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Synthesis, antitumor evaluation in vitro and interaction with ct-DNA of novel imidazo[4, 5- b]pyridine derivatives

In spite of great advances in cancer therapy, there has been tremendous growth in recent years in the number and types of new anticancer agents, with an emphasis on creating new DNA- active drugs. One of the most used classes of chemotherapeutic agents in cancer therapy comprise molecules that interact with DNA, such as groove binders, DNA alkylating agents or intercalators. The activity of many antitumor drugs is based on intercalation.1 Azino-fused cyclic derivatives have drawn considerable attention of medicinal and organic chemists due to a wide range of biological activities exerted by this class of compounds.2, 3 As a part of our medicinal chemistry project aimed at the synthesis of potential heterocyclic anticancer agents, we have prepared novel imidazo[4, 5-b]pyridine derivatives. 2-styryl- imidazo[4, 5-b]pyridines were prepared by using classical organic synthesis reactions. Their cyclic analogues, triazabenzo[c]fluorenes were prepared by photochemical dehydrocyclization and thermic cyclization reactions. Structures of prepared compounds were confirmed by means of 1H, 13C NMR, IR and UV spectroscopy. Antitumor activity in vitro was tested on 6 human tumour cell lines, as well as on normal (diploid) human fibroblasts. Some of tested compounds showed a differential and significant antiproliferative effect at micromole concentrations. Interaction with ct-DNA of triazabenzo[c]fluorene 5 was studied by using 4 different methods including thermal denaturation experiment, spectroscopic UV/Vis, fluorimetric and CD titrations with ct- DNA. Cyclic derivative 5 showed significant interaction with ct-DNA and based on all experiment results, we can conclude that one of the mechanisms of its biological action is intercalation into DNA.

Synthesis; antitumor evaluation in vitro and interaction with ct-DNA of novel imidazo[4; 5-b]pyridine derivatives

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