Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.
   PubMed Web of Science ®Google Scholar
• Ferlay J, Ervik M, Lam F, et al. Global cancer observatory: cancer today. Vol. 25. Lyon, France: International Agency for Research on Cancer; 2020.
   Google Scholar
• Dienstmann R, Rodon J, Serra V, Tabernero J. Picking the point of inhibition: a comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 2014;13:1021–31.
   PubMed Web of Science ®Google Scholar
• Sanchez VE, Nichols C, Kim HN, et al. Targeting PI3K signaling in acute lymphoblastic leukemia. Int J Mol Sci 2019;20:412.
   PubMed Web of Science ®Google Scholar
• Khan MA, Jain VK, Rizwanullah M, Ahmad J, et al. PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges. Drug Discov Today 2019;24:2181–91.
   PubMed Web of Science ®Google Scholar
• Song M, Bode AM, Dong Z, Lee MH. AKT as a therapeutic target for cancer. Cancer Res 2019;79:1019–31.
   PubMed Web of Science ®Google Scholar
• Burris HA. Overcoming acquired resistance to anticancer therapy: focus on the PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol 2013;71:829–42.
   PubMed Web of Science ®Google Scholar
• Zuo WQ, Hu R, Wang WL, et al. Identification of a potent and selective phosphatidylinositol 3-kinase δ inhibitor for the treatment of non-Hodgkin’s lymphoma. Bioorg Chem 2020;105:104344.
   PubMed Web of Science ®Google Scholar
• LoRusso PM. Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol 2016;34:3803–15.
   PubMed Web of Science ®Google Scholar
• Wang J, Xu-Monette ZY, Jabbar KJ, et al. AKT hyperactivation and the potential of AKT-targeted therapy in diffuse large B-cell lymphoma. Am J Pathol 2017;187:1700–16.
   PubMed Web of Science ®Google Scholar
• Vasudevan KM, Barbie DA, Davies MA, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009;16:21–32.
   PubMed Web of Science ®Google Scholar
• Dotolo S, Cervellera C, Russo M, et al. Virtual screening of natural compounds as potential PI3K-AKT1 signaling pathway inhibitors and experimental validation. Molecules 2021;26:492.
   PubMed Web of Science ®Google Scholar
• O’Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500–8.
   PubMed Web of Science ®Google Scholar
• Sahu ME, Siddiqui NA. A review on biological importance of pyrimidines in the new era. Int J Pharm Pharm Sci 2016;8:8–21.
   Web of Science ®Google Scholar
• Bhat AR. Biological activity of pyrimidine derivatives: a review. Org Med Chem I J 2017;2:23–6.
   Google Scholar
• Kaur R, Kaur P, Sharma S, et al. Anti-cancer pyrimidines in diverse scaffolds: a review of patent literature. Recent Pat Anticancer Drug Discov 2015;10:23–71.
   PubMed Web of Science ®Google Scholar
• Radi M, Dreassi E, Brullo C, et al. Design, synthesis, biological activity, and ADME properties of pyrazolo[3,4-d]pyrimidines active in hypoxic human leukemia cells: a lead optimization study. J Med Chem 2011;54:2610–26.
   PubMed Web of Science ®Google Scholar
• Blake JF, Xu R, Bencsik JR, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem 2012;55:8110–27.
   PubMed Web of Science ®Google Scholar
• Schmid P, Cortes J, Robson ME, et al. A phase III trial of capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer (CAPItello290). J Clin Oncol 2020;38: TPS1109–TPS1109.
   Web of Science ®Google Scholar
• Dong X, Zhan W, Zhao M, et al. Discovery of 3,4,6-trisubstituted piperidine derivatives as orally active, low hERG blocking Akt inhibitors via conformational restriction and structure-based design. J Med Chem 2019;62:7264–88.
   PubMed Web of Science ®Google Scholar
• Liu Y, Yin Y, Zhang Z, et al. Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity. Eur J Med Chem 2017;138:543–51.
   PubMed Web of Science ®Google Scholar
• Yu M, Zeng M, Pan Z, et al. Discovery of novel akt1 inhibitor induces autophagy associated death in hepatocellular carcinoma cells. Eur J Med Chem 2020;189:112076.
   PubMed Web of Science ®Google Scholar
• Lu JW, Lin YM, Lai YL, et al. MK-2206 induces apoptosis of AML cells and enhances the cytotoxicity of cytarabine. Med Oncol 2015;32:206–9.
   PubMed Web of Science ®Google Scholar
• Yamaji M, Ota A, Wahiduzzaman M, et al. Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med 2017;6:2646–59.
   PubMed Web of Science ®Google Scholar
• Wang S, Yuan XH, Wang SQ, et al. FDA-approved pyrimidine-fused bicyclic heterocycles for cancer therapy: synthesis and clinical application. Eur J Med Chem 2021;214:113218.
   PubMed Web of Science ®Google Scholar
• Helwa AA, El-Dydamony NM, Radwan RA, Abdelraouf SM, et al. Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking. Bioorg Chem 2020;102:104051.
   PubMed Web of Science ®Google Scholar
• Zhou H, McGowan MA, Lipford K, et al. Discovery and optimization of heteroaryl piperazines as potent and selective PI3Kδ inhibitors. Bioorg Med Chem Lett 2020;30:126715.
   PubMed Web of Science ®Google Scholar
• Pancholi S, Leal MF, Ribas R, et al. Combination of mTORC1/2 inhibitor vistusertib plus fulvestrant in-vitro and in-vivo targets oestrogen receptor-positive endocrine-resistant breast cancer. Breast Cancer Res 2019;21:1–4.
   PubMed Web of Science ®Google Scholar
• Ram VJ. Chemotherapeutic agents, XVIII: Synthesis of pi-deficient pyrimidines and fused pyrimidines as leishmanicidal agents. Arch Pharm (Weinheim) 1990;323:895–9.
   PubMed Web of Science ®Google Scholar
• Taher AT, Helwa AA. Synthesis, antitumor and antimicrobial testing of some new thiopyrimidine analogues. Chem Pharm Bull (Tokyo) 2012;60:1305–13.
   PubMed Web of Science ®Google Scholar
• Agarwal N, Raghuwanshi SK, Upadhyay DN, et al. Suitably functionalised pyrimidines as potential antimycotic agents. Bioorg Med Chem Lett 2000;10:703–6.
   PubMed Web of Science ®Google Scholar
• Carmichael J, DeGraff WG, Gazdar AF, Minna JD, et al. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 1987;47:936–42.
   PubMed Web of Science ®Google Scholar
• Takeuchi H, Baba M, Shigeta S. An application of tetrazolium (MTT) colorimetric assay for the screening of anti-herpes simplex virus compounds. J Virol Methods 1991;33:61–71.
   PubMed Web of Science ®Google Scholar
• Pozarowski P, Darzynkiewicz Z. Analysis of cell cycle by flow cytometry. Methods Mol Biol 2004; 28:1301–11.
   Google Scholar
• Darzynkiewicz Z, Bedner E, Smolewski P. Flow cytometry in analysis of cell cycle and apoptosis. Semin Hematol 2001;38:179–93.
   PubMed Web of Science ®Google Scholar
• Vermes I, Haanen C, Steffens-Nakken H, Reutellingsperger C. A novel assay for apoptosis Flow cytometric detection of phosphatidylserine early apoptotic cells using fluorescein labelled expression on Annexin V. J Immunol Meth 1995;184:39–51.
   PubMed Web of Science ®Google Scholar
• Lakshmanan I, Batra SK. Protocol for apoptosis assay by flow cytometry using annexin V staining method. Bio Protoc 2013;3:374.
   Google Scholar
• Tang C, Lu YH, Xie JH, et al. Downregulation of survivin and activation of caspase-3 through the PI3K/Akt pathway in ursolic acid-induced HepG2 cell apoptosis. Anticancer Drugs 2009;20:58–249.
   Web of Science ®Google Scholar
• Bae H, Lim W, Bazer FW, et al. Mitigation of ER-stress and inflammation by chemokine (C-C motif) ligand 21 during early pregnancy. Dev Comp Immunol 2019;94:73–84.
   PubMed Web of Science ®Google Scholar
• Oecd TN. 425: acute oral toxicity: up-and-down procedure. OECD guidelines for the testing of chemicals, section. Vol. 4. Paris, France: OECD Publishing; 2008: 1–27.
   Google Scholar
• Huck BR, Mochalkin I. Recent progress towards clinically relevant ATP-competitive Akt inhibitors. Bioorg Med Chem Lett 2017;27:2838–48.
   PubMed Web of Science ®Google Scholar
• Ashwell MA, Lapierre JM, Brassard C, et al. Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors. J Med Chem 2012;55:5291–310.
   PubMed Web of Science ®Google Scholar
• Badisa RB, Darling-Reed SF, Joseph P, et al. Selective cytotoxic activities of two novel synthetic drugs on human breast carcinoma MCF-7 cells. Anticancer Res 2009;29:2993–6.
   PubMed Web of Science ®Google Scholar
• Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261–74.
   PubMed Web of Science ®Google Scholar
• Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489–501.
   PubMed Web of Science ®Google Scholar
• Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999;401:86–90.
   PubMed Web of Science ®Google Scholar
• Wang X, Wu Q, Zhang L, et al. Wortmannin induced apoptosis of leukemia cells by reducing PI3K/Akt. Chin Ger J Clin Oncol 2010;9:734–8.
   Google Scholar
• Lin K, Lin J, Wu WI, et al. An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci Signal 2012;5:ra37.
   PubMed Web of Science ®Google Scholar
• Staben ST, Siu M, Goldsmith R, et al. Structure-based design of thienobenzoxepin inhibitors of PI3-kinase. Bioorg Med Chem Lett 2011;21:4054–8.
   PubMed Web of Science ®Google Scholar
• Murahari M, Prakash KV, Peters GJ, Mayur YC. Acridone-pyrimidine hybrids- design, synthesis, cytotoxicity studies in resistant and sensitive cancer cells and molecular docking studies. Eur J Med Chem 2017;139:961–81.
   PubMed Web of Science ®Google Scholar
• Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 2001;46:3–26.
   PubMed Web of Science ®Google Scholar