1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies

References

• Baselga J, Bhardwaj N, Cantley LC, et al. AACR cancer progress report 2015. Clin Cancer Res 2015;21:S1–S128.
   PubMed Web of Science ®Google Scholar
• WHO, Cancer. https://www.who.int/health-topics/cancer#tab=tab_1. (Accessed May 2020 2020).
   Google Scholar
• Thurston DE. Chemistry and pharmacology of anticancer drugs. 2nd ed. London: CRC Press, Tylor and Francis; 2006.
   Google Scholar
• Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: a current overview. Clin Exp Metastasis 2018;35:309–18.
   PubMed Web of Science ®Google Scholar
• El-Zahabi MA, Sakr H, El-Adl K, et al. Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents. Bioorg Chem 2020;104:104218.
   PubMed Web of Science ®Google Scholar
• Nasser AA, Eissa IH, Oun MR, et al. Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFRWT and EGFRT790M. Org Biomol Chem 2020;18:7608–34.
   PubMed Web of Science ®Google Scholar
• Eldehna WM, Abo-Ashour MF, Nocentini A, et al. Novel 4/3-((4-oxo-5-(2-oxoindolin-3-ylidene)thiazolidin-2-ylidene)amino) benzenesulfonamides: synthesis, carbonic anhydrase inhibitory activity, anticancer activity and molecular modelling studies. Eur J Med Chem 2017;139:250–62.
   PubMed Web of Science ®Google Scholar
• El-Adl K, El-Helby A-GA, Sakr H, et al. Design, synthesis, molecular docking and anticancer evaluations of 5-benzylidenethiazolidine-2,4-dione derivatives targeting VEGFR-2 enzyme. Bioorg Chem 2020;102:104059.
   PubMed Web of Science ®Google Scholar
• Eissa IH, El-Helby A-GA, Mahdy HA, et al. Discovery of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors: design, synthesis, and anti-proliferative evaluation. Bioorg Chem 2020;105:104380.
   PubMed Web of Science ®Google Scholar
• Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 2006;9:225–30.
   PubMedGoogle Scholar
• Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharma Bull 2011;34:1785–8.
   PubMed Web of Science ®Google Scholar
• Flister MJ, Wilber A, Hall KL, et al. Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. J Am Soc Hematol 2010;115:418–29.
   Google Scholar
• El‐Adl K, Ibrahim MK, Khedr F, et al. N‐Substituted‐4‐phenylphthalazin‐1‐amine‐derived VEGFR‐2 inhibitors: design, synthesis, molecular docking, and anticancer evaluation studies. Archiv Pharma 2021;354:2000219.
   Web of Science ®Google Scholar
• Padro T, Bieker R, Ruiz S, et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia 2002;16:1302–10.
   PubMed Web of Science ®Google Scholar
• Yang C, Qin S. Apatinib targets both tumor and endothelial cells in hepatocellular carcinoma. Cancer Med 2018;7:4570–83.
   PubMed Web of Science ®Google Scholar
• Guo S, Colbert LS, Fuller M, et al. Vascular endothelial growth factor receptor-2 in breast cancer. Biochim Biophys Acta 2010;1806:108–21.
   PubMed Web of Science ®Google Scholar
• Martins SF, Garcia EA, Luz MAM, et al. Clinicopathological correlation and prognostic significance of VEGF-A, VEGF-C, VEGFR-2 and VEGFR-3 expression in colorectal cancer. Cancer Genomics Proteomics 2013;10:55–67.
   PubMed Web of Science ®Google Scholar
• Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal 2007;19:2003–12.
   PubMed Web of Science ®Google Scholar
• Kaipainen A, Korhonen J, Mustonen T, et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 1995;92:3566–70.
   PubMed Web of Science ®Google Scholar
• Tammela T, Zarkada G, Wallgard E, et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 2008;454:656–60.
   PubMed Web of Science ®Google Scholar
• Peng F-W, Liu D-K, Zhang Q-W, et al. VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012–2016). Expert Opin Ther Pat 2017;27:987–1004.
   PubMed Web of Science ®Google Scholar
• Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007;25:884–96.
   PubMed Web of Science ®Google Scholar
• Song Y, Wang J, Ren X, et al. Vorolanib, an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors: an open-label, phase I dose escalation and dose expansion trial. Chin J Cancer Res 2021;33:103–14.
   PubMed Web of Science ®Google Scholar
• Jamil MO, Hathaway A, Mehta A. Tivozanib: status of development. Curr Oncol Rep 2015;17:24.
   PubMed Web of Science ®Google Scholar
• Xie Q-Q, Xie H-Z, Ren J-X, et al. Pharmacophore modeling studies of type I and type II kinase inhibitors of Tie2. J Mol Graph Model 2009;27:751–8.
   PubMed Web of Science ®Google Scholar
• Lee K, Jeong K-W, Lee Y, et al. Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors. Eur J Med Chem 2010;45:5420–7.
   PubMed Web of Science ®Google Scholar
• Eskander RN, Tewari KS. Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma-mechanistics, review of phase III randomized clinical trials, and regulatory implications. Gynecol Oncol 2014;132:496–505.
   PubMed Web of Science ®Google Scholar
• Eissa IH, Ibrahim MK, Metwaly AM, et al. Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma. Bioorg Chem 2021;107:104532.
   PubMed Web of Science ®Google Scholar
• El-Metwally SA, Abou-El-Regal MM, Eissa IH, et al. Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents. Bioorg Chem 2021;112:104947.
   PubMed Web of Science ®Google Scholar
• Alsaif NA, Dahab MA, Alanazi MM, et al. New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: design, molecular modeling, and synthesis. Bioorg Chem 2021;110:104807.
   PubMed Web of Science ®Google Scholar
• Machado VA, Peixoto D, Costa R, 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. Bioorg Med Chem 2015;23:6497–509.
   PubMed Web of Science ®Google Scholar
• Wang Z, Wang N, Han S, et al. Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PLOS One 2013;8:e68566.
   PubMed Web of Science ®Google Scholar
• Dietrich J, Hulme C, Hurley LH. 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. Bioorg Med Chem 2010;18:5738–48.
   PubMed Web of Science ®Google Scholar
• Mahdy HA, Ibrahim MK, Metwaly AM, et al. Design, synthesis, molecular modeling, in vivo studies and anticancer evaluation of quinazolin-4(3H)-one derivatives as potential VEGFR-2 inhibitors and apoptosis inducers. Bioorg Chem 2020;94:103422.
   PubMed Web of Science ®Google Scholar
• El‐Helby AGA, Sakr H, Eissa IH, et al. Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: design, synthesis, molecular docking, and anticancer evaluations. Archiv Pharma 2019;352:1900178.
   Web of Science ®Google Scholar
• El‐Helby AGA, Sakr H, Eissa IH, et al. Design, synthesis, molecular docking, and anticancer activity of benzoxazole derivatives as VEGFR‐2 inhibitors. Archiv Pharm 2019;352:1900113.
   Web of Science ®Google Scholar
• Alanazi MM, Mahdy HA, Alsaif NA, et al. New bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, and anticancer evaluation. Bioorg Chem 2021;112:104949.
   PubMed Web of Science ®Google Scholar
• Alanazi MM, Eissa IH, Alsaif NA, et al. Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers. J Enzyme Inhib Med Chem 2021;36:1760–82.
   PubMed Web of Science ®Google Scholar
• Parmar DR, Soni JY, Guduru R, et al. Discovery of new anticancer thiourea-azetidine hybrids: design, synthesis, in vitro antiproliferative, SAR, in silico molecular docking against VEGFR-2, ADMET, toxicity, and DFT studies. Bioorg Chem 2021;115:105206.
   PubMed Web of Science ®Google Scholar
• Abadi AH, Eissa AAH, Hassan GS. Synthesis of novel 1,3,4-trisubstituted pyrazole derivatives and their evaluation as antitumor and antiangiogenic agents. Chem Pharm Bull 2003;51:838–44.
   PubMed Web of Science ®Google Scholar
• Vaidya A, Pathak D, Shah K. 1,3,4-oxadiazole and its derivatives: a review on recent progress in anticancer activities. Chem Biol Drug Des 2021;97:572–91.
   PubMed Web of Science ®Google Scholar
• Wang G, Peng Z, Zhang J, et al. Synthesis, biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site. Bioorg Chem 2018;78:332–40.
   PubMed Web of Science ®Google Scholar
• Wang G, Liu W, Gong Z, et al. Synthesis, biological evaluation, and molecular modelling of new naphthalene-chalcone derivatives as potential anticancer agents on MCF-7 breast cancer cells by targeting tubulin colchicine binding site. J Enzyme Inhib Med Chem 2020;35:139–44.
   PubMed Web of Science ®Google Scholar
• Ibrahim M, Taghour M, Metwaly A, et al. Design, synthesis, molecular modeling and anti-proliferative evaluation of novel quinoxaline derivatives as potential DNA intercalators and topoisomerase II inhibitors. Eur J Med Chem 2018;155:117–34.
   PubMed Web of Science ®Google Scholar
• Ibrahim MK, Eissa IH, Abdallah AE, et al. Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of novel quinoxaline derivatives as potential PPARγ and SUR agonists. Bioorg Med Chem 2017;25:1496–513.
   PubMed Web of Science ®Google Scholar
• Hou T, Zhu L, Chen L, Xu X. Mapping the binding site of a large set of quinazoline type EGF-R inhibitors using molecular field analyses and molecular docking studies. J Chem Inform Comput Sci 2003;43:273–87.
   PubMedGoogle Scholar
• Bhinge SD, Chature V, Sonawane LV. Synthesis of some novel 1,3,4-thiadiazole derivatives and biological screening for anti-microbial, antifungal and anthelmintic activity. Pharma Chem J 2015;49:367–72.
   Web of Science ®Google Scholar
• Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358–64.
   PubMed Web of Science ®Google Scholar
• Xia X, Maliski EG, Gallant P, Rogers D. Classification of kinase inhibitors using a Bayesian model. J Med Chem 2004;47:4463–70.
   PubMed Web of Science ®Google Scholar
• BIOVIA, QSAR, ADMET and Predictive Toxicology.https://www.3dsbiovia.com/products/collaborative-science/biovia-discovery-studio/qsar-admet-and-predictive-toxicology.html. (Accessed May 2020).
   Google Scholar
• Gold L S, Slone T H, Bernstein L J E H P, Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database,  (1989);79:259-272.
   Google Scholar
• Goodman G, Wilson R. Comparison of the dependence of the TD50 on maximum tolerated dose for mutagens and nonmutagens. Risk Anal 1992;12:525–33.
   PubMed Web of Science ®Google Scholar
•  Haseman J, Seilkop S J F, Toxicology A, An examination of the association between maximum-tolerated dose and carcinogenicity in 326 long-term studies in rats and mice,  (1992);19(2):207-213.
   Google Scholar
• Diaza RG, Manganelli S, Esposito A, et al. Comparison of in silico tools for evaluating rat oral acute toxicity. SAR QSAR Environ Res 2015;26:1–27.
   PubMed Web of Science ®Google Scholar
• Pizzo F, Benfenati E. In silico models for repeated-dose toxicity (RDT): prediction of the no observed adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) for drugs. In: In silico methods for predicting drug toxicity. Switzerland AG: Springer; 2016:163–76.
   Google Scholar
• Venkatapathy R, Moudgal CJ, Bruce RM. Assessment of the oral rat chronic lowest observed adverse effect level model in TOPKAT, a QSAR software package for toxicity prediction. J Chem Inform Comput Sci 2004;44:1623–9.
   PubMedGoogle Scholar
• Wilhelmus KR. The Draize eye test. Surv Ophthalmol 2001;45:493–515.
   PubMed Web of Science ®Google Scholar
• Han Mİ, Bekçi H, Uba AI, et al. Synthesis, molecular modeling, in vivo study, and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen. Arch Pharm 2019;352:1800365.
   Web of Science ®Google Scholar
• El-Husseiny WM, Magda A-A, Abdel-Aziz NI, et al. Structural alterations based on naproxen scaffold: synthesis, evaluation of antitumor activity and COX-2 inhibition, and molecular docking. Eur J Med Chem 2018;158:134–43.,
   PubMed Web of Science ®Google Scholar
• Sefried S, Häring H-U, Weigert C, Eckstein SS. Suitability of hepatocyte cell lines HepG2, AML12 and THLE-2 for investigation of insulin signalling and hepatokine gene expression. Open Biol 2018;8:180147.
   PubMed Web of Science ®Google Scholar
• Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.
   PubMed Web of Science ®Google Scholar
• Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods 1986;89:271–7.
   PubMed Web of Science ®Google Scholar
• Thabrew MI, Hughes RD, McFarlane IG. Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity assay. J Pharma Pharmacol 2011;49:1132–5.
   Google Scholar
• Al-Rashood ST, Hamed AR, Hassan GS, et al. Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity. J Enzyme Inhib Med Chem 2020;35:831–9.
   PubMed Web of Science ®Google Scholar
• Ismail A, Doghish AS, Elsadek BE, et al. Hydroxycitric acid potentiates the cytotoxic effect of tamoxifen in MCF-7 breast cancer cells through inhibition of ATP citrate lyase. Steroids 2020;160:108656.
   PubMed Web of Science ®Google Scholar
• Sharma K, Suresh P, Mullangi R, Srinivas N. Quantitation of VEGFR2 (vascular endothelial growth factor receptor) inhibitors-review of assay methodologies and perspectives. Biomed Chromatogr 2015;29:803–34.
   PubMed Web of Science ®Google Scholar
• El-Mahdy HA, El-Husseiny AA, Kandil YI, El-Din AMG. Diltiazem potentiates the cytotoxicity of gemcitabine and 5-fluorouracil in PANC-1 human pancreatic cancer cells through inhibition of P-glycoprotein. Life Sci 2020;262:118518.
   PubMed Web of Science ®Google Scholar
• Kassab AE, Gedawy EM, Hamed MI, et al. Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers. J Enzyme Inhib Med Chem 2021;36:922–39.
   PubMed Web of Science ®Google Scholar
• Eldehna WM, Hassan GS, Al-Rashood ST, et al. Synthesis and in vitro anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents. J Enzyme Inhib Med Chem 2019;34:322–32.,
   PubMed Web of Science ®Google Scholar
• Al-Warhi T, Abo-Ashour MF, Almahli H, et al. Novel [(N-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and in silico studies. J Enzyme Inhib Med Chem 2020;35:1300–9.
   PubMed Web of Science ®Google Scholar
• Sabt A, Abdelhafez OM, El-Haggar RS, et al. Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: synthesis, in vitro biological evaluation, and QSAR studies. J Enzyme Inhib Med Chem 2018;33:1095–107.
   PubMed Web of Science ®Google Scholar
• Al-Sanea MM, Al-Ansary GH, Elsayed ZM, et al. Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells. J Enzyme Inhib Med Chem 2021;36:987–99.
   PubMed Web of Science ®Google Scholar
• El-Zahabi MA, Elbendary ER, Bamanie FH, et al. Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of phthalimide-sulfonylurea hybrids as PPARγ and SUR agonists. Bioorg Chem 2019;91:103115.
   PubMed Web of Science ®Google Scholar
• Ibrahim MK, Eissa IH, Alesawy MS, et al. Design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazolin-4(3H)-one derivatives as potential PPARγ and SUR agonists. Bioorg Med Chem 2017;25:4723–44.
   PubMed Web of Science ®Google Scholar
• El-Gamal KM, El-Morsy AM, Saad AM, et al. Synthesis, docking, QSAR, ADMET and antimicrobial evaluation of new quinoline-3-carbonitrile derivatives as potential DNA-gyrase inhibitors. J Mol Struct 2018;1166:15–33.
   Web of Science ®Google Scholar
• El-Naggar AM, Eissa IH, Belal A, El-Sayed AA. Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5(4H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site. RSC Adv 2020;10:2791–811.
   PubMed Web of Science ®Google Scholar
• El-Demerdash A, Metwaly AM, Hassan A, et al. Comprehensive virtual screening of the antiviral potentialities of marine polycyclic guanidine alkaloids against SARS-CoV-2 (COVID-19). Biomolecules 2021;11:460.
   PubMed Web of Science ®Google Scholar
• Eissa IH, Dahab MA, Ibrahim MK, et al. Design and discovery of new antiproliferative 1,2,4-triazin-3(2H)-ones as tubulin polymerization inhibitors targeting colchicine binding site. Bioorg Chem 2021;112:104965.
   PubMed Web of Science ®Google Scholar