Synthesis of novel dimeric and oligomeric benzimidazoles targeted to nucleic acid minor groove binding

  • Shatha Alaqeel

Student thesis: Phd


Amido-oligopyrroles/imidazoles and dimeric benzimidazoles are heterocyclic compounds which are nucleic acid minor groove binding agents. The targets for this project were symmetrical and unsymmetrical amide-linked di- and tri- and tetrameric benzimidazoles to evaluate as potential DNA binding agents. Syntheses involved linkage between C2 and C5 positions of 2-carboxy, 5-carboxy or 2,5-dicarboxy and 2-amino, 5-amino or 2,5-diamino-bearing benzimidazoles. This matrix of substrates could be coupled directly C2-C5 by amide linkage, or these same precursors could also be dimerized symmetrically using small bifunctional linkers (diamine or diacid), affording symmetrical C2-C2 or C5-C5 dimer types of orientation, such as head-to- head, and tail-to tail systems. Monomeric building block benzimidazoles were prepared by condensation of o- phenylene diamines with either aldehydes or carboxylic acids affording the corresponding C2 or C5 amino and C5 carboxybenzimidazoles. 2- Carboxybenzimidazoles were however prepared by condensation of o-phenylene diamines with trichloroacetimidate followed by hydrolysis. New different novel symmetrical and unsymmetrical-bis(benzimidazole) libraries (C2-C2, C5-C5 and C5- C2 orientation) were prepared via coupling of different aminobenzimidazoles with different carboxybenzimidazoles from the matrix of available monomers. Novel tris(benzimidazoles) with differently linked orientations were prepared either by coupling one equivalent of 2,5-dicarboxybenzimidazole with two equivalents of aminobenzimidazole or coupling one equivalent of 2,5-diaminobenzimidazole with two equivalents of carboxybenzimidazole. A second set of novel tris(benzimidazoles) was prepared via reduction of a nitro- to amino bearing dimer followed by coupling with another carboxybenzimidazole monomer. Novel symmetrical tetra(benzimidazoles) (C2-C2-C2-C2 and C5-C2-C2-C5 orientation) were synthesized via either coupling one equivalent 2-dicarboxy dimeric benzimidazole with two equivalents of 2 or 5-aminobenzimidazole or via coupling one equivalent of 2-diaminobis(benzimidazole) with two equivalents of 2 or 5- carboxybenzimidazoles. Novel symmetrical bis(benzimidazoles) piperidine derivatives were synthesized via coupling one equivalent of 2-dicarboxy dimericbenzimidazole with two equivalents of piperidine derivatives. Forty oligomeric benzimidazoles were evaluated using Surface Plasmon Resonance (SPR) for binding to a series of three oligonucleotides containing A2T2, or A3T3 or A4T4 sequences. Data are presented showing the identification of four optimum ligands from a screen of 40, primarily 2L2552L2 tetramers but also several 2L5 dimers and dimeric 5,5-units without terminal additional benzimidazoles.
Date of Award31 Dec 2009
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorJohn Gardiner (Supervisor)


  • oligomeric benzimidazoles

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