Type IIA - Type IIB protein tyrosine kinase inhibitors hybridization as an efficient approach for potent multikinase inhibitor development: Design, synthesis, anti-proliferative activity, multikinase inhibitory activity and molecular modeling of novel indolinone-based ureides and amides

被引:66
作者
Eldehna, Wagdy M. [1 ]
El Kerdawy, Ahmed M. [2 ,3 ,4 ]
Al-Ansary, Ghada H. [5 ,6 ]
Al-Rashood, Sara T. [7 ]
Ali, Mamdouh M. [8 ]
Mahmoud, Abeer E. [8 ]
机构
[1] Kafrelsheikh Univ, Dept Pharmaceut Chem, Fac Pharm, Kafrelsheikh 33516, Egypt
[2] Cairo Univ, Dept Pharmaceut Chem, Fac Pharm, Kasr El Aini St,POB 11562, Cairo, Egypt
[3] Cairo Univ, Mol Modeling Unit, Fac Pharm, Kasr El Aini St,POB 11562, Cairo, Egypt
[4] New Giza Univ, Dept Pharmaceut Chem, Fac Pharm, Km 22 Cairo Alexandria Desert Rd, Cairo, Egypt
[5] Ain Shams Univ, Dept Pharmaceut Chem, Fac Pharm, POB 11566, Cairo, Abbassia, Egypt
[6] Batterejee Med Coll, Dept Pharmaceut Chem, Pharm Program, POB 6231, Jeddah, Saudi Arabia
[7] King Saud Univ, Dept Pharmaceut Chem, Coll Pharm, POB 2457, Riyadh 11451, Saudi Arabia
[8] Natl Res Ctr, Genet Engn & Biotechnol Res Div, Biochem Dept, Giza 12622, Egypt
关键词
Multikinase inhibitor; Synthesis; Indolinone; Molecular modeling; VEGFR-2; FGFR-1 and PDGFR-b; BIOLOGICAL EVALUATION; VEGFR-2; INHIBITORS; ANTICANCER AGENTS; CANCER STATISTICS; DRUG DISCOVERY; BINDING; ABSORPTION; UREAS; KLIFS;
D O I
10.1016/j.ejmech.2018.11.061
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Pursuing on our efforts regarding development of novel multikinase inhibitors, herein we report the design and synthesis of novel 2-indolinone-based ureides 6a-u and amides 10a J. In this work we adopt a hybridization strategy between type IIA PTK inhibitor (sorafenib) and type IIB PTK inhibitors (sunitinib and nintedanib). This was implemented via linking the indolinone core, in both sunitinib and nintedanib, which is well-fitted in the hinge region in the kinase domain front cleft and the biaryl urea extension, in sorafenib, which is accommodated in the gate area and the hydrophobic back pocket. Molecular docking of the designed hybrid compounds in VEGFR-2 and FGFR-1 active sites revealed, as planned, their ability to establish the binding interactions achieved by both original type IIA and type IIB inhibitors. The designed compounds were evaluated for their multikinase inhibitory activity towards VEGFR-2, PDGFR-b and FGFR-1 and anti-proliferative activity towards HepG2, MCF-7, A549 and A498 cancer cell lines. The ureido analogue 6u emerged as the most potent multikinase inhibitor in the ureido series with VEGFR-2, FGFR-1 and PDGFR-b IC50 of 0.18, 0.23 and 0.10 M, respectively. Whereas, the amido congener 10j emerged as the most potent multikinase inhibitor in the amide series with VEGFR-2, FGFR-1 and PDGF-Rb IC50 of 0.28, 0.46 and 0.09 M, respectively. While, indolinone 6u was the most potent derivative towards HepG2 cells (IC50 = 2.67 0.14 i.tM), 6r stood out as the most potent indolinone against A498 cells (IC50 = 0.78 0.02 M). Additionally, the target indolinones displayed non-significant cytotoxic impact towards human normal melanocyte (HFB4). ADME prediction study of the designed compounds showed that they are not only with promising multikinase inhibitory activity but also with favorable pharmacokinetic and drug-likeness properties. Compounds 6r and 10j are revealed to be the best compounds in terms of multikinase activity and pharmacokinetics. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:37 / 53
页数:17
相关论文
共 54 条
[1]   Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling [J].
Abdel-Aziz, Hatem A. ;
Eldehna, Wagdy M. ;
Keeton, Adam B. ;
Piazza, Gary A. ;
Kadi, Adnan A. ;
Attwa, Mohamed W. ;
Abdelhameed, Ali S. ;
Attia, Mohamed I. .
DRUG DESIGN DEVELOPMENT AND THERAPY, 2017, 11 :2333-2346
[2]   Synthesis, Crystal Structure, and Biological Activity of cis/trans Amide Rotomers of (Z)-N′-(2-Oxoindolin-3-ylidene)formohydrazide [J].
Abdel-Aziz, Hatem A. ;
Ghabbour, Hazem A. ;
Eldehna, Wagdy M. ;
Qabeel, Maha M. ;
Fun, Hoong-Kun .
JOURNAL OF CHEMISTRY, 2014, 2014
[3]   1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation [J].
Abou-Seri, Sahar M. ;
Eldehna, Wagdy M. ;
Ali, Mamdouh M. ;
Abou El Ella, Dalal A. .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2016, 107 :165-179
[4]   Molecular regulation of angiogenesis and lymphangiogenesis [J].
Adams, Ralf H. ;
Alitalo, Kari .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (06) :464-478
[5]   New hydrazonoindolin-2-ones: Synthesis, exploration of the possible anti-proliferative mechanism of action and encapsulation into PLGA microspheres [J].
Attia, Mohamed I. ;
Eldehna, Wagdy M. ;
Afifi, Samar A. ;
Keeton, Adam B. ;
Piazza, Gary A. ;
Abdel-Aziz, Hatem A. .
PLOS ONE, 2017, 12 (07)
[6]   THE MECHANISM OF THE REACTION OF ARYL ISOCYANATES WITH ALCOHOLS AND AMINES .6. PRELIMINARY INVESTIGATIONS WITH AMINES - COMPLEX-FORMATION BY AMINES AND UREAS IN BENZENE SOLUTION [J].
BAKER, JW ;
BAILEY, DN .
JOURNAL OF THE CHEMICAL SOCIETY, 1957, (NOV) :4649-4651
[7]   Multi-kinase inhibitors create buzz at ASCO [J].
Branca, MA .
NATURE BIOTECHNOLOGY, 2005, 23 (06) :639-639
[8]   Tyrosine kinase inhibitors: Multi-targeted or single-targeted? [J].
Broekman, Fleur ;
Giovannetti, Elisa ;
Peters, Godefridus J. .
WORLD JOURNAL OF CLINICAL ONCOLOGY, 2011, 2 (02) :80-93
[9]   Computation of octanol-water partition coefficients by guiding an additive model with knowledge [J].
Cheng, Tiejun ;
Zhao, Yuan ;
Li, Xun ;
Lin, Fu ;
Xu, Yong ;
Zhang, Xinglong ;
Li, Yan ;
Wang, Renxiao ;
Lai, Luhua .
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2007, 47 (06) :2140-2148
[10]   SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules [J].
Daina, Antoine ;
Michielin, Olivier ;
Zoete, Vincent .
SCIENTIFIC REPORTS, 2017, 7