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3-(Benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives as novel scaffold topoisomerase I inhibitor via DNA intercalation: design, synthesis, and antitumor activities.
- Source :
- New Journal of Chemistry; 7/14/2020, Vol. 44 Issue 26, p11203-11214, 12p
- Publication Year :
- 2020
-
Abstract
- Twenty-seven 3-(benzo[d]thiazol-2-yl)-4-aminoquinoline derivatives have been designed and synthesized as topoisomerase I inhibitors. The in vitro anti-proliferation evaluation against four human cancer cell lines (MGC-803, HepG-2, T24, and NCI-H460) and one normal cell line (HL-7702) indicated that most of them exhibited potent cytotoxicity. Among them, 5a was identified as the most promising candidate with a low IC<subscript>50</subscript> value of about 2.20 ± 0.14 and was selected for further exploration. Spectroscopic analyses and agarose-gel electrophoresis assays indicated that 5a could interact with DNA and strongly inhibit topoisomerase I (Topo I). Further screening of the Topo I activity of compounds 5b, 5c, 5e, 5f, 5h, 5i, 5j, 5l, and 5n suggested that some of the compounds might exert quite a different cytotoxicity profile to that of 5a. Molecular modeling studies confirmed that 5a adopts a unique mode to interact with DNA and Topo I. Other molecular mechanistic studies suggested that the treatment of MGC-803 cells with 5a induces S phase arrest, up-regulates the pro-apoptotic protein, down-regulates the anti-apoptotic protein, activates caspase-3, and subsequently induces mitochondrial dysfunction so as to induce cell apoptosis. The in vivo efficiency of 5a was also evaluated on MGC-803 xenograft nude mice and the relative tumor growth inhibition was 42.4% at 12 mg kg<superscript>−1</superscript> without an obvious loss in the body weight. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 11440546
- Volume :
- 44
- Issue :
- 26
- Database :
- Complementary Index
- Journal :
- New Journal of Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 144410485
- Full Text :
- https://doi.org/10.1039/c9nj05846j