3,649
Views
45
CrossRef citations to date
0
Altmetric
Research Paper

Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers

, , , , , , , & show all
Pages 1760-1782 | Received 14 Jun 2021, Accepted 12 Jul 2021, Published online: 02 Aug 2021

References

  • Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394–424.
  • Barbosa IR, Souza D. LB d, Bernal MM, Costa Í. d CC. Cancer mortality in Brazil: temporal trends and predictions for the year 2030. Medicine 2015;94:e746.
  • El Newahie AM, Ismail NS, Abou El Ella DA, Abouzid KA. Quinoxaline-based scaffolds targeting tyrosine kinases and their potential anticancer activity. Arch Pharm 2016;349:309–26.
  • Nam NH, Parang K. Current targets for anticancer drug discovery. Curr Drug Targets 2003;4:159–79.
  • Chu H, Wang Y. Therapeutic angiogenesis: controlled delivery of angiogenic factors. Ther Deliv 2012;3:693–714.
  • Ghith A, Ismail NS, Youssef K, Abouzid KA. Medicinal attributes of thienopyrimidine based scaffold targeting tyrosine kinases and their potential anticancer activities. Arch Pharm 2017;350:1700242.
  • Sajib S, Zahra FT, Lionakis MS, et al. Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis 2018;21:1–14.
  • Hamerlik P, Lathia JD, Rasmussen R, et al. Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med 2012;209:507–20.
  • Guo S, Colbert LS, Fuller M, et al. Vascular endothelial growth factor receptor-2 in breast cancer. Biochim Biophys Acta Rev Cancer 2010;1806:108–21.
  • Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life 2009;61:915–22.
  • Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 2006;9:225–30.
  • Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull 2011;34:1785–8.
  • Flister MJ, Wilber A, Hall KL, et al. Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 2010;115:418–29.
  • 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.
  • Modi SJ, Kulkarni VM. Vascular endothelial growth factor receptor (VEGFR-2)/KDR inhibitors: medicinal chemistry perspective. Med Drug Discov 2019;2:100009.
  • 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.
  • Zhang L, Shan Y, Ji X, et al. Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents. Oncotarget 2017;8:104745–60.
  • Abdel-Mohsen HT, Abdullaziz MA, Kerdawy AME, et al. Targeting receptor tyrosine kinase VEGFR-2 in hepatocellular cancer: rational design, synthesis and biological evaluation of 1, 2-disubstituted benzimidazoles. Molecules 2020;25:770.
  • Rampogu S, Baek A, Park C, et al. Discovery of small molecules that target vascular endothelial growth factor receptor-2 signalling pathway employing molecular modelling studies. Cells 2019;8:269.
  • Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358–64.
  • Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 2005;102:7665–70.
  • Ghorab MM, Alsaid MS, Soliman AM, Ragab FA. VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo[g]quinazolin bearing benzenesulfonamide moiety. J Enzyme Inhib Med Chem 2017;32:893–907.
  • Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006;5:835–44.
  • Woo HY, Heo J. Sorafenib in liver cancer. Expert Opin Pharmacother 2012;13:1059–67.
  • Wilhelm S, Dumas J, Ladouceur G, et al. Diaryl ureas with kinase inhibiting activity, Google Patents; 2007.
  • Albiges L, Barthélémy P, Gross-Goupil M, et al. TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2021;32:97–102.
  • Bedke J, Albiges L, Capitanio U, et al. Updated European Association of Urology guidelines on renal cell carcinoma: nivolumab plus cabozantinib joins immune checkpoint inhibition combination therapies for treatment-naïve metastatic clear-cell renal cell carcinoma. Eur Urol Suppl 2021;79:339–42.
  • Szarek M, Needle MN, Rini BI, et al. Q-TWiST analysis of tivozanib versus sorafenib in patients with advanced renal cell carcinoma in the TIVO-3 study. Clin Genitourin Cancer 2021.
  • Roskoski R Jr., Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun 2007;356:323–8.
  • Zeidan MA, Mostafa AS, Gomaa RM, et al. Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors. Eur J Med Chem 2019;168:315–29.
  • Hassan A, Badr M, Hassan HA, et al. Novel 4-(piperazin-1-yl)quinolin-2(1H)-one bearing thiazoles with antiproliferative activity through VEGFR-2-TK inhibition. Bioorg Med Chem 2021;40:116168.
  • McTigue M, Murray BW, Chen JH, et al. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci USA 2012;109:18281–9.
  • 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.
  • Abdullaziz MA, Abdel-Mohsen HT, El Kerdawy AM, et al. Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors. Eur J Med Chem 2017;136:315–29.
  • 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.
  • 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.
  • Sobhy MK, Mowafy S, Lasheen DS, et al. 3D-QSAR pharmacophore modelling, virtual screening and docking studies for lead discovery of a novel scaffold for VEGFR 2 inhibitors: design, synthesis and biological evaluation. Bioorg Chem 2019;89:102988.
  • 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.
  • Shahin MI, Abou El Ella DA, Ismail NS, Abouzid KA. Design, synthesis and biological evaluation of type-II VEGFR-2 inhibitors based on quinoxaline scaffold. Bioorg Chem 2014;56:16–26.
  • Reed JC. Apoptosis-targeted therapies for cancer. Cancer Cell 2003;3:17–22.
  • Reed JC. Mechanisms of apoptosis. Am J Pathol 2000;157:1415–30.
  • Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem 1999;68:383–424.
  • Cohen GM. Caspases: the executioners of apoptosis. Biochem J 1997;326:1–16.
  • Porter AG, Jänicke RU. Emerging roles of caspase-3 in apoptosis. Cell Death Differ 1999;6:99–104.
  • Kuida K. Caspase-9. Int J Biochem Cell Biol 2000;32:121–4.
  • Cotter T, Daniel PT, Schulze-Osthoff K, et al. Guardians of cell death: the Bcl-2 family proteins. Essays BIOCHEM 2003;39:73–88.
  • Chen H-C, Kanai M, Inoue-Yamauchi A, et al. An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 2015;17:1270–81.
  • Hsu SY, Kaipia A, McGee E, et al. Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proc Natl Acad Sci USA 1997;94:12401–6.
  • Harmey JH, Bouchier-Hayes D. Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays 2002;24:280–3.
  • Ling Y, Lu N, Gao Y, et al. Endostar induces apoptotic effects in HUVECs through activation of caspase-3 and decrease of Bcl-2. Anticancer Res 2009;29:411–7.
  • 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.
  • Scott LJ. Lenvatinib: first global approval. Drugs 2015;75:553–60.
  • Plé PA, Jung F, Ashton S, et al. Discovery of AZD2932, a new quinazoline ether inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases. Bioorg Med Chem Lett 2012;22:262–6.
  • Cetin B, Yılmaz GE, Armagan B, et al. Pazopanib-induced hepatotoxicity in an experimental rat model. Chemotherapy 2018;63:39–45.
  • Pinheiro AC, Mendonça Nogueira TC, VN de Souza M. Quinoxaline nucleus: a promising scaffold in anti-cancer drug discovery. Anti-Cancer Agent 2016;16:1339–52.
  • Kaushal T, Srivastava G, Sharma A, Negi AS. An insight into medicinal chemistry of anticancer quinoxalines. Bioorg Med Chem 2019;27:16–35.
  • El-Adl K, El-Helby A-GA, Sakr H, Elwan A. Design, synthesis, molecular docking and anti-proliferative evaluations of [1,2,4]triazolo[4,3-a]quinoxaline derivatives as DNA intercalators and topoisomerase II inhibitors. Bioorg Chem 2020;105:104399.
  • El-Adl K, El-Helby A-GA, Sakr H, Elwan A. [1,2,4] Triazolo [4,3-a] quinoxaline and [1,2,4] triazolo [4,3-a] quinoxaline-1-thiol-derived DNA intercalators: design, synthesis, molecular docking, in silico ADMET profiles and anti-proliferative evaluations. New J Chem 2021;45:881–97.
  • Whatmore JL, Swann E, Barraja P, et al. Comparative study of isoflavone, quinoxaline and oxindole families of anti-angiogenic agents. Angiogenesis 2002;5:45–51.
  • Weng Q, Zhang J, Cao J, et al. Q39, a quinoxaline 1,4-Di-N-oxide derivative, inhibits hypoxia-inducible factor-1α expression and the Akt/mTOR/4E-BP1 signaling pathway in human hepatoma cells. Investigational New Drugs 2011;29:1177–87.
  • Khandan M, Sadeghian-Rizi S, Khodarahmi G, Hassanzadeh F. Synthesis and cytotoxic evaluation of some novel quinoxalinedione diarylamide sorafenib analogues. Res Pharm Sci 2018;13:168–76.
  • Sadeghian-Rizi S, Khodarahmi GA, Sakhteman A, et al. Biological evaluation, docking and molecular dynamic simulation of some novel diaryl urea derivatives bearing quinoxalindione moiety. Res Pharm Sci 2017;12:500–9.
  • 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.
  • 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.
  • 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.
  • Abdallah AE, Eissa SI, Al Ward MMS, et al. Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation. Bioorg Chem 2021;109:104695.
  • Ibrahim M-K, Abd-Elrahman AA, Ayyad RR, et al. Design and synthesis of some novel 2-(3-methyl-2-oxoquinoxalin-1 (2H)-yl)-N-(4-(substituted) phenyl) acetamide derivatives for biological evaluation as anticonvulsant agents. Bull Fac Pharm Cairo Univ 2013;51:101–11.
  • Singh DP, Deivedi SK, Hashim SR, Singhal RG. Synthesis and antimicrobial activity of some new quinoxaline derivatives. Pharmaceuticals 2010;3:2416–25.
  • Morrison D, Furst A. Quinoxaline-2-thiols. J Org Chem 1956;21:470–1.
  • Saoudi B, Teniou A, Debache A, et al. Cyclisation reaction between 3-methylquinoxaline-2-thione and benzaldehydes into 3-benzyl-2-aryl-thieno [2,3-b] quinoxaline promoted by Brønsted acids. C R Chim 2015;18:808–15.
  • Jacobs WA, Heidelberger M. Method for the acylation of aromatic amino compounds and ureas, with special reference to chloroacetylation. J Am Chem Soc 1917;39:1439–47.
  • Panga S, Podila NK, Asres K, Ciddi V. Synthesis and anticancer activity of new isatin-benzoic acid conjugates. Ethiop Pharm J 2016;31:75–92.
  • Abdel-Latif E, Fahad MM, Ismail MA. Synthesis of N-aryl 2-chloroacetamides and their chemical reactivity towards various types of nucleophiles. Synth Commun 2020;50:289–314.
  • Newahie AE, Nissan YM, Ismail NS, et al. Design and synthesis of new quinoxaline derivatives as anticancer agents and apoptotic inducers. Molecules 2019;24:1175.
  • Liu Y, Lotero E, Goodwin JG. Jr, Effect of carbon chain length on esterification of carboxylic acids with methanol using acid catalysis. J Catal 2006;243:221–8.
  • Yadagiri B, Holagunda UD, Bantu R, et al. Rational design, synthesis and anti-proliferative evaluation of novel benzosuberone tethered with hydrazide-hydrazones. Bioorg Med Chem Lett 2014;24:5041–4.
  • Abd Alla MSM, Hegab MI, Abo Taleb NA, et al. Synthesis and anti-inflammatory evaluation of some condensed [4-(3,4-dimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic acid hydrazide. Eur J Med Chem 2010;45:1267–77.
  • Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.
  • Scudiero DA, Shoemaker RH, Paull KD, et al. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 1988;48:4827–33.
  • Seglen PO. Preparation of isolated rat liver cells. Methods Cell Biol 1976;13:29–83.
  • Fulda S, Debatin K-M. Resveratrol modulation of signal transduction in apoptosis and cell survival: a mini-review. Cancer Detect Prev 2006;30:217–23.
  • Alenzi FQ. Links between apoptosis, proliferation and the cell cycle. Br J Biomed Sci 2004;61:99–102.
  • Pucci B, Kasten M, Giordano A. Cell cycle and apoptosis. Neoplasia 2000;2:291–9.
  • Wang J, Lenardo MJ. Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies. J. Cell Sci 2000;113:753–7.
  • Riccardi C, Nicoletti I. Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 2006;1:1458–61.
  • Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled annexin V. J Immunol Methods 1995;184:39–51.
  • Hirano S. Western blot analysis. In: Reineke J, ed. Nanotoxicity. New York: Springer; 2012:87–97.
  • Abdelhameid MK, Zaki I, Mohammed MR, Mohamed KO. Design, synthesis, and cytotoxic screening of novel azole derivatives on hepatocellular carcinoma (HepG2 Cells). Bioorg Chem 2020;101:103995.
  • Mohammed AE-SM. Synthesis of some novel thieno[2,3-d]pyrimidine derivatives of expected anticancer activity [CU theses]; 2019.
  • Al-Qathama A, Gibbons S, Prieto JM. Differential modulation of Bax/Bcl-2 ratio and onset of caspase-3/7 activation induced by derivatives of Justicidin B in human melanoma cells A375. Oncotarget 2017;8:95999–6012.
  • Sakinah SS, Handayani ST, Hawariah LA. Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio. Cancer Cell Int 2007;7:1–11.
  • Hasegawa M, Nishigaki N, Washio Y, et al. Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors. J Med Chem 2007;50:4453–70.
  • Xia X, Maliski EG, Gallant P, Rogers D. Classification of kinase inhibitors using a Bayesian model. J Med Chem 2004;47:4463–70.
  • Ho J, Sciuscio D, Kogel U, et al. Evaluation of toxicity of aerosols from flavored e-liquids in Sprague-Dawley rats in a 90-day OECD inhalation study, complemented by transcriptomics analysis. Arch Toxicol 2020;94:2179–206.
  • 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.
  • Abou-Seri SM, Eldehna WM, Ali MM, Abou El Ella DA. 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: synthesis and in vitro biological evaluation. Eur J Med Chem 2016;107:165–79.
  • Scientific TF. CellROX® reagents and kits. Available from: http://www.thermofisher.com/us/en/home/brands/molecular-probes/key-molecular-probes-products/cellrox-reagentskits-ros-detection.html#flow [last accessed 26 Jul 2020].
  • Aborehab NM, Elnagar MR, Waly NE. Gallic acid potentiates the apoptotic effect of paclitaxel and carboplatin via overexpression of Bax and P53 on the MCF‐7 human breast cancer cell line. J Biochem Mol Toxicol 2020;35:e22638.
  • Elnagar MR, Walls AB, Helal GK, et al. Functional characterization of α7 nicotinic acetylcholine and NMDA receptor signaling in SH-SY5Y neuroblastoma cells in an ERK phosphorylation assay. Eur J Pharmacol 2018;826:106–13.
  • 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.
  • 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.
  • El-Naggar AM, Eissa IH, Belal A, El-Sayed AA. El-Sayed, 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.
  • 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.