Synthesis, and Docking Studies of Some Fused-quinazolines and Quinazolines Carrying Biological Active Isatin Moiety as Cell-cycle Inhibitors of Breast Cancer Cell Lines

 

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Abstract

3 series of novel fused heterocyclic systems, viz. triazolo[4,3-a]quinazolin-7-ones (3), [1] [2] [4] [5]-tetrazino[4,3-a]-quinazolin-8-ones (5) and Schiff’s bases of isatin derivatives with 2-hydrazinoquinazolin-4-ones (7) have been synthesized. Several of them showed variable and promising in vitro antiproliferative activity against the MCF-7 cells. Compounds 3a-3c, 6, 7a-7 f showed promising activity (IC50=12.45–15.79 μM). Compound 7 f possessed notable cell cycle disrupting and apoptotic activities with enhanced selectivity against cancer cells, suggesting the potential for the development of new selective cell cycle inhibitors. In silico docking study of the compound 7 f with EGFR enzyme postulated that the designed compound might act on the same enzyme target where DJK_3021_A x-ray structure acted.

• References

• 1 Medina JC, Roche D, Shan B et al. Novel halogenated sulfonamides inhibit the growth of multidrug resistant MCF-7/ADR cancer cells. Bioorg Med Chem Lett 1999; 9: 1843-1846
  CrossrefPubMedGoogle Scholar
• 2 Medina JC, Shan B, Beckmann H et al. Novel antineoplastic agents with efficacy against multidrug resistant tumor cells. Bioorg Med Chem Lett 1998; 8: 2653-2656
  CrossrefPubMedGoogle Scholar
• 3 Choo HYP, Kim M, Lee SK et al. Solid-phase combinatorial synthesis and cytotoxicity of 3-aryl-2,4-quinazolindiones. Bioorg Med Chem 2002; 10: 517-523
  CrossrefPubMedGoogle Scholar
• 4 Eckhardt S. Recent progress in the development of anticancer agents. Curr Med Chem, Anti-Canc Agents 2002; 2: 419-439
  PubMedGoogle Scholar
• 5 Abdel-Aziz AAM. Novel and versatile methodology for synthesis of cyclic imides and evaluation of their cytotoxic, DNA binding, apoptotic inducing activities and molecular modeling study. Eur J Med Chem 2007; 42: 614-626
  CrossrefPubMedGoogle Scholar
• 6 Hwang HS, Moon EY, Seong SK et al. Characterization of the anticancer activity of DW2282, a new anticancer agent. Anticancer Res 1999; 19: 5087-5093
  PubMedGoogle Scholar
• 7 Al-Rashood ST, Aboldahab IA, Nagi MN et al. Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs. Bioorg Med Chem 2006; 14: 8608-8621
  CrossrefPubMedGoogle Scholar
• 8 Al-Obaid AM, Abdel-Hamide SG, El-Kashef HA et al. Substituted quinazolines, part 3. Synthesis, in vitro antitumor activity and molecular modeling study of certain 2-thieno-4(3H)-quinazolinone analogs. Eur J Med Chem 2009; 44: 2379-2391
  CrossrefPubMedGoogle Scholar
• 9 Al-Omary FAM, Abouzeid LA, Nagi MN et al. Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones. Bioorg Med Chem 2010; 18: 2849-2863
  CrossrefPubMedGoogle Scholar
• 10 Smith RA, Cokkinides V, Brawley OW. Cancer screening in the United States, a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin 2009; 59: 27-41
  CrossrefPubMedGoogle Scholar
• 11 Rajo F, Albanell J, Rovira A et al. Targeted therapies in breast cancer. Semin Diagn Pathol 2008; 25: 245-261
  CrossrefPubMedGoogle Scholar
• 12 Arteaga CL, Johnson DH. Tyrosine kinase inhibitors-ZD1839 (Iressa). Curr Opin Oncol 2001; 13: 491-498
  CrossrefPubMedGoogle Scholar
• 13 Baker AJ, Gibson KH, Grundy W et al. Studies leading to the identification of ZD1839 (iressa™): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Bioorg Med Chem Lett 2001; 11: 1911-1914
  CrossrefPubMedGoogle Scholar
• 14 Hennequin LF, Stokes ESE, Thomas AP et al. Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. J Med Chem 2002; 45: 1300-1312
  CrossrefPubMedGoogle Scholar
• 15 Wood ER, Truesdale AT, McDonald OB et al. A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib): Relationships among Protein Conformation, Inhibitor Off-Rate, and Receptor Activity in Tumor Cells. Cancer Res 2004; 64: 6652-6659
  CrossrefPubMedGoogle Scholar
• 16 Barlesi F, Tchouhadjian C, Doddoli C et al. Gefitinib (ZD1839, IressaR) in non-small-cell lung cancer: a review of clinical trials from a daily practice perspective. Fundam Clin Pharmacol 2005; 19: 385-393
  CrossrefPubMedGoogle Scholar
• 17 Burris HA, Hurwitz HI, Dees EC et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 2005; 23: 5305-5313
  CrossrefPubMedGoogle Scholar
• 18 Dhillon S, Wagstaff AJ. Lapatinib. Drugs 2007; 67: 2101-2108
  CrossrefPubMedGoogle Scholar
• 19 Ganjoo KN, Wakelee H. Review of erlotinib in the treatment of advanced non-small cell lung cancer. Biologics Targets Ther 2007; 1: 335-346
  PubMedGoogle Scholar
• 20 Kopper I. Lapatinib: a sword with two edges. Pathol Oncol Res 2008; 14: 1-8
  CrossrefPubMedGoogle Scholar
• 21 Cockerill GS, Lackey KE. Small molecule inhibitors of the class 1 receptor tyrosine kinase family. Curr Top Med Chem 2002; 2: 1001-1010
  CrossrefPubMedGoogle Scholar
• 22 Srinivasan M, Trivadi SG. Tyrosine kinase inhibitors in cancer therapy. Clin Biochem 2004; 37: 618-635
  CrossrefPubMedGoogle Scholar
• 23 Fricker J. Tyrosine kinase inhibitors: the next generation. Lancet Oncol 2006; 7: 621-622
  CrossrefPubMedGoogle Scholar
• 24 Garofalo S, Rosa R, Bianco R et al. EGFR-targeting agents in oncology. Expert Opin Ther. Patents 2008; 18: 889-901
  PubMedGoogle Scholar
• 25 Bramson HN, Corona J, Davis ST et al. Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis. J Med Chem 2001; 44: 4339-4358
  CrossrefPubMedGoogle Scholar
• 26 Matesic L, Locke JM, Bremner JB et al. N-Phenethyl and N-naphthylmethyl isatins and analogues as in vitro cytotoxic agents. Bioorg Med Chem 2008; 16: 3118-3124
  CrossrefPubMedGoogle Scholar
• 27 Solomon VR, Hu C, Lee H. Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: A hybrid pharmacophore approach. Bioorg Med Chem 2010; 18: 1563-1572
  CrossrefPubMedGoogle Scholar
• 28 Radwan AA, El-Shorbagi AA, Abdel-Alim AM et al. Synthesis and evaluation of the cytotoxic and antiviral activities of 5,6-disubstituted isocytosine derivatives. Alex J Pharm Sci 1994; 8: 155-162
  PubMedGoogle Scholar
• 29 Radwan AA, Al-Dhfyan A, Hamid MK et al. 3,5-Disubstituted thiadiazine-2-thiones: new cell-cycle inhibitors. Arch. Pharm Res 2012; 35: 35-49
  CrossrefPubMedGoogle Scholar
• 30 Fadok VA, Voelker DR, Campbell PA et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 1992; 148: 2207-2216
  PubMedGoogle Scholar
• 31 Koopman G, Reutelingsperger CPM, Kuijten GAM et al. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 1994; 84: 1415-1420
  PubMedGoogle Scholar
• 32 Lang PT, Brozell SR, Mukherjee S et al. DOCK 6: combining techniques to model RNA-small molecule complexes. RNA 2009; 15: 1219-1230
  CrossrefPubMedGoogle Scholar
• 33 Blair JA, Rauh D, Kung C et al. Structure-guided development of affinity probes for tyrosine kinases using chemical genetics. Nat Chem Biol 2007; 3: 229-238
  CrossrefPubMedGoogle Scholar