
Pages 295-300 | Received 11 Feb 2010, Accepted 03 Jun 2010, Published online: 08 Jul 2010

Figures & data

Figure 1.   Chemical structures of dimeric bisbenzimidazoles DB(n), bis-Ht (NMe), monomeric bisbenzimidazoles (MB), and Hoeсhst 33258. The numbering of piperazine and benzimidazole hydrogen atoms is shown.

Figure 1.   Chemical structures of dimeric bisbenzimidazoles DB(n), bis-Ht (NMe), monomeric bisbenzimidazoles (MB), and Hoeсhst 33258. The numbering of piperazine and benzimidazole hydrogen atoms is shown.

Scheme  1.  Synthesis of DB(1–5,7,11). Reagents and conditions: (a) iBuOCOCl, NMM, Boc-Gly-OH; (b) AcOH, 65–70°C, 1 h; (c) AcOH, 120°C, 4 h, 58% (for a–c); (d) HClgas/EtOH, 0–4°C, 1 h, 23°C, 3 days; (e) AcOH/EtOH, 95°C, 1 h, N2, 78% (for d–e); (f) HClconc, 105°C, 20 min, 89%; (g) for DB(1,2): DMF, DIPEA, BOP, HOOC-(CH2)n-COOH (n = 1,2), 0°C, 1 h, 23°C, 1 day, HCl/MeOH, DB(1), 22%, DB(2), 24%; for DB(3–5,7,11): DMF, Et3N, XOOC-(CH2)n-COOX (X = Np; Pfp; Su; n = 3,4,5,7,11), HCl/MeOH, DB(3), 73%, DB(4), 68%, DB(5), 51%, DB(7), 78%, DB(11), 61%. All DB(n) were purified by refluxing in methanol followed by cooling and filtration of the target precipitate. AcOH, acetic acid; Boc-Gly-OH, tert-butyloxycarbonyl-glycine; BOP, (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; DIPEA, N,N-diisopropylethylamine; DMF, dimethylformamide; Et3N, triethylamine; EtOH, ethanol; iBuOCOCl, isobutyl chloroformate; MeOH, methanol; NMM, N-methylmorpholine; Np, p-nitrophenyl; Pfp, 2,3,4,5,6-pentafluorophenуl; Su, N-oxysuccinimide.

Scheme  1.  Synthesis of DB(1–5,7,11). Reagents and conditions: (a) iBuOCOCl, NMM, Boc-Gly-OH; (b) AcOH, 65–70°C, 1 h; (c) AcOH, 120°C, 4 h, 58% (for a–c); (d) HClgas/EtOH, 0–4°C, 1 h, 23°C, 3 days; (e) AcOH/EtOH, 95°C, 1 h, N2, 78% (for d–e); (f) HClconc, 105°C, 20 min, 89%; (g) for DB(1,2): DMF, DIPEA, BOP, HOOC-(CH2)n-COOH (n = 1,2), 0°C, 1 h, 23°C, 1 day, HCl/MeOH, DB(1), 22%, DB(2), 24%; for DB(3–5,7,11): DMF, Et3N, XOOC-(CH2)n-COOX (X = Np; Pfp; Su; n = 3,4,5,7,11), HCl/MeOH, DB(3), 73%, DB(4), 68%, DB(5), 51%, DB(7), 78%, DB(11), 61%. All DB(n) were purified by refluxing in methanol followed by cooling and filtration of the target precipitate. AcOH, acetic acid; Boc-Gly-OH, tert-butyloxycarbonyl-glycine; BOP, (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; DIPEA, N,N-diisopropylethylamine; DMF, dimethylformamide; Et3N, triethylamine; EtOH, ethanol; iBuOCOCl, isobutyl chloroformate; MeOH, methanol; NMM, N-methylmorpholine; Np, p-nitrophenyl; Pfp, 2,3,4,5,6-pentafluorophenуl; Su, N-oxysuccinimide.

Scheme  2.  Synthesis of bis-HT(NMe). Reagents and conditions: (а) Cl(CH2)3N(CH3)(CH2)3Cl, NaH, DMF; (b) HCl, EtOH; (c) AcOH, N2, 120°C, HCl/MeOH, 20%. bis-HT(NMe) was purified by recrystallization from a mixture of MeOH-H2O-HCl.

Scheme  2.  Synthesis of bis-HT(NMe). Reagents and conditions: (а) Cl(CH2)3N(CH3)(CH2)3Cl, NaH, DMF; (b) HCl, EtOH; (c) AcOH, N2, 120°C, HCl/MeOH, 20%. bis-HT(NMe) was purified by recrystallization from a mixture of MeOH-H2O-HCl.

Table 1.   Inhibition of the methylation of duplex A by Dnmt3a-CD in the presence of DB(n).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related Research Data

Cooperation of Dnmt1 and Dnmt3a
Source: Wiley
Molecular Enzymology of the Catalytic Domains of the Dnmt3a and Dnmt3b DNA Methyltransferases
Source: American Society for Biochemistry & Molecular Biology (ASBMB)
Cyclical DNA methylation of a transcriptionally active promoter
Source: Springer Science and Business Media LLC
Noncovalent drug-DNA binding interactions that inhibit and stimulate (A)BC excinuclease.
Source: American Chemical Society (ACS)
Binding characteristics of Hoechst 33258 with calf thymus DNA, poly[d(A-T)] and d(CCGGAATTCCGG): Multiple stoichiometries and determination of tight binding with a wide spectrum of site affinities
Source: American Chemical Society (ACS)
Hhal methyltransferase flips its target base out of the DNA helix
Source: Elsevier BV
Formation of nucleoprotein filaments by mammalian DNA methyltransferase Dnmt3a in complex with regulator Dnmt3L
Source: Oxford University Press (OUP)
Worms gang up on bacteria
Source: Springer Science and Business Media LLC
Design, synthesis, inhibitory activity, and binding mode study of novel DNA methyltransferase 1 inhibitors.
Source: Elsevier BV
Impact of 7,8-dihydro-8-oxoguanine on methylation of the CpG site by Dnmt3a.
Source: American Chemical Society (ACS)
Dimeric bisbenzimidazole Hoechst 33258-related dyes as novel AT-specific DNA-binding fluorochromes for human and plant cytogenetics
Source: Pleiades Publishing Ltd
DNA sequence-specific ligands: XIV. Synthesis of fluorescent biologically active dimeric bisbenzimidazoles DB(3, 4, 5, 7, 11)
Source: Pleiades Publishing Ltd
Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation
Source: Springer Science and Business Media LLC
Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases.
Source: American Association for Cancer Research (AACR)
Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine
Source: Proceedings of the National Academy of Sciences
Structure and function of eukaryotic DNA methyltransferases.
Source: Elsevier
Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles)
Source: American Chemical Society (ACS)
Binding of Hoechst 33258 to the minor groove of B-DNA.
Source: Elsevier BV
The Hoechst 33258 covalent dimer covers a total turn of the double-stranded DNA.
Source: Informa UK Limited
Stereochemistry of B[a]P-N2-dG affects methylation
Source: Wiley
Hoechst 33258--poly(dG-dC).poly(dG-dC) complexes of three types.
Source: Informa UK Limited

Linking provided by 

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.