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

被引：51

作者：

El-Helby, Abdel-Ghany A. ^{[1
]}

Sakr, Helmy ^{[1
]}

Ayyad, Rezk R. ^{[1
]}

Mahdy, Hazem A. ^{[1
]}

Khalifa, Mohamed M. ^{[1
]}

Belal, Amany ^{[2
]}

Rashed, Mahmoud ^{[1
]}

El-Sharkawy, Abdou ^{[3
,4
]}

Metwaly, Ahmed M. ^{[5
]}

Elhendawy, Mostafa A. ^{[6
]}

Radwan, Mohamed M. ^{[7
,8
]}

ElSohly, Mahmoud A. ^{[7
,9
]}

Eissa, Ibrahim H. ^{[1
]}

机构：

[1] Al Azhar Univ, Fac Pharm Boys, Pharmaceut Med Chem & Drug Design Dept, Cairo 11884, Egypt

[2] Beni Suef Univ, Fac Pharm, Med Chem Dept, Bani Suwayf 62514, Egypt

[3] Al Azhar Univ, Fac Med, Dept Anat, Cairo, Egypt

[4] Jouf Univ, Coll Med, Dept Anat, Sakakah, Saudi Arabia

[5] Al Azhar Univ, Fac Pharm Boys, Pharmacognosy Dept, Cairo 11884, Egypt

[6] Damietta Univ, Fac Agr, Dept Agr Chem, Dumyat, Egypt

[7] Univ Mississippi, Natl Ctr Nat Prod Res, University, MS 38677 USA

[8] Alexandria Univ, Fac Pharm, Dept Pharmacognosy, Alexandria, Egypt

[9] Univ Mississippi, Dept Pharmaceut & Drug Delivery, University, MS 38677 USA

来源：

BIOORGANIC CHEMISTRY | 2020年 / 103卷

关键词：

Anticancer; Apoptosis; DNA-intercalation; Molecular docking; Phthalazine; Topoisomerase II; RAPID COLORIMETRIC ASSAY; BIOLOGICAL EVALUATION; QUINOXALINE DERIVATIVES; ANTITUMOR-ACTIVITY; ACTINOMYCIN-D; CELL-CYCLE; BINDING; AGENTS; MITOXANTRONE; AMETANTRONE;

D O I：

10.1016/j.bioorg.2020.104233

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu M, while compounds 27 and 32a were found to be the most potent DNA binders at IC50, values of 36.02 and 48.30 mu M, 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 mu M, and Topo II catalytic inhibitory effect at a concentration of 10 mu M. 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.

引用

页数：24

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