Synthesis, biological evaluation, and in silico studies of indole-tethered pyrazoline derivatives as anticancer agents targeting topoisomerase IIα.

Autor: Haider K; Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India., Sharma S; Faculty of Life Science and Biotechnology, South Asian University, New Delhi, India., Pokharel YR; Faculty of Life Science and Biotechnology, South Asian University, New Delhi, India., Das S; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India., Joseph A; Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India., Najmi AK; Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India., Ahmad F; Faculty of Life Science and Biotechnology, South Asian University, New Delhi, India., Yar MS; Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2022 Nov; Vol. 83 (7), pp. 1555-1577. Date of Electronic Publication: 2022 Jul 27.
DOI: 10.1002/ddr.21976
Abstrakt: We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC 50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.
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Databáze: MEDLINE
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