Semi-synthesized anticancer theobromine derivatives targeting VEGFR-2: in silico and in vitro evaluations

References

• Abdelgalil, A. A., Alkahtani, H. M., & Al-Jenoobi, F. I. (2019). Sorafenib. Profiles of Drug Substances, Excipients, and Related Methodology, 44, 239–266.
   PubMedGoogle Scholar
• Aborehab, N. M., Elnagar, M. R., & Waly, N. E. (2021). 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. Journal of Biochemical and Molecular Toxicology, 35(2), e22638. https://doi.org/10.1002/jbt.22638
   PubMed Web of Science ®Google Scholar
• Abou-Zied, H. A., Youssif, B. G., Mohamed, M. F., Hayallah, A. M., & Abdel-Aziz, M. (2019). EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules. Bioorganic Chemistry, 89, 102997. https://doi.org/10.1016/j.bioorg.2019.102997
   PubMed Web of Science ®Google Scholar
• Alanazi, M. M., Eissa, I. H., Alsaif, N. A., Obaidullah, A. J., Alanazi, W. A., Alasmari, A. F., Albassam, H., Elkady, H., & Elwan, A. (2021a). Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers. Journal of Enzyme Inhibition and Medicinal Chemistry, 36(1), 1760–1782. https://doi.org/10.1080/14756366.2021.1956488
   PubMed Web of Science ®Google Scholar
• Alanazi, M. M., Mahdy, H. A., Alsaif, N. A., Obaidullah, A. J., Alkahtani, H. M., Al-Mehizia, A. A., Alsubaie, S. M., Dahab, M. A., & Eissa, I. H. (2021b). 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. Bioorganic Chemistry, 112, 104949. https://doi.org/10.1016/j.bioorg.2021.104949
   PubMed Web of Science ®Google Scholar
• Alanazi, M. M., Elkady, H., Alsaif, N. A., Obaidullah, A. J., Alkahtani, H. M., Alanazi, M. M., Alharbi, M. A., Eissa, I. H., & Dahab, M. A. (2021c). New quinoxaline-based VEGFR-2 inhibitors: Design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies. RSC Advances, 11(48), 30315–30328. https://doi.org/10.1039/d1ra05925d
   PubMed Web of Science ®Google Scholar
• Al-Husein, B. A., Mhaidat, N. M., Alzoubi, K. H., Alzoubi, G. M., Alqudah, M. A., Albsoul-Younes, A. M., & Matalqah, S. M. (2022). Pentoxifylline induces caspase-dependent apoptosis in colorectal cancer cells. Informatics in Medicine Unlocked, 31, 100997. https://doi.org/10.1016/j.imu.2022.100997
   Google Scholar
• Al-Rashood, S. T., Hamed, A. R., Hassan, G. S., Alkahtani, H. M., Almehizia, A. A., Alharbi, A., Al-Sanea, M. M., & Eldehna, W. M. (2020). Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity. Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), 831–839. https://doi.org/10.1080/14756366.2020.1743281
   PubMed Web of Science ®Google Scholar
• Alsaif, N. A., Dahab, M. A., Alanazi, M. M., Obaidullah, A. J., Al-Mehizia, A. A., Alanazi, M. M., Aldawas, S., Mahdy, H. A., & Elkady, H. (2021). New quinoxaline derivatives as VEGFR-2 inhibitors with anticancer and apoptotic activity: Design, molecular modeling, and synthesis. Bioorganic Chemistry, 110, 104807. https://doi.org/10.1016/j.bioorg.2021.104807
   PubMed Web of Science ®Google Scholar
• Al-Salama, Z. T., Syed, Y. Y., & Scott, L. J. (2019). Lenvatinib: A review in hepatocellular carcinoma. Drugs, 79(6), 665–674. https://doi.org/10.1007/s40265-019-01116-x
   PubMed Web of Science ®Google Scholar
• Balah, A., Ezzat, O., & Akool, E.-S. (2018). Vitamin E inhibits cyclosporin A-induced CTGF and TIMP-1 expression by repressing ROS-mediated activation of TGF-β/Smad signaling pathway in rat liver. International Immunopharmacology, 65, 493–502. https://doi.org/10.1016/j.intimp.2018.09.033
   PubMed Web of Science ®Google Scholar
• Bellesoeur, A., Carton, E., Alexandre, J., Goldwasser, F., & Huillard, O. (2017). Axitinib in the treatment of renal cell carcinoma: Design, development, and place in therapy. Drug Design, Development and Therapy, 11, 2801–2811. https://doi.org/10.2147/DDDT.S109640
   PubMed Web of Science ®Google Scholar
• Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424.
   PubMed Web of Science ®Google Scholar
• Cadona, F. C., Dantas, R. F., de Mello, G. H., & Silva, F. P. Jr, (2022). Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+)-catechin. Critical Reviews in Food Science and Nutrition, 62(26), 7222–7241. https://doi.org/10.1080/10408398.2021.1913091
   PubMed Web of Science ®Google Scholar
• Callagy, G. M., Webber, M. J., Pharoah, P. D., & Caldas, C. (2008). Meta-analysis confirms BCL2 is an independent prognostic marker in breast cancer. BMC Cancer, 8(1), 153. https://doi.org/10.1186/1471-2407-8-153
   PubMedGoogle Scholar
• Chabner, B. A., & Roberts, T. G. Jr, (2005). Chemotherapy and the war on cancer. Nature Reviews. Cancer, 5(1), 65–72. https://doi.org/10.1038/nrc1529
   PubMed Web of Science ®Google Scholar
• Chu, J. S., Ge, F. J., Zhang, B., Wang, Y., Silvestris, N., Liu, L. J., Zhao, C. H., Lin, L., Brunetti, A. E., Fu, Y. L., Wang, J., Paradiso, A., & Xu, J. M. (2013). Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma. Journal of Experimental & Clinical Cancer Research, 32(1), 1–8. https://doi.org/10.1186/1756-9966-32-16
   PubMedGoogle Scholar
• Denizot, F., & Lang, R. (1986). Rapid colorimetric assay for cell growth and survival: Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. Journal of Immunological Methods, 89(2), 271–277. https://doi.org/10.1016/0022-1759(86)90368-6
   PubMed Web of Science ®Google Scholar
• DeVita, V. T., Jr., & Chu, E. (2008). A history of cancer chemotherapy. Cancer Research, 68(21), 8643–8653. https://doi.org/10.1158/0008-5472.CAN-07-6611
   PubMed Web of Science ®Google Scholar
• Eissa, I. H., Yousef, R. G., Elkady, H., Alsfouk, A. A., Alsfouk, B. A., Husein, D. Z., Ibrahim, I. M., Elkaeed, E. B., & Metwaly, A. M. (2023). A new anticancer semisynthetic theobromine derivative targeting EGFR protein: CADDD study. Life, 13(1), 191. https://doi.org/10.3390/life13010191
   PubMedGoogle Scholar
• El-Adl, K., Sakr, H. M., Yousef, R. G., Mehany, A. B., Metwaly, A. M., Elhendawy, M. A., Radwan, M. M., ElSohly, M. A., Abulkhair, H. S., & Eissa, I. H. (2021). Discovery of new quinoxaline-2 (1H)-one-based anticancer agents targeting VEGFR-2 as inhibitors: Design, synthesis, and anti-proliferative evaluation. Bioorganic Chemistry, 114, 105105. https://doi.org/10.1016/j.bioorg.2021.105105
   PubMed Web of Science ®Google Scholar
• Eldehna, W. M., Hassan, G. S., Al-Rashood, S. T., Al-Warhi, T., Altyar, A. E., Alkahtani, H. M., Almehizia, A. A., & Abdel-Aziz, H. A. (2019). Synthesis and in vitro anticancer activity of certain novel 1-(2-methyl-6-arylpyridin-3-yl)-3-phenylureas as apoptosis-inducing agents. Journal of Enzyme Inhibition and Medicinal Chemistry, 34(1), 322–332. https://doi.org/10.1080/14756366.2018.1547286
   PubMed Web of Science ®Google Scholar
• Elkady, H., Elwan, A., El-Mahdy, H. A., Doghish, A. S., Ismail, A., Taghour, M. S., Elkaeed, E. B., Eissa, I. H., Dahab, M. A., Mahdy, H. A., & Khalifa, M. M. (2022). New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 403–416. https://doi.org/10.1080/14756366.2021.2015343
   Web of Science ®Google Scholar
• Elkaeed, E. B., Yousef, R. G., Elkady, H., Alsfouk, A. A., Husein, D. Z., Ibrahim, I. M., Alswah, M., Elzahabi, H. S., Metwaly, A. M., & Eissa, I. H. (2022a). A new theobromine-based EGFRWT and EGFRT790M inhibitor and apoptosis inducer: Design, semi-synthesis, docking, DFT, MD simulations, and in vitro studies. Processes, 10(11), 2290. https://doi.org/10.3390/pr10112290
   Web of Science ®Google Scholar
• Elkaeed, E. B., Yousef, R. G., Elkady, H., Mehany, A. B., Alsfouk, B. A., Husein, D. Z., Ibrahim, I. M., Metwaly, A. M., & Eissa, I. H. (2022b). In silico, in vitro VEGFR-2 inhibition, and anticancer activity of a 3-(hydrazonomethyl) naphthalene-2-ol derivative. Journal of Biomolecular Structure and Dynamics, 1–16. https://doi.org/10.1080/07391102.2022.2127907
   Web of Science ®Google Scholar
• Elkaeed, E. B., Yousef, R. G., Elkady, H., Gobaara, I. M., Alsfouk, B. A., Husein, D. Z., Ibrahim, I. M., Metwaly, A. M., & Eissa, I. H. (2022c). Design, synthesis, docking, DFT, MD simulation studies of a new nicotinamide-based derivative: In vitro anticancer and VEGFR-2 inhibitory effects. Molecules, 27(14), 4606. https://doi.org/10.3390/molecules27144606
   PubMed Web of Science ®Google Scholar
• Elkaeed, E. B., Yousef, R. G., Elkady, H., Gobaara, I. M., Alsfouk, A. A., Husein, D. Z., Ibrahim, I. M., Metwaly, A. M., & Eissa, I. H. (2022d). The assessment of anticancer and VEGFR-2 inhibitory activities of a new 1 H-indole derivative: In silico and in vitro approaches. Processes, 10(7), 1391. https://doi.org/10.3390/pr10071391
   Web of Science ®Google Scholar
• Elkaeed, E. B., Youssef, F. S., Eissa, I. H., Elkady, H., Alsfouk, A. A., Ashour, M. L., El Hassab, M. A., Abou-Seri, S. M., & Metwaly, A. M. (2022e). Multi-step in silico discovery of natural drugs against COVID-19 targeting main protease. International Journal of Molecular Sciences, 23(13), 6912. https://doi.org/10.3390/ijms23136912
   PubMed Web of Science ®Google Scholar
• Elkaeed, E. B., Taghour, M. S., Mahdy, H. A., Eldehna, W. M., El-Deeb, N. M., Kenawy, A. M., A Alsfouk, B., Dahab, M. A., Metwaly, A. M., Eissa, I. H., & El-Zahabi, M. A. (2022f). New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: Design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 2191–2205. https://doi.org/10.1080/14756366.2022.2110869
   PubMed Web of Science ®Google Scholar
• Elnagar, M. R., Walls, A. B., Helal, G. K., Hamada, F. M., Thomsen, M. S., & Jensen, A. A. (2018). Functional characterization of α7 nicotinic acetylcholine and NMDA receptor signaling in SH-SY5Y neuroblastoma cells in an ERK phosphorylation assay. European Journal of Pharmacology, 826, 106–113. https://doi.org/10.1016/j.ejphar.2018.02.047
   PubMed Web of Science ®Google Scholar
• Elrazaz, E. Z., Serya, R. A., Ismail, N. S., Albohy, A., Abou El Ella, D. A., & Abouzid, K. A. (2021). Discovery of potent thieno [2, 3-d] pyrimidine VEGFR-2 inhibitors: Design, synthesis and enzyme inhibitory evaluation supported by molecular dynamics simulations. Bioorganic Chemistry, 113, 105019. https://doi.org/10.1016/j.bioorg.2021.105019
   PubMed Web of Science ®Google Scholar
• Elwan, A., Abdallah, A. E., Mahdy, H. A., Dahab, M. A., Taghour, M. S., Elkaeed, E. B., Mehany, A. B. M., Nabeeh, A., Adel, M., Alsfouk, A. A., Elkady, H., & Eissa, I. H. (2022). Modified benzoxazole-based VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, and anti-proliferative evaluation. Molecules, 27(15), 5047. https://doi.org/10.3390/molecules27155047
   PubMed Web of Science ®Google Scholar
• Farghaly, T. A., Al-Hasani, W. A., & Abdulwahab, H. G. (2021). An updated patent review of VEGFR-2 inhibitors (2017-present). Expert Opinion on Therapeutic Patents, 31(11), 989–1007. https://doi.org/10.1080/13543776.2021.1935872
   PubMed Web of Science ®Google Scholar
• Ferreira, L. L., & Andricopulo, A. D. (2019). ADMET modeling approaches in drug discovery. Drug Discovery Today. 24(5), 1157–1165. https://doi.org/10.1016/j.drudis.2019.03.015
   PubMed Web of Science ®Google Scholar
• Fidler, I. J., & Ellis, L. M. (2000). Chemotherapeutic drugs—more really is not better. Nature Medicine, 6(5), 500–502. https://doi.org/10.1038/74969
   PubMed Web of Science ®Google Scholar
• Goel, P. N., & Gude, R. (2011). Unravelling the antimetastatic potential of pentoxifylline, a methylxanthine derivative in human MDA-MB-231 breast cancer cells. Molecular and Cellular Biochemistry, 358(1–2), 141–151. https://doi.org/10.1007/s11010-011-0929-8
   PubMed Web of Science ®Google Scholar
• Guo, P., Fang, Q., Tao, H.-Q., Schafer, C. A., Fenton, B. M., Ding, I., Hu, B., & Cheng, S.-Y. (2003). Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo. Cancer Research, 63(15), 4684–4691.
   PubMed Web of Science ®Google Scholar
• Hagras, M., Saleh, M. A., Ezz Eldin, R. R., Abuelkhir, A. A., Khidr, E. G., El-Husseiny, A. A., El-Mahdy, H. A., Elkaeed, E. B., & Eissa, I. H. (2022). 1, 3, 4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: Design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 386–402. https://doi.org/10.1080/14756366.2021.2015342
   Web of Science ®Google Scholar
• Jang, K., Kim, M., Gilbert, C. A., Simpkins, F., Ince, T. A., & Slingerland, J. M. (2017). VEGFA activates an epigenetic pathway upregulating ovarian cancer‐initiating cells. EMBO Molecular Medicine, 9(3), 304–318. https://doi.org/10.15252/emmm.201606840
   PubMed Web of Science ®Google Scholar
• Kamran, M. Z., & Gude, R. P. (2012). Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 66(8), 617–626. https://doi.org/10.1016/j.biopha.2012.03.006
   PubMed Web of Science ®Google Scholar
• Lee, K., Jeong, K.-W., Lee, Y., Song, J. Y., Kim, M. S., Lee, G. S., & Kim, Y. (2010). Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors. European Journal of Medicinal Chemistry, 45(11), 5420–5427. https://doi.org/10.1016/j.ejmech.2010.09.002
   PubMed Web of Science ®Google Scholar
• Lian, L., Li, X.-L., Xu, M.-D., Li, X.-M., Wu, M.-Y., Zhang, Y., Tao, M., Li, W., Shen, X.-M., Zhou, C., & Jiang, M. (2019). VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer. BMC Cancer, 19(1), 1–15. https://doi.org/10.1186/s12885-019-5322-0
   PubMedGoogle Scholar
• Liu, K., Ren, T., Huang, Y., Sun, K., Bao, X., Wang, S., Zheng, B., & Guo, W. (2017). Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma. Cell Death & Disease, 8(8), e3015-e3015. https://doi.org/10.1038/cddis.2017.422
   Google Scholar
• Lo, K. K.-W., Lee, T. K.-M., Lau, J. S.-Y., Poon, W.-L., & Cheng, S.-H. (2008). Luminescent biological probes derived from ruthenium (II) estradiol polypyridine complexes. Inorganic Chemistry, 47(1), 200–208. https://doi.org/10.1021/ic701735q
   PubMed Web of Science ®Google Scholar
• Lu-Emerson, C., Duda, D. G., Emblem, K. E., Taylor, J. W., Gerstner, E. R., Loeffler, J. S., Batchelor, T. T., & Jain, R. K. (2015). Lessons from anti–vascular endothelial growth factor and anti–vascular endothelial growth factor receptor trials in patients with glioblastoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 33(10), 1197–1213. https://doi.org/10.1200/JCO.2014.55.9575
   PubMed Web of Science ®Google Scholar
• Mahfouz, N., Tahtouh, R., Alaaeddine, N., El Hajj, J., Sarkis, R., Hachem, R., Raad, I., & Hilal, G. (2017). Gastrointestinal cancer cells treatment with bevacizumab activates a VEGF autoregulatory mechanism involving telomerase catalytic subunit hTERT via PI3K-AKT, HIF-1α and VEGF receptors. PLoS One, 12(6), e0179202. https://doi.org/10.1371/journal.pone.0179202
   PubMed Web of Science ®Google Scholar
• McDonnell, T. J., & Korsmeyer, S. J. (1991). Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t (14; 18). Nature, 349(6306), 254–256. https://doi.org/10.1038/349254a0
   PubMed Web of Science ®Google Scholar
• Metwaly, A. M., Ghoneim, M. M., Eissa, I. H., Elsehemy, I. A., Mostafa, A. E., Hegazy, M. M., Afifi, W. M., & Dou, D. (2021). Traditional ancient Egyptian medicine: A review. Saudi Journal of Biological Sciences, 28(10), 5823–5832. https://doi.org/10.1016/j.sjbs.2021.06.044
   PubMed Web of Science ®Google Scholar
• Metwaly, A. M., Lianlian, Z., Luqi, H., & Deqiang, D. (2019). Black ginseng and its saponins: Preparation, phytochemistry and pharmacological effects. Molecules, 24(10), 1856. https://doi.org/10.3390/molecules24101856
   PubMed Web of Science ®Google Scholar
• Mohamed, H. A., Lake, B. R., Laing, T., Phillips, R. M., & Willans, C. E. (2015). Synthesis and anticancer activity of silver (I)–N-heterocyclic carbene complexes derived from the natural xanthine products caffeine, theophylline and theobromine. Dalton Transactions (Cambridge, England : 2003), 44(16), 7563–7569. https://doi.org/10.1039/c4dt03679d
   PubMed Web of Science ®Google Scholar
• Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65(1–2), 55–63. https://doi.org/10.1016/0022-1759(83)90303-4
   PubMed Web of Science ®Google Scholar
• Peng, L., & Schwarz, R. E. (2013). Pancreatic neuroendocrine tumors: Signal pathways and targeted therapies. Current Molecular Medicine, 13(3), 333–339. https://doi.org/10.2174/1566524011313030002
   PubMed Web of Science ®Google Scholar
• Pengcheng, S., Ziqi, W., Luyao, Y., Xiangwei, Z., Liang, L., Yuwei, L., Lechen, L., & Wanhai, X. (2017). MicroRNA-497 suppresses renal cell carcinoma by targeting VEGFR-2 in ACHN cells. Bioscience Reports, 37(3), 1–10. https://doi.org/10.1042/BSR20170270
   Google Scholar
• Pietenpol, J., & Stewart, Z. (2002). Cell cycle checkpoint signaling:: Cell cycle arrest versus apoptosis. Toxicology, 181–182, 475–481. https://doi.org/10.1016/S0300-483X(02)00460-2
   PubMed Web of Science ®Google Scholar
• Riquelme, E., Suraokar, M., Behrens, C., Lin, H. Y., Girard, L., Nilsson, M. B., Simon, G., Wang, J., Coombes, K. R., Lee, J. J., Hong, W. K., Heymach, J., Minna, J. D., & Wistuba, I. I. (2014). VEGF/VEGFR-2 upregulates EZH2 expression in lung adenocarcinoma cells and EZH2 depletion enhances the response to platinum-based and VEGFR-2–targeted TherapyVEGF/VEGFR-2 induces EZH2 expression in lung adenocarcinoma. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 20(14), 3849–3861. https://doi.org/10.1158/1078-0432.CCR-13-1916
   PubMed Web of Science ®Google Scholar
• Sabt, A., Abdelhafez, O. M., El-Haggar, R. S., Madkour, H. M., Eldehna, W. M., El-Khrisy, E. E.-D. A., Abdel-Rahman, M. A., & Rashed, L. A. (2018). Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: Synthesis, in vitro biological evaluation, and QSAR studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 1095–1107. https://doi.org/10.1080/14756366.2018.1477137
   PubMed Web of Science ®Google Scholar
• Shah, A. A., Kamal, M. A., & Akhtar, S. (2021). Tumor angiogenesis and VEGFR-2: Mechanism, pathways and current biological therapeutic interventions. Current Drug Metabolism, 22(1), 50–59. https://doi.org/10.2174/1389200221666201019143252
   PubMed Web of Science ®Google Scholar
• Simons, M., Gordon, E., & Claesson-Welsh, L. (2016). Mechanisms and regulation of endothelial VEGF receptor signalling. Nature Reviews. Molecular Cell Biology, 17(10), 611–625. https://doi.org/10.1038/nrm.2016.87
   PubMed Web of Science ®Google Scholar
• Taghour, M. S., Elkady, H., Eldehna, W. M., El-Deeb, N. M., Kenawy, A. M., Elkaeed, E. B., Alsfouk, A. A., Alesawy, M. S., Metwaly, A. M., & Eissa, I. H. (2022a). Design and synthesis of thiazolidine-2, 4-diones hybrids with 1, 2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: In-vitro anticancer evaluation and in-silico studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 1903–1917. https://doi.org/10.1080/14756366.2022.2085693
   PubMed Web of Science ®Google Scholar
• Taghour, M. S., Elkady, H., Eldehna, W. M., El-Deeb, N., Kenawy, A. M., Elkaeed, E. B., Alsfouk, B. A., Alesawy, M. S., Husein, D. Z., Metwaly, A. M., & Eissa, I. H. (2022b). Design, synthesis, anti-proliferative evaluation, docking, and MD simulations studies of new thiazolidine-2, 4-diones targeting VEGFR-2 and apoptosis pathway. PLoS One, 17(9), e0272362. https://doi.org/10.1371/journal.pone.0272362
   PubMed Web of Science ®Google Scholar
• Taghour, M. S., Elkady, H., Eldehna, W. M., El-Deeb, N., Kenawy, A. M., Abd El-Wahab, A. E., Elkaeed, E. B., Alsfouk, B. A., Metwaly, A. M., & Eissa, I. H. (2023). Discovery of new quinoline and isatine derivatives as potential VEGFR-2 inhibitors: Design, synthesis, antiproliferative, docking and MD simulation studies. Journal of Biomolecular Structure and Dynamics, 1–16. https://doi.org/10.1080/07391102.2022.2164356
   PubMedGoogle Scholar
• Wang, J., & Lenardo, M. J. (2000). Roles of caspases in apoptosis, development, and cytokine maturation revealed by homozygous gene deficiencies. Journal of Cell Science, 113(5), 753–757. https://doi.org/10.1242/jcs.113.5.753
   PubMed Web of Science ®Google Scholar
• Wang, Z., Wang, N., Han, S., Wang, D., Mo, S., Yu, L., Huang, H., Tsui, K., Shen, J., & Chen, J. (2013). Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway. PloS One, 8(7), e68566. https://doi.org/10.1371/journal.pone.0068566
   PubMed Web of Science ®Google Scholar
• Ward, R. A., Fawell, S., Floc’h, N., Flemington, V., McKerrecher, D., & Smith, P. D. (2021). Challenges and opportunities in cancer drug resistance. Chemical Reviews, 121(6), 3297–3351. https://doi.org/10.1021/acs.chemrev.0c00383
   PubMed Web of Science ®Google Scholar
• WHO. (2023). Cancer overview. https://www.who.int/health-topics/cancer#tab=tab_1
   Google Scholar
• Yousef, R. G., Elkady, H., Elkaeed, E. B., Gobaara, I. M., Al-Ghulikah, H. A., Husein, D. Z., Ibrahim, I. M., Metwaly, A. M., & Eissa, I. H. (2022a). (E)-N-(3-(1-(2-(4-(2, 2, 2-Trifluoroacetamido) benzoyl) hydrazono) ethyl) phenyl) nicotinamide: A novel pyridine derivative for inhibiting vascular endothelial growth factor receptor-2: Synthesis, computational, and anticancer studies. Molecules, 27(22), 7719. https://doi.org/10.3390/molecules27227719
   PubMed Web of Science ®Google Scholar
• Yousef, R. G., Elwan, A., Gobaara, I. M., Mehany, A. B., Eldehna, W. M., El-Metwally, S. A., Alsfouk, B. A., Elkaeed, E. B., Metwaly, A. M., & Eissa, I. H. (2022b). Anti-cancer and immunomodulatory evaluation of new nicotinamide derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: In vitro and in silico studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 2206–2222. https://doi.org/10.1080/14756366.2022.2110868
   PubMed Web of Science ®Google Scholar
• Yousef, R. G., Ibrahim, A., Khalifa, M. M., Eldehna, W. M., Gobaara, I. M., Mehany, A. B., Elkaeed, E. B., Alsfouk, A. A., Metwaly, A. M., & Eissa, I. H. (2022c). Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: Virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies. Journal of Enzyme Inhibition and Medicinal Chemistry, 37(1), 1389–1403. https://doi.org/10.1080/14756366.2022.2070744
   PubMed Web of Science ®Google Scholar
• Zhang, S., Gao, X., Fu, W., Li, S., & Yue, L. (2017). Immunoglobulin-like domain 4-mediated ligand-independent dimerization triggers VEGFR-2 activation in HUVECs and VEGFR2-positive breast cancer cells. Breast Cancer Research and Treatment, 163(3), 423–434. https://doi.org/10.1007/s10549-017-4189-5
   PubMed Web of Science ®Google Scholar
• Zhong, Z., Huang, M., Lv, M., He, Y., Duan, C., Zhang, L., & Chen, J. (2017). Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. Cancer Letters, 403, 305–317. https://doi.org/10.1016/j.canlet.2017.06.027
   PubMed Web of Science ®Google Scholar