Synthesis and sequence-specific DNA binding of a topoisomerase inhibitory analog of Hoechst 33258 designed for altered base and sequence recognition

Abstract

The preparation and DNA binding characteristics of a structural analog of Hoechst 33258 bearing two pyridinic nitrogen atoms are described. The 1H NMR signals of the complex formed between the new ligand 1 and decadeoxyribonucleotide d(CATGGCCATG)2 were assigned by employing one- and two-dimensional NMR techniques. Intermolecular nuclear Overhauser effects (NOE) between the ligand and the DNA receptor fragment confirm that the ligand binds in the minor groove of the DNA, interacting with the centrally located 5'-GGCCA segment. In contrast to the steric clash between the benzimidazole rings of the parent Hoechst 33258 molecule and the guanine 2-NH2 groups, which renders it G.C avoiding and thus A.T base pair preferring, the ligand 1 described here overcomes these unfavorable interactions and instead exhibits a marked preference of G.C base pairs. This behavior appears to arise from additional stabilization due to H-bonding with the guanine 2-NH2 groups. Although a ligand-induced distortion at the binding site is qualitatively assessable, the overall B-type conformation of the DNA fragment is retained upon complexation. The structural conclusions drawn from the NOE-NMR evidence were confirmed by molecular mechanics and molecular modeling studies.

DNA minor groove binders as potential antitumor and antimicrobial agents

“…41 An analog of Hoechst 33258, bearing a phenolic hydroxyl group in the meta rather than para position, was considerably less cytotoxic than the para one 42 and this difference may reflect cell permeation or ligand access to the nucleus once internalized. The structural modification that were employed included the replacement of one of both benzoimidazole rings with benzoxazoles 43 and pyridoimidazole, 43,44 the introduction of an N 1 -alkoxyalkyl moiety 45 and the alkylation of the terminal phenoxy moiety. 46,47 These modifications produced an enhanced cytotoxic potency with respect to parent compound Hoechst 33258.…”

“…Furthermore, this substitution could confer to the dimer or trimer agents' different properties in in vivo studies. Some examples of heteroaryl derivatives of CPI are depicted (compounds [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61]. Each of these compounds showed different degrees of cytotoxicity and they have been used to obtain new pharmacological tools but, most importantly, they can represent possible probes for investigating the bioorganic properties of this exceptionally potent class of derivatives.…”

Study of Interaction of Dextromethorphan Hydrobromide with Deoxyribonucleic Acid by Fluorescence Quenching

“…It is significant not only in understanding the mechanism of interaction, but also for guiding the design of new drugs. So it is necessary to understand the modes and the factors affecting the binding of small molecules to DNA (Singh et al, 1992). Studying the binding mechanism is of great importance in terms of life science, chemicals, pharmaceuticals, and clinical medicines (Bera et al, 2008;Zhao et al, 2003).…”

Synthesis of thieno[2,3-b]benzo[1,8]naphthyridine-2-carboxylic acids under microwave irradiation and interaction with DNA studies

“…This finding has stimulated the research in finding new antitumour drugs containing planar fused ring system. In recent years various fused systems such as thiophene, 15 furan and pyridine analogues of ellipticine 16 and benzothiazoloquinolines 17 have been studied for their properties. Recently, Cao and He 15 studied DNA affinity properties of safranine-T which features a planar phenazine ring and have shown that electrostatic binding plays an important role in the intercalation of safranine-T.…”