DNA Binding Compounds. V. Synthesis and Characterization of Boron Containing Bibenzimidazoles Related to the DNA Minor Groove Binder, Hoechst-33258

New analogues of the minor groove binding ligand Hoechst 33342 have been investigated in an attempt to improve radioprotective activity. The synthesis, DNA binding, and in vitro radioprotective properties of methylproamine, the most potent derivative, are reported. Experiments with V79 cells have shown that methylproamine is ϳ100-fold more potent than the classical aminothiol radioprotector WR1065. The crystal structures of methylproamine and proamine complexes with the dodecamer d(CGC-GAATTCGCG) 2 confirm that the new analogues also are minor groove binders. It is proposed that the DNA-bound methylproamine ligand acts as a reducing agent by an electron transfer mechanism, repairing transient radiation-induced oxidizing species on DNA.

show abstract

“…Methylproamine was synthesized according to the general procedures described previously (10,11). The details are available as supplementary data.…”

Section: Methodsmentioning

confidence: 99%

In Vitro Studies with Methylproamine

et al. 2004

View full text Add to dashboard Cite

show abstract

“…These benzimidazoles containing the weinreb amide functionality were then easily reduced to their corresponding aldehydes (DPA 151c-DPA 154c) using lithium aluminum hydride. Coupling of these aldehydes with 4-(4-methylpiperazin-1-yl) benzene-1, 2-diamine, 21 in the presence of an oxidant resulted in the synthesis of target bisbenzimidazoles DPA 151-DPA 154 in good yields. The presence of a rather inert functional group alkyne also makes these molecules useful for further modifications using click chemistry applications.…”

Section: Resultsmentioning

confidence: 99%

Selective inhibition of bacterial topoisomerase I by alkynyl-bisbenzimidazoles

et al. 2014

View full text Add to dashboard Cite

Hoechst dyes are well known DNA binders that non-selectively inhibit the function of mammalian topoisomerase I and II. Herein, we show that Hoechst 33258 based bisbenzimidazoles (DPA 151–154), containing a terminal alkyne, are effective and selective inhibitors of E. coli. topoisomerase I. These bisbenzimidazoles displayed topoisomerase I inhibition much better than Hoechst 33342 or Hoechst 33258 with IC50 values in the range of 2.47–6.63 μM. Bisbenzimidazoles DPA 151-154 also display selective inhibition of E. coli. topoisomerase I over DNA gyrase and Human topoisomerases I and II, and effectively inhibit bacterial growth.

show abstract

“…To determine the equilibrium association constants by ESI-MS, we assume that the response factors of the complexes and the duplex are the same (eq. 3), because the ligand is inserted deeply in the minor groove of the DNA and the double helix conformation of the duplex is not perturbed by the minor groove binding mode (Kelly et al, 1994;Geierstranger and Wemmer, 1995;Neidle, 1997). Therefore, the duplex and the complexes are likely to have a similar response factor.…”

Section: Thermal Denaturation Studiesmentioning

confidence: 98%

Evaluation of Electronic Effect of Phenyl Ring Substituents on the DNA Minor Groove Binding Properties of Novel Bis and Terbenzimidazoles: Synthesis and Spectroscopic Studies of Ligand-DNA Interaction

2009

View full text Add to dashboard Cite

Several minor groove binding agents (MGBD) were synthesized to study their binding behaviors and sequence specificity with DNA. In order to further understand the binding interactions of the MGBD to DNA, we have synthesized some novel benzimidazoles, which have electron donating (OCH(3), OCH(2)CH(3), OH, O(CH(2))(3)NH(2)) and electron withdrawing cyano groups on the phenyl ring. The interaction of these new benzimidazoles along with parent compounds Hoechst 33342 have been studied with CT DNA, two A-T rich [d(GA(5)T(5)C) and d(CGCA(3)T(3)G)] and one G-C rich [d(GCATGGCCATGC)] oligonucleotide sequences using electrospray ionization mass spectrometry (ESI-MS), absorption, fluorescence, and circular dichroism (CD) spectroscopy. Bisubstituted analogs, which have electron-donating groups, were found to form more stable ligand-DNA complex than Hoechst 33342, while the benzimidazole with electron withdrawing cyano group resulted comparatively in less stable ligand DNA complex. The ESI-MS also gave reliable information about the A-T sequence selectivity as we did not observe any signal with G-C sequence in mass with parent as well as novel ligands. Similar studies with ESI-MS suggest that Hoechst 33342, ETBBZ, and MMBBZ form complexes of 2:1 stoichiometry with d(GA(5)T(5)C) duplex while rest of the ligands form complexes of 1:1 stoichiometry with d(GA(5)T(5)C). Thus, this present study provides the rationalization for the difference in binding behaviors of minor groove binding benzimidazole analogs having different substitution on the phenyl ring.

show abstract

DNA Binding Compounds. V. Synthesis and Characterization of Boron Containing Bibenzimidazoles Related to the DNA Minor Groove Binder, Hoechst-33258

Cited by 33 publications

References 0 publications

In Vitro Studies with Methylproamine

In Vitro Studies with Methylproamine

Selective inhibition of bacterial topoisomerase I by alkynyl-bisbenzimidazoles

Evaluation of Electronic Effect of Phenyl Ring Substituents on the DNA Minor Groove Binding Properties of Novel Bis and Terbenzimidazoles: Synthesis and Spectroscopic Studies of Ligand-DNA Interaction

Contact Info

Product

Resources

About