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Design, synthesis, molecular modeling, in vivo studies and anticancer activity evaluation of new phthalazine derivatives as potential DNA intercalators and topoisomerase II inhibitors.

Abstract：

:Herein we report the design and synthesis of a new series of phthalazine derivatives as Topo II inhibitors and DNA intercalators. The synthesized compounds were in vitro evaluated for their cytotoxic activities against HepG-2, MCF-7 and HCT-116 cell lines. Additionally, Topo II inhibitory activity and DNA intercalating affinity were investigated for the most active compounds as a potential mechanism for the anticancer activity. Compounds 15h, 23c, 32a, 32b, and 33 exhibited the highest activities against Topo II with IC50 ranging from 5.44 to 8.90 µM, while compounds 27 and 32a were found to be the most potent DNA binders at IC50 values of 36.02 and 48.30 µM, respectively. Moreover, compound 32a induced apoptosis in HepG-2 cells and arrested the cell cycle at the G2/M phase. Besides, compound 32a showed Topo II poisoning effect at concentrations of 2.5 and 5 μM, and Topo II catalytic inhibitory effect at a concentration of10 μM. In addition, compound 32b showed in vivo a significant tumor growth inhibition effect. Furthermore, molecular docking studies were carried out against DNA-Topo II complex and DNA to investigate the binding patterns of the designed compounds.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

El-Helby AA,Sakr H,Ayyad RR,Mahdy HA,Khalifa MM,Belal A,Rashed M,El-Sharkawy A,Metwaly AM,Elhendawy MA,Radwan MM,ElSohly MA,Eissa IH

doi

10.1016/j.bioorg.2020.104233

subject

Has Abstract

pub_date

2020-10-01 00:00:00

pages

104233

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(20)31530-3

journal_volume

103

pub_type

杂志文章

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