Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold

被引：59

作者：

Elzahabi, Heba S. A. ^{[1
]}

Nossier, Eman S. ^{[1
]}

Khalifa, Nagy M. ^{[2
]}

Alasfoury, Rania A. ^{[1
]}

El-Manawaty, May A. ^{[3
]}

机构：

[1] Al Azhar Univ, Fac Pharm Girls, Dept Pharmaceut Chem, Cairo, Egypt

[2] King Saud Univ, Dept Pharmaceut Chem, Coll Pharm, DEDC, Riyadh 11451, Saudi Arabia

[3] Natl Res Ctr, Pharmaceut Sci Div, Dept Pharmacognosy, Cairo, Egypt

来源：

JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY | 2018年 / 33卷 / 01期

关键词：

Pyrido[2,3-d]pyrimidine derivatives; anticancer activity; EGFR; CDK4/cyclin D1; molecular docking; AGENTS; APOPTOSIS; ANTITUMOR; GROWTH;

D O I：

10.1080/14756366.2018.1437729

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：

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC50: 0.3, 6.6 and 7 mu M) relative to the standard doxorubicin (IC50: 0.6, 6.8 and 12.8 mu M), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR , EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 mu M in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

引用

页码：546 / 557

页数：12

共 27 条

[21] Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor [J].

Stamos, J ;

Sliwkowski, MX ;

Eigenbrot, C .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (48) :46265-46272

[22] Targeting multidrug resistance in cancer [J].

Szakács, G ;

Paterson, JK ;

Ludwig, JA ;

Booth-Genthe, C ;

Gottesman, MM .

NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (03) :219-234

[23] Targeting CDK6 in cancer: State of the art and new insights [J].

Tadesse, Solomon ;

Yu, Mingfeng ;

Kumarasiri, Malika ;

Bich Thuy Le ;

Wang, Shudong .

CELL CYCLE, 2015, 14 (20) :3220-3230

[24] Strategies toward the design of novel and selective protein tyrosine kinase inhibitors [J].

Traxler, P ;

Furet, P .

PHARMACOLOGY & THERAPEUTICS, 1999, 82 (2-3) :195-206

[25] The new era in cancer research [J].

Varmus, Harold .

SCIENCE, 2006, 312 (5777) :1162-1165

[26]

Wu H.C., 2006, J CANC MOL, V2, P57

[27] Synthesis of novel oxime-containing pyrazole derivatives and discovery of regulators for apoptosis and autophagy in A549 lung cancer cells [J].

Zheng, Liang-Wen ;

Li, Ying ;

Ge, Di ;

Zhao, Bao-Xiang ;

Liu, Ying-Rui ;

Lv, Hong-Shui ;

Ding, Jun ;

Miao, Jun-Ying .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (16) :4766-4770

← 1 2 3 →