Advanced search
Publication Cover
Journal of Enzyme Inhibition and Medicinal Chemistry Volume 37, 2022 - Issue 1
Submit an article Journal homepage
3,268
Views
8
CrossRef citations to date
0
Altmetric
Research Papers

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers

Heba S. A. Elzahabia Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, EgyptCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-7023-6364View further author information
ORCID Icon,
Eman S. Nossiera Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, EgyptView further author information
,
Rania A. Alasfourya Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, EgyptView further author information
,
May El-Manawatyb Pharmacognosy Department, National Research Centre, Dokki, Cairo, EgyptView further author information
,
Sara M. Sayedc Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, EgyptView further author information
,
Eslam B. Elkaeedd Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi ArabiaView further author information
,
Ahmed M. Metwalye Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt;f Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, EgyptView further author information
,
Mohamed Hagrasg Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptView further author information
&
Ibrahim H. Eissah Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-6955-2263View further author information
ORCID Icon show all
Pages 1053-1076 | Received 12 Jan 2022, Accepted 01 Apr 2022, Published online: 12 Jul 2022

References

  • WHO. Cancer. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer. (last accessed 13 Jan 2022).
  • Boyle P, Ferlay JJ. Cancer incidence and mortality in Europe, 2004. Annals Oncol 2005;16:481–8.
  • Gavalas NG, Karadimou A, Dimopoulos MA, et al. Immune response in ovarian cancer: how is the immune system involved in prognosis and therapy: potential for treatment utilization. J Immunol Res 2010;2010:1–15.
  • Li M, Huo X, Davuljigari CB, et al. MicroRNAs and their role in environmental chemical carcinogenesis. Environ Geochem Health 2019;41:225–47.
  • Chorawala M, Oza P, Shah GJ. Mechanisms of anticancer drugs resistance: an overview. J Pharm Technol Drug Res 2012;4:1–9.
  • Lavogina D, Enkvist E, Uri A. Bisubstrate inhibitors of protein kinases: from principle to practical applications. ChemMedChem 2010;5:23–34.
  • Luković E, González-Vera JA, Imperiali B. Recognition-domain focused chemosensors: versatile and efficient reporters of protein kinase activity. J Am Soc 2008;130:12821–7.
  • Braun T, Gautel MJ. Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. Nat Rev Mol cell Biol 2011;12:349–61.
  • Meulenbeld HJ, Mathijssen RH, Verweij J, et al. Danusertib, an aurora kinase inhibitor. Expert Opin Investig Drugs 2012;21:383–93.
  • Abdellatif KR, Bakr RB. Pyrimidine and fused pyrimidine derivatives as promising protein kinase inhibitors for cancer treatment. Med Chem J 2021;30:31–49.
  • Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990;61:203–12.
  • Voldborg BR, Damstrup L, Spang-Thomsen M, Poulsen HS. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann Oncol 1997;8:1197–206.
  • Meierjohann S, Mueller T, Schartl M, Buehner MJZ. A structural model of the extracellular domain of the oncogenic EGFR variant Xmrk. Zebrafish 2006;3:359–69.
  • Ren S, Chen X, Kuang P, et al. Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma. Cancer 2012;118:5588–94.
  • Normanno N, De Luca A, Bianco C, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366:2–16.
  • Godin-Heymann N, Ulkus L, Brannigan BW, et al. The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther 2008;7:874–9.
  • Abdelsalam EA, Zaghary WA, Amin KM, et al. Synthesis and in vitro anticancer evaluation of some fused indazoles, quinazolines and quinolines as potential EGFR inhibitors. Bioorg Chem 2019;89:102985.
  • Ismail RS, Abou-Seri SM, Eldehna WM, et al. Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells. Eur J Med Chem 2018;155:782–96.
  • Gandin V, Ferrarese A, Dalla Via M, 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. Sci Rep 2015;5:16750.
  • Traxler P, Furet P. Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Therapeutics 1999;82:195–206.
  • Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 2009;9:28–39.
  • Gaber AA, Bayoumi AH, El-Morsy AM, et al. Design, synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers. Bioorg Chem 2018;80:375–95.
  • Sharma VK, Nandekar PP, Sangamwar A, et al. Structure guided design and binding analysis of EGFR inhibiting analogues of erlotinib and AEE788 using ensemble docking, molecular dynamics and MM-GBSA. RSC Adv 2016;6:65725–35.
  • Mowafy S, Galanis A, Doctor ZM, et al. Toward discovery of mutant EGFR inhibitors; design, synthesis and in vitro biological evaluation of potent 4-arylamino-6-ureido and thioureido-quinazoline derivatives. Biorg Med Chem 2016;24:3501–12.
  • Zhao Z, Wu H, Wang L, et al. Exploration of type II binding mode: a privileged approach for kinase inhibitor focused drug discovery? ACS Chem Biol 2014;9:1230–41.
  • Liu Y, Gray NS. Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2006;2:358–64.
  • Bonomi P. Erlotinib: a new therapeutic approach for non-small cell lung cancer. Expert Opin Invest Drugs 2003;12:1395–401.
  • Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.
  • Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLOS Med 2005;2:e73.
  • Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–92.
  • 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.
  • Engelman JA, Zejnullahu K, Gale C-M, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007;67:11924–32.
  • Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27:4702–11.
  •  Sohn SH, Sul HJ, Kim B, et al. RNF43 and PWWP2B inhibit cancer cell proliferation and are predictive or prognostic biomarker for FDA-approved drugs in patients with advanced gastric cancer. J Cancer. 2021;12:4616–25.
  • Sequist LV, Besse B, Lynch TJ, et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non–small-cell lung cancer. J Clin Oncol 2010;28:3076–83.
  • Kim Y, Ko J, Cui Z, et al. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Therapeutics 2012;11:784–91.
  • Jänne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med 2015;372:1689–99.
  • J. Carroll. Following lethal tox report, Boehringer scraps plans for high-speed development, kills $730M Hanmi deal; 2016. Available from: https://endpts.com/following-lethal-tox-report-boehringer-scraps-plans-for-high-speed-development-kills-730m-hanmi-deal/. (last accessed May 2019).
  • P, Callery G, Peter Cancer and cancer chemotherapy. In: David, AW and Thomas, LL, eds. Foye’s principles of medical chemistry. Philadelphia: Lippincott, Williams and Wilkins; 2002.
  • Abdel-Mohsen HT, Ragab FA, Ramla MM, El Diwani HI. Novel benzimidazole-pyrimidine conjugates as potent antitumor agents. Eur J Med Chem 2010;45:2336–44.
  • Shao H, Shi S, Foley DW, et al. Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents. Eur J Med Chem 2013;70:447–55.
  • Fathalla O, Zeid I, Haiba M, et al. Synthesis, antibacterial and anticancer evaluation of some pyrimidine derivatives. World J Chem 2009;4:127–32.
  • Yu L, Huang M, Xu T, et al. A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties. Eur J Med Chem 2017;126:1107–17.
  • Xu T, Peng T, Ren X, et al. C5-substituted pyrido [2, 3-d] pyrimidin-7-ones as highly specific kinase inhibitors targeting the clinical resistance-related EGFR T790M mutant. MedChemComm 2015;6:1693–7.
  • El-Naggar AM, Abou-El-Regal MM, El-Metwally SA, et al. Synthesis, characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents. Mol Div 2017;21:967–83.
  • 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.
  • El-Naggar AM, Eissa IH, Belal A, El-Sayed AA. Design, eco-friendly synthesis, molecular modeling and anticancer evaluation of thiazol-5 (4 H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site. RSC Adv 2020;10:2791–811.
  • Eissa IH, El-Naggar AM, El-Hashash MA. Design, synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents. Bioorg Chem 2016;67:43–56.
  • Eissa IH, El-Naggar AM, Abd El-Sattar NE, Youssef AS. Design and discovery of novel quinoxaline derivatives as dual DNA intercalators and topoisomerase II inhibitors. Anti-Cancer Agents Med Chem 2018;18:195–209.
  • 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.
  • Eissa IH, Metwaly AM, Belal A, et al. Discovery and antiproliferative evaluation of new quinoxalines as potential DNA intercalators and topoisomerase II inhibitors. Archiv der Pharmazie 2019;352:1900123.
  • 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.
  • El‐Helby AGA, Sakr H, Eissa IH, et al. Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: design, synthesis, molecular docking, and anticancer evaluations. Archiv der Pharmazie 2019;352:1900178.
  • Elmetwally SA, Saied KF, Eissa IH, Elkaeed EB. Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers. Bioorg Chem 2019;88:102944.
  • 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.
  • Othman IM, Alamshany ZM, Tashkandi NY, et al. New pyrimidine and pyrazole-based compounds as potential EGFR inhibitors: synthesis, anticancer, antimicrobial evaluation and computational studies. Bioorg Chem 2021;114:105078.
  • Abd El-Meguid EA, Moustafa GO, Awad HM, et al. Novel benzothiazole hybrids targeting EGFR: design, synthesis, biological evaluation and molecular docking studies. Anticancer Agents Med Chem 2021;1240:130595.
  • Khattab RR, Alshamari AK, Hassan AA, et al. Click chemistry based synthesis, cytotoxic activity and molecular docking of novel triazole-thienopyrimidine hybrid glycosides targeting EGFR. J Enzyme Inhib Med Chem 2021;36:504–16.
  • Elzahabi HS, Nossier ES, Khalifa NM, et al. Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold. J Enzyme Inhib Med Chem 2018;33:546–57.
  • Khalifa NM, Adel A-H, Abd-Elmoez SI, et al. A convenient synthesis of some new fused pyridine and pyrimidine derivatives of antimicrobial profiles. Res Chem Intermed 2015;41:2295–305.
  • Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55–63.
  • Denizot F, Lang RJJoim. 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.
  • Thabrew MI, Hughes RD, McFarlane IGJJop. Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity assay. J Pharm Pharmacol 2011;49:1132–5.
  • Jia Y, Quinn CM, Gagnon AI, Talanian R. Homogeneous time-resolved fluorescence and its applications for kinase assays in drug discovery. Anal Biochem 2006;356:273–81.
  • 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.
  • 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.
  • Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Ann Rev Biochem 1999;68:383–424.
  • Bortner CD, Cidlowski JA. Apoptotic volume decrease and the incredible shrinking cell. Cell Death Different 2002;9:1307–10.
  • Bae SS, Choi JH, Oh YS, et al. Proteolytic cleavage of epidermal growth factor receptor by caspases. FEBS Lett 2001;491:16–20.
  • He Y, Huang J, Chignell C. Cleavage of epidermal growth factor receptor by caspase during apoptosis is independent of its internalization. Oncogene 2006;25:1521–31.
  • Park JH, Liu Y, Lemmon MA, Radhakrishnan R. Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. Biochem J 2012;448:417–23.
  • Sogabe S, Kawakita Y, Igaki S, et al. Structure-based approach for the discovery of pyrrolo[3,2-d]pyrimidine-based EGFR T790M/L858R mutant inhibitors. ACS Med Chem Lett 2013;4:201–5.
  • Taylor EC, Cheng C. Studies in purine chemistry. VI. A convenient one-step synthesis of hypoxanthine. J Am Chem Soc 1959;1:9–11.
  • 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.
  • 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.
  • Lo KK-W, Lee TK-M, Lau JS-Y, et al. Luminescent biological probes derived from ruthenium(II) estradiol polypyridine complexes. Inorg Chem 2008;47:200–8.
  • 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.
  • 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.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.