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Novel halogenated pyrido[2,3-a]carbazole with enhanced aromaticity as potent anticancer and antioxidant: Rationale design and microwave assisted synthesis

Abstract

Design, synthesis of a novel series of 4a,5,6,11-tetrahydro-4H-thieno[3',2':5,6]pyrido[2,3-a]carbazol-4-one derivatives (3a-3g), and evaluation for their anticancer activity (HeLa, MCF-7 and HEp-2 cell lines by MTT assay method) and antioxidant (DPPH and -OH radical scavenging) activity. Designed compounds (3a-3g) were synthesized by microwave irradiation in the presence of p-TsOH, with yield up to 89%, in short time (11min). Halogenated compounds (3e and 3f) strongly bind with calf thymus (CT-DNA) helix via intercalation and showed more hypochromicity (84% and 81% respectively) with red shift (12 nm and 20 nm, respectively). Compounds (3e and 3f) completely cleaved pBR322 DNA by oxidative cleavage. In general, it was observed that chloro and bromo substituted compounds (3e and 3f) showed excellent anticancer activity and strongly binds to CT-DNA, which may be due to the stronger electron withdrawing tendency of the chloro and bromo groups than that of the electron donating and unsubstitutedcarbazole derivatives. The most outranged compounds 3e (2.05, 3.35, and 10.24 fold) and 3f (3.62, 6.28 and 8.09 fold), displayed stronger cytotoxicity than the positive control Cisplatin, also compared with Ellipticine. Compound 3g (with -OCH3 substitution and 3e with chloro substitution exhibit greater antioxidant than standard Ascorbic acid. In order to understand the nature of the interaction of these molecules, we carried out molecular docking studies using the CK2 protein inhibitors. All the molecules were found to accommodate well in the ATP-binding site of human CK2 formed by residue Asn118, Ile174, Val53, Val116). The adopted design strategy provided two potent halogenated compounds (3e and 3f), which may be required further in-vivo investigations before subjecting to clinical trials, and also some useful insights about the future design of more potent inhibitors for the treatment of cancer.

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Publication details

The article was received on 26 Dec 2018, accepted on 19 Jun 2019 and first published on 19 Jun 2019


Article type: Paper
DOI: 10.1039/C8NJ06504G
New J. Chem., 2019, Accepted Manuscript

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    Novel halogenated pyrido[2,3-a]carbazole with enhanced aromaticity as potent anticancer and antioxidant: Rationale design and microwave assisted synthesis

    S. Munusamy, V. N. Badavath, S. Maji, S. M and M. Shabbir, New J. Chem., 2019, Accepted Manuscript , DOI: 10.1039/C8NJ06504G

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