Design, synthesis and biological evaluation of a new thieno[2,3-d]pyrimidine-based urea derivative with potential antitumor activity against tamoxifen sensitive and resistant breast cancer cell lines

References

• World Health Organization (WHO) Breast Cancer: Prevention and Control. http://www.who.int/cancer/detection/breastcancer/en/ (2018).
   Google Scholar
• World Health Organization (WHO) Media Centre-Cancer. http://www.who.int/mediacentre/factsheets/fs297/en/ (2018).
   Google Scholar
• Mittal S, Brown NJ, Holen I. The breast tumor microenvironment: role in cancer development, progression and response to therapy. Expert Rev Mol Diagn 2018;18:227–43.
   PubMed Web of Science ®Google Scholar
• Zhang J, Wang Q, Wang Q, et al. Mechanisms of resistance to estrogen receptor modulators in ER+/HER2- advanced breast cancer. Cell Mol Life Sci 2020;77:559–72.
   PubMed Web of Science ®Google Scholar
• Mansouri S, Feizi N, Mahdi A, et al. A review on the role of VEGF in tamoxifen resistance. Anticancer Agents Med Chem 2018;18:2006–9.
   PubMed Web of Science ®Google Scholar
• Saman H, Raza SS, Uddin S, Rasul K. Inducing angiogenesis, a key step in cancer vascularization, and treatment approaches. Cancers 2020;12:1172.
   PubMed Web of Science ®Google Scholar
• Sanphanya K, Wattanapitayakul SK, Phowichit S, et al. Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach. Bioorg. Med. Chem. Lett 2013;23:2962–7.
   PubMed Web of Science ®Google Scholar
• Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 2020;77:1745–70.
   PubMed Web of Science ®Google Scholar
• Fontanella C, Ongaro E, Bolzonello S, et al. Clinical advances in the development of novel VEGFR2 inhibitors. Ann Transl Med 2014;2:123.
   PubMedGoogle Scholar
• Farzaneh Behelgardi M, Zahri S, Gholami Shahvir Z, et al. Targeting signaling pathways of VEGFR1 and VEGFR2 as a potential target in the treatment of breast cancer. Mol Biol Rep 2020;47:2061–71.
   PubMed Web of Science ®Google Scholar
• Wang H, Liu XY, Jiang YZ, Shao ZM. Challenges and countermeasures in the treatment of luminal breast cancer. Zhonghua Zhong Liu Za Zhi 2020;42:192–6.
   PubMedGoogle Scholar
• Kim JW, Gautam J, Kim JE, et al. Inhibition of tumor growth and angiogenesis of tamoxifen-resistant breast cancer cells by ruxolitinib, a selective JAK2 inhibitor. Oncol Lett 2019;17:3981–9.
   PubMed Web of Science ®Google Scholar
• Abdelgalil AA, Alkahtani HM, Al-Jenoobi FI. Sorafenib. Profiles Drug Subst Excip Relat Methodol 2019;44:239–66.
   PubMedGoogle Scholar
• Pedersen AM, Thrane S, Lykkesfeldt AE, Yde CW. Sorafenib and nilotinib resensitize tamoxifen resistant breast cancer cells to tamoxifen treatment via estrogen receptor α. Int J Oncol 2014;45:2167–75.
   PubMed Web of Science ®Google Scholar
• Kong X, Zeyu Yao Z, Zuopeng He Z, et al. Design, synthesis and biological evaluation of thiourea and nicotinamide-containing Sorafenib analogs as antitumor agents. Med Chem Commun 2015;6:867–70.
   Web of Science ®Google Scholar
• Yao J, Chen j, He Z, et al. Thiourea and thioether derivatives of sorafenib: synthesis, crystal structure, and antiproliferative activity. Med Chem Res 2013;22:3959–68.
   Web of Science ®Google Scholar
• Sun S, Zhang J, Wang N, et al. Design and discovery of quinazoline- and thiourea-containing Sorafenib analogs as EGFR and VEGFR-2 dual TK inhibitors. Molecules 2017;23:24.
   Web of Science ®Google Scholar
• Yang LL, Li GB, Ma S, Zou C, et al. Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo. J Med Chem 2013;56:1641–55.
   PubMed Web of Science ®Google Scholar
• Adepu R, Rambabu D, Prasad B, et al. Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation. Org Biomol Chem 2012;10:5554–69.
   PubMed Web of Science ®Google Scholar
• Modica M, Santagati M, Guccione S, et al. Design, synthesis and binding properties of novel and selective 5-HT(3) and 5-HT(4) receptor ligands. Eur J Med Chem 2000;35:1065–79.
   PubMed Web of Science ®Google Scholar
• Modica M, Romeo G, Materia L, et al. Synthesis and binding properties of novel selective 5-HT3 receptor ligands. Bioorg Med Chem 2004;12:3891–901.
   PubMed Web of Science ®Google Scholar
• Gorja DR, Kumar KS, Mukkanti K, Pal M. C-C (alkynylation) vs C-O (ether) bond formation under Pd/C-Cu catalysis: synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines. Beilstein J Org Chem 2011;7:338–45.
   PubMed Web of Science ®Google Scholar
• Aziz MA, Serya RA, Lasheen DS, et al. Discovery of potent VEGFR-2 inhibitors based on furopyrimidine and thienopyrimidne scaffolds as cancer targeting agents. Sci Rep 2016;6:24460.
   PubMed Web of Science ®Google Scholar
• Kassab AE, Gedawy EM, El-Malah AA, Abdelghany TM, et al. Synthesis, anticancer activity, effect on cell cycle profile, and apoptosis-inducing ability of novel hexahydrocyclooctathieno[2,3-d]pyrimidine derivatives. Chem Pharm Bull (Tokyo). 2016;64:490–6.
   PubMed Web of Science ®Google Scholar
• Mghwary AE, Gedawy EM, Kamal AM, Abuel-Maaty SM. Novel thienopyrimidine derivatives as dual EGFR and VEGFR-2 inhibitors: design, synthesis, anticancer activity and effect on cell cycle profile. J Enzyme Inhib Med Chem 2019;34:838–52.
   PubMed Web of Science ®Google Scholar
• Jain L, Gardner E, Venitz J, et al. Development of a rapid and sensitive LC-MS/MS assay for the determination of Sorafenib in human plasma. J Pharm Biomed Anal 2008;46:362–7.
   PubMed Web of Science ®Google Scholar
• Allard M, Khoudour N, Rousseau V, et al. Simultaneous analysis of regorafenib and Sorafenib and three of their metabolites in human plasma using LC-MS/MS. J Pharm Biomed Anal 2017;142:42–8.
   PubMed Web of Science ®Google Scholar
• Stout D, Matier W, Barcelon-Yang C, et al. Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. Modifications to the linkage region (region 3). J Med Chem 1985;28:295–8.
   PubMed Web of Science ®Google Scholar
• Nirogi RVS, Kambhampati RS, Kothmirkar P, et al. Convenient and efficient synthesis of some novel fused thieno pyrimidines using Gewald's reaction. Synth Commun 2011;41:2835–51.
   Web of Science ®Google Scholar
• Sopbué Fondjo E, Döpp D, Henkel G. Reactions of some anellated 2-aminothiophenes with electron poor acetylenes. Tetrahedron 2006;62:7121–31.
   Web of Science ®Google Scholar
• El-Baih F, Al-Blowy H, Al-Hazimi H. Synthesis of some thienopyrimidine derivatives. Molecules 2006;11:498–513.
   PubMed Web of Science ®Google Scholar
• Skehan P, Storeng R, Scudiero D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990;82:1107–12.
   PubMed Web of Science ®Google Scholar
• Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70–7.
   PubMed Web of Science ®Google Scholar
• Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 2001;5:62–7.
   PubMed Web of Science ®Google Scholar
• Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402–8.
   PubMed Web of Science ®Google Scholar
• Snoek-van Beurden PA, Von den Hoff JW. Zymographic techniques for the analysis of matrix metalloproteinases and their inhibitors. Biotechniques 2005;38:73–83.
   PubMed Web of Science ®Google Scholar
• Perrot-Applanat M, Di Benedetto M. Autocrine functions of VEGF in breast tumor cells: adhesion, survival, migration and invasion. Cell Adh Migr 2012;6:547–53.
   PubMed Web of Science ®Google Scholar
• Oguro Y, Miyamoto N, Okada K, et al. Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation. Bioorg Med Chem 2010;18: 7260–73.
   PubMed Web of Science ®Google Scholar
• Kristensen TB, Knutsson MLT, Wehland M, et al. Anti-vascular endothelial growth factor therapy in breast cancer. Int J Mol Sci 2014;15:23024–41.
   PubMed Web of Science ®Google Scholar
• Kazi AA, Koos RD. Estrogen-induced activation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor expression, and edema in the uterus are mediated by the phosphatidylinositol 3-kinase/Akt pathway. Endocrinology 2007;148:2363–74.
   PubMed Web of Science ®Google Scholar
• Garvin S, Nilsson U, Dabrosin C. Effects of oestradiol and tamoxifen on VEGF, soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells. Br J Cancer 2005;93:1005–10.
   PubMed Web of Science ®Google Scholar
• Kreipe H. Ki67: biological intertumor variance versus variance of assay. Pathologe 2018;39:272–7.
   PubMed Web of Science ®Google Scholar
• Stathopoulos GP, Malamos NA, Markopoulos C, et al. The role of Ki-67 in the proliferation and prognosis of breast cancer molecular classification subtypes. Anticancer Drugs 2014;25:950–7.
   PubMed Web of Science ®Google Scholar
• Elzawahry HM, Saber MM, Mokhtar NM, et al. Role of Ki67 in predicting resistance to adjuvant tamoxifen in postmenopausal breast cancer patients. J Egypt Natl Canc Inst 2013;25:181–91.
   PubMedGoogle Scholar
• Andersen KJ, Knudsen AR, Kannerup AS, et al. Sorafenib inhibits liver regeneration in rats. HPB (Oxford) 2013;15:944–50.
   PubMed Web of Science ®Google Scholar
• Thrane S, Lykkesfeldt AE, Larsen MS, et al. Estrogen receptor α is the major driving factor for growth in tamoxifen-resistant breast cancer and supported by HER/ERK signaling. Breast Cancer Res Treat 2013;139:71–80.
   PubMed Web of Science ®Google Scholar
• Yang H, Villani RM, Wang H, et al. The role of cellular reactive oxygen species in cancer chemotherapy. J Exp Clin Cancer Res 2018;37:266.
   PubMed Web of Science ®Google Scholar
• Coriat R, Nicco C, Chereau C, et al. Sorafenib-induced hepatocellular carcinoma cell death depends on reactive oxygen species production in vitro and in vivo. Mol Cancer Ther 2012;11:2284–93.
   PubMed Web of Science ®Google Scholar
• Huang R, Chen XQ, Huang Y, et al. The multikinase inhibitor Sorafenib induces caspase-dependent apoptosis in PC-3 prostate cancer cells. Asian J Androl 2010;12:527–34.
   PubMed Web of Science ®Google Scholar
• Haupt S, Mitchell C, Corneille V, et al. Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner. Cell Cycle 2013;12:1722–31.
   PubMed Web of Science ®Google Scholar
• Wei J-c, Meng F-d, Qu K, et al. Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1. Acta Pharmacol Sin 2015;36:241–51.
   PubMed Web of Science ®Google Scholar
• Zhang GJ, et al. Tamoxifen-induced apoptosis in breast cancer cells relates to down-regulation of bcl-2, but not bax and bcl-X(L), without alteration of p53 protein levels. Clin Cancer Res 1999;5:2971–7.
   PubMed Web of Science ®Google Scholar
• Treeck O, Zhou R, Diedrich K, Ortmann O. Tamoxifen long-term treatment in vitro alters the apoptotic response of MCF-7 breast cancer cells. Anticancer Drugs 2004;15:787–93.
   PubMed Web of Science ®Google Scholar
• Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene 2005;24:6861–9.
   PubMed Web of Science ®Google Scholar
• Fernando J, Sancho P, Fernández-Rodriguez CM, et al. Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli. J Cell Physiol 2012;227:1319–25.
   PubMed Web of Science ®Google Scholar
• Chan FK, Moriwaki K, De Rosa MJ. Detection of necrosis by release of lactate dehydrogenase activity. Methods Mol Biol 2013;979:65–70.
   PubMedGoogle Scholar
• Hamanaka RB, Chandel NS. Targeting glucose metabolism for cancer therapy. J Exp Med 2012;209:211–5.
   PubMed Web of Science ®Google Scholar
• Dronamraju Ibrahim BA, Briski KP, Sylvester PW. γ-Tocotrienol suppression of the Warburg effect is mediated by AMPK activation in human breast cancer cells. Nutr Cancer 2019;6:1–15.
   Google Scholar
• Fumarola C, Caffarra C, La Monica S, et al. Effects of sorafenib on energy metabolism in breast cancer cells: role of AMPK-mTORC1 signaling. Breast Cancer Res Treat 2013;141:67–78.
   PubMed Web of Science ®Google Scholar
• Chen K-F, Chen H-L, Tai W-T, et al. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther 2011;337:155–61.
   PubMed Web of Science ®Google Scholar
• Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7.
   PubMed Web of Science ®Google Scholar
• Hoellen F, Kelling K, Dittmer C, et al. Impact of cyclooxygenase-2 in breast cancer. Anticancer Res 2011;31:4359–67.
   PubMed Web of Science ®Google Scholar
• Solanki R, Agrawal N, Ansari M, et al. COX-2 expression in breast carcinoma with correlation to clinicopathological parameters. Asian Pac J Cancer Prev 2018;19:1971–5.
   PubMedGoogle Scholar
• Jiménez-Garduño AM, Mendoza-Rodríguez MG, Urrutia-Cabrera D, et al. IL-1β induced methylation of the estrogen receptor ERα gene correlates with EMT and chemoresistance in breast cancer cells. Biochem Biophys Res Commun 2017;490:780–5.
   PubMed Web of Science ®Google Scholar
• Gyamfi J, Lee YH, Eom M, Choi J. Interleukin-6/STAT3 signalling regulates adipocyte induced epithelial-mesenchymal transition in breast cancer cells. Sci Rep 2018;8:8859.
   PubMed Web of Science ®Google Scholar
• Zanotto-Filho A, Rajamanickam S, Loranc E, et al. Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer cells. Cancer Lett 2018;425:101–15.
   PubMed Web of Science ®Google Scholar
• Martin del Campo SE, Levine KM, Mundy-Bosse BL, et al. The Raf Kinase Inhibitor Sorafenib inhibits JAK-STAT signal transduction in human immune cells. J Immunol 2015;195:1995–2005.
   PubMed Web of Science ®Google Scholar
• Hu H, Li M, Luo T, et al. Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cell Mol Life Sci 2011;68: 3853–68.
   PubMed Web of Science ®Google Scholar
• Li H, Qiu Z, Li F, Wang C. The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. Oncol Lett 2017;14:5865–70.
   PubMed Web of Science ®Google Scholar
• Hiscox S, Jiang WG, Obermeier K, et al. Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer 2006;118:290–301.
   PubMed Web of Science ®Google Scholar
• Ha T-Y, Hwang S, Moon K-M, et al. Sorafenib inhibits migration and invasion of hepatocellular carcinoma cells through suppression of matrix metalloproteinase expression. Anticancer Res 2015;35:1967–76.
   PubMed Web of Science ®Google Scholar
• Lee JH, Shim JW, Choi YJ, et al. The combination of Sorafenib and radiation preferentially inhibits breast cancer stem cells by suppressing HIF-1α sing HIF-1α expression. Oncol Rep 2013;29:917–9124.
   PubMed Web of Science ®Google Scholar
• Nilsson UW, Garvin S, Dabrosin C. MMP-2 and MMP-9 activity is regulated by estradiol and tamoxifen in cultured human breast cancer cells. Breast Cancer Res Treat 2007;102:253–61.
   PubMed Web of Science ®Google Scholar