38652-80-1Relevant academic research and scientific papers
Topology specific stabilization of promoter over telomeric g-quadruplex dnas by bisbenzimidazole carboxamide derivatives
Dhamodharan,Harikrishna,Bhasikuttan, Achikanath C.,Pradeepkumar
, p. 821 - 833 (2015)
Various potential G-quadruplex forming sequences present in the genome offer a platform to modulate their function by means of stabilizing molecules. Though G-quadruplex structures exhibit diverse structural topologies, the presence of G-quartets as a common structural element makes the design of topology specific ligands a daunting task. To address this, the subtle structural variations of loops and grooves present in the quadruplex structures can be exploited. To this end, we report the design and synthesis of quadruplex stabilizing agents based on bisbenzimidazole carboxamide derivatives of pyridine, 1,8-naphthyridine, and 1,10-phenanthroline. The designed ligands specifically bind to and stabilize promoter quadruplexes having parallel topology over any of the human telomeric quadruplex topologies (parallel, hybrid, or antiparallel) and duplex DNAs. CD melting studies indicate that ligands could impart higher stabilization to c-MYC and c-KIT promoter quadruplexes (up to 21 °C increment in Tm) than telomeric and duplex DNAs (Tm ≤ 2.5 °C). Consistent with a CD melting study, ligands bind strongly (Kb = ～104 to 105 M-1) to c-MYC quadruplex DNA. Molecular modeling and dynamics studies provide insight into how the specificity is achieved and underscore the importance of flexible N-alkyl side chains attached to the benzimidazole-scaffold in recognizing propeller loops of promoter quadruplexes. Overall, the results reported here demonstrate that the benzimidazole scaffold represents a potent and powerful side chain, which could judiciously be assembled with a suitable central core to achieve specific binding to a particular quadruplex topology.
Synthesis, DNA binding and in vitro antiproliferative activity of purinoquinazoline, pyridopyrimidopurine and pyridopyrimidobenzimidazole derivatives as potential antitumor agents
Da Settimo, Antonio,Da Settimo, Federico,Marini, Anna Maria,Primofiore, Giampaolo,Salerno, Silvia,Viola, Giampietro,Dalla Via, Lisa,Marciani Magno, Sebastiano
, p. 685 - 696 (2007/10/03)
In the search for new antitumor agents, 8,10-dimethylpurino[7,8- a]quinazoline-5,9,11(6H,8H,10H)-triones 1, 8,10-dimethyl- pyrido[2',3':4,5]pyrimido[1,2-f]purine-5,9,11(6H,8H,10H)-triones 2, and 5,7- dihydro-5-oxopyrido[3',2':5,6]pyrimido[1,2-a]benzimidazoles 3, a series of new planar heteropolycyclic compounds, were synthesized. The approach to understanding their structure-activity relationship involved a physico- chemical investigation of the binding process of these molecules to DNA, considered to be an important target for drug action, and an examination of their biological activity. Thermodynamic parameters of the DNA binding process, intrinsic binding constant and exclusion parameter were determined. The mode of interaction was additionally investigated by means of linear flow dichroism studies. Evaluation of the biological activity included cell growth inhibition in human tumoral cell lines and the ability to indUCe DNA cleavage in the presence of eukaryotic topoisomerase II. Only compounds of the purinoquinazoline series 1, which are able to form a complex with DNA and to inhibit the topoisomerase II, show antiproliferative activity.
Anti-inflammatory 1-[3-(dialkylamino)propyl]-2-acylaminobenzimidazoles and 2-acylamino-3-[3-(dialkylamino)-propyl]imidazo[4,5-b]pyridines
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, (2008/06/13)
1-[3-(Dialkylamino)propyl]-2-acylaminobenzimidazoles and 2-acylamino-3-[3-(dialkylamino)propyl]imidazo[4,5-b]pyridines and salts thereof with pharmaceutically acceptable acids, a novel class of compounds useful in the treatment of inflammatory conditions. Alternate methods of preparation are provided and the primary synthetic route is described in detail.
