Design, synthesis, in silico docking, ADMET and anticancer evaluations of thiazolidine-2,4-diones bearing heterocyclic rings as dual VEGFR-2/EGFRT790M tyrosine kinase inhibitors

Fourteen recent thiazolidine-2,4-diones bearing furan and/or thiophene heterocyclic rings have been designed, synthesized and assessed for their anticancer activities against four human tumor cell lines HepG2, A549, MCF-7 and HCT-116 targeting both VEGFR-2 and EGFR tyrosine kinases. Molecular design was carried out to investigate the binding mode of the proposed compounds with VEGFR-2 and EGFR receptors. HepG2 was the most susceptible cell line to the influence of our derivatives. Compounds 5g and 4g revealed the highest activities against HepG2 (IC50 = 3.86 and 6.22 μM), A549 (IC50 = 7.55 and 12.92 μM), MCF-7 (IC50 = 10.65 and 10.66 μM) and HCT116 (IC50 = 9.04 and 11.17 μM) tumor cell lines. Sorafenib (IC50 = 4.00, 4.04, 5.58 and 5.05 μM) and elotinib (IC50 = 7.73, 5.49, 8.20 and 13.91 μM) were used as reference standards. Furthermore, the most active cytotoxic compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were selected to assess their VEGFR-2 inhibitory effects. Derivatives 5g, 4g and 4f were observed to be the highest effective derivatives that inhibited VEGFR-2 at the submicromolar level (IC50 = 0.080, 0.083 and 0.095 μM respectively) in comparison to sorafenib (IC50 = 0.084 μM). As well, compounds 4d, 4e, 4f, 4g, 5d, 5e, 5f and 5g were additionally assessed for their inhibitory activities against mutant EGFRT790M. Compounds 5g and 4g could interfere with the EGFRT790M activity exhibiting stronger activities than elotinib with IC50 = 0.14 and 0.23 μM respectively. Finally, our derivatives 4g, 5f and 5g showed a good in silico calculated ADMET profile. The obtained results showed that our compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective dual VEGFR-2/EGFRT790M inhibitors with higher anticancer activity.

[1]  S. Dixit,et al.  Discovery of Rhodanine and Thiazolidinediones as Novel Scaffolds for EGFR Inhibition: Design, Synthesis, Analysis and CoMSIA Studies , 2020, Polycyclic Aromatic Compounds.

[2]  X. Le,et al.  Dual EGFR/VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC. , 2020, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[3]  K. Saied,et al.  Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. , 2019, Bioorganic chemistry.

[4]  Qingsong Liu,et al.  Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC. , 2017, European journal of medicinal chemistry.

[5]  Huabei Zhang,et al.  Development of a series of novel 4-anlinoquinazoline derivatives possessing quinazoline skeleton: Design, synthesis, EGFR kinase inhibitory efficacy, and evaluation of anticancer activities in vitro. , 2017, European journal of medicinal chemistry.

[6]  F. Halaweish,et al.  Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma. , 2017, Bioorganic & medicinal chemistry.

[7]  Shuifa Wu,et al.  Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiency in vitro , 2017, Oncotarget.

[8]  Li‐Ping Sun,et al.  Design and discovery of 4-anilinoquinazoline-urea derivatives as dual TK inhibitors of EGFR and VEGFR-2. , 2017, European journal of medicinal chemistry.

[9]  P. Kulkarni,et al.  5-Benzylidene-2,4-thiazolidenedione derivatives: Design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2. , 2016, Bioorganic chemistry.

[10]  V. Gandin,et al.  Targeting kinases with anilinopyrimidines: discovery of N-phenyl-N’-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily , 2015, Scientific Reports.

[11]  Rui M. V. Abreu,et al.  Synthesis, antiangiogenesis evaluation and molecular docking studies of 1-aryl-3-[(thieno[3,2-b]pyridin-7-ylthio)phenyl]ureas: Discovery of a new substitution pattern for type II VEGFR-2 Tyr kinase inhibitors. , 2015, Bioorganic & medicinal chemistry.

[12]  R. McCormack,et al.  EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). , 2015, American journal of cancer research.

[13]  P. Jänne,et al.  AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. , 2015, The New England journal of medicine.

[14]  S. Knapp,et al.  Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery? , 2014, ACS chemical biology.

[15]  C. Ramaa,et al.  A new dawn for the use of thiazolidinediones in cancer therapy , 2014, Expert opinion on investigational drugs.

[16]  F. Totzke,et al.  Novel 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors. , 2014, European journal of medicinal chemistry.

[17]  Jianping Chen,et al.  Dietary Compound Isoliquiritigenin Inhibits Breast Cancer Neoangiogenesis via VEGF/VEGFR-2 Signaling Pathway , 2013, PloS one.

[18]  P. Hoff,et al.  Role of angiogenesis in the pathogenesis of cancer. , 2012, Cancer treatment reviews.

[19]  Satoru Takahashi,et al.  Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. , 2011, Biological & pharmaceutical bulletin.

[20]  A. Larsen,et al.  Targeting EGFR and VEGF(R) pathway cross-talk in tumor survival and angiogenesis. , 2011, Pharmacology & therapeutics.

[21]  H. Jaafar,et al.  Breast Tumor Angiogenesis and Tumor-Associated Macrophages: Histopathologist's Perspective , 2011, Pathology research international.

[22]  Kyungik Lee,et al.  Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors. , 2010, European journal of medicinal chemistry.

[23]  E. Gershtein,et al.  Vascular Endothelial Growth Factor and Its Type 2 Receptor in Hepatocellular Carcinoma , 2010, Bulletin of Experimental Biology and Medicine.

[24]  Christopher Hulme,et al.  The design, synthesis, and evaluation of 8 hybrid DFG-out allosteric kinase inhibitors: a structural analysis of the binding interactions of Gleevec, Nexavar, and BIRB-796. , 2010, Bioorganic & medicinal chemistry.

[25]  Ji-Xia Ren,et al.  Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2. , 2009, Journal of molecular graphics & modelling.

[26]  K. Menon,et al.  Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro. , 2007, Fertility and sterility.

[27]  R. Talanian,et al.  Homogeneous time-resolved fluorescence and its applications for kinase assays in drug discovery. , 2006, Analytical biochemistry.

[28]  Susan M. Kilroy,et al.  PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. , 2002, The Journal of clinical investigation.

[29]  M. Aebi,et al.  The MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] Assay Is a Fast and Reliable Method for Colorimetric Determination of Fungal Cell Densities , 1999, Applied and Environmental Microbiology.

[30]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[31]  Mamdouh M. Ali,et al.  1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation. , 2016, European journal of medicinal chemistry.

[32]  P. Depreux,et al.  [4-(6,7-Disubstituted quinazolin-4-ylamino)phenyl] carbamic acid esters: a novel series of dual EGFR/VEGFR-2 tyrosine kinase inhibitors , 2011 .