Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting
Breast Cancer - An in-silico approach

Kalirajan      Rajagopal; Vulsi   Bodhya   Sri; Gowramma       Byran; Swaminathan      Gomathi
doi:10.2174/2589977513666210617160302
Abstract

Background: Breast cancer is one of the malignant tumours which mainly affect the female population. 20% of the cases of breast cancer are due to the over-expression of Human epidermal growth factor receptor-2 (HER2), which is the dominant tyrosine kinase receptor. In general, 9-anilinoacridine derivatives play an important role in antitumor activity due to their DNA-intercalating properties.
Objective: Some novel 9-anilinoacridines substituted with pyrazole moiety (1a-z) were designed and their HER2enzyme (PDB id-3PP0) inhibition activity was performed by molecular docking studies using the Glide module of Schrodinger suite 2019-4.
Methods: Glide module of the Schrodinger suite was used to perform docking studies; qikprop module was used for in-silico ADMET screening and the Prime-MMGBSA module was used for free binding energy calculations. Based on GLIDE scoring functions, we can determine the binding affinity of ligands (1a-z) towards HER2.
Results: The inhibitory activity of ligands against HER2 was mainly due to the strong hydrophobic and hydrogen bonding interactions. Almost all the compounds 1a-z exhibited a good binding affinity with Glide scores in the range of -4.9 to -9.75, when compared with the standard drugs CK0403 (-4.105) and Tamoxifen (-3.78). From the results of in-silico ADMET properties, it was evident that most of the compounds fell within the recommended values. MM-GBSA binding calculations of the most potent inhibitors were found to be more favourable.
Conclusion: The results of in-silico studies provide strong evidence for the potential of valuable ligands in pyrazole substituted 9-anilinoacridines as HER2 inhibitors, and the compounds, 1v,s,r,d,a,o with significant Glide scores may produce significant anti-breast cancer activity.
Keywords: HER2 inhibition, breast cancer, acridine, pyrazole, docking studies, in-silico ADMET screening, MM-GBSA.
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[1] 
Denny WA. Acridine derivatives as chemotherapeutic agents. Curr Med Chem  2002; 9(18): 1655-65.
[http://dx.doi.org/10.2174/0929867023369277] [PMID: 12171548] 
[2] 
Nelson EM, Tewey KM, Liu LF. Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4′-(9-acridinylamino)-methanesulfon-m-anisidide. Proc Natl Acad Sci USA  1984; 81(5): 1361-5.
[http://dx.doi.org/10.1073/pnas.81.5.1361] [PMID: 6324188] 
[3] 
Sharhan O, Heidelberg T, Mohd Hashim N, Al-Madhagi WM, Mohd Ali H. Benzimidazolium-acridine-based silver N-heterocyclic carbene complexes as potential anti-bacterial and anticancer drug. Inorg Chim Acta  2020; 504: 119462.
[http://dx.doi.org/10.1016/j.ica.2020.119462] 
[4] 
Chen R, Huo L, Jaiswal Y, et al. Design, synthesis, antimicrobial, and anticancer activities of Acridine Thiosemicarbazides derivatives. Molecules  2019; 24(11): 2065.
[http://dx.doi.org/10.3390/molecules24112065] [PMID: 31151235] 
[5] 
Kapuriya N, Kapuriya K, Zhang X, et al. Synthesis and biological activity of stable and potent antitumor agents, aniline nitrogen mustards linked to 9-anilinoacridines via a urea linkage. Bioorg Med Chem  2008; 16(10): 5413-23.
[http://dx.doi.org/10.1016/j.bmc.2008.04.024] [PMID: 18450456] 
[6] 
Baselga J, Swain SM. CLEOPATRA: A phase III evaluation of pertuzumab and trastuzumab for HER2-positive metastatic breast cancer. Clin Breast Cancer  2010; 10(6): 489-91.
[http://dx.doi.org/10.3816/CBC.2010.n.065] [PMID: 21147694] 
[7] 
Gajria D, Chandarlapaty S. HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther  2011; 11(2): 263-75.
[http://dx.doi.org/10.1586/era.10.226] [PMID: 21342044] 
[8] 
Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol  2010; 28(7): 1138-44.
[http://dx.doi.org/10.1200/JCO.2009.24.2024] [PMID: 20124182] 
[9] 
Cardoso F, Durbecq V, Laes JF, et al. Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner. Mol Cancer Ther  2006; 5(12): 3042-51.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0104] [PMID: 17148762] 
[10] 
Nielsen DL, Andersson M, Kamby C. HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. Cancer Treat Rev  2009; 35(2): 121-36.
[http://dx.doi.org/10.1016/j.ctrv.2008.09.003] [PMID: 19008049] 
[11] 
Chang BY, Kim SA, Malla B, Kim SY. The effect of Selective Estrogen Receptor Modulators (SERMs) on the tamoxifen resistant breast cancer cells. Toxicol Res  2011; 27(2): 85-93.
[http://dx.doi.org/10.5487/TR.2011.27.2.085] [PMID: 24278556] 
[12] 
Musiliyu A, Musaa M, Omar F, Khanb JSC. Synthesis and Antiproliferative activity of coumarin-estrogen conjugates against breast cancer cell lines. Lett Drug Des Discov  2012; 76: 211-20.
[13] 
Luo G, Chen M, Lyu W, et al. Design, synthesis, biological evaluation and molecular docking studies of novel 3-aryl-4-anilino-2H-chromen-2-one derivatives targeting ERα as anti-breast cancer agents. Bioorg Med Chem Lett  2017; 27(12): 2668-73.
[http://dx.doi.org/10.1016/j.bmcl.2017.04.029] [PMID: 28460819] 
[14] 
Berger C, Qian Y, Chen X. The p53-estrogen receptor loop in cancer. Curr Mol Med  2013; 13(8): 1229-40.
[http://dx.doi.org/10.2174/15665240113139990065] [PMID: 23865427] 
[15] 
Menendez JA, Lupu R. Fatty acid synthase regulates estrogen receptor-α signaling in breast cancer cells. Oncogenesis  2017; 6(2): e299.
[http://dx.doi.org/10.1038/oncsis.2017.4] [PMID: 28240737] 
[16] 
Harmey JH, Dimitriadis E, Kay E, Redmond HP, Bouchier-Hayes D. Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor beta-1. Ann Surg Oncol  1998; 5(3): 271-8.
[http://dx.doi.org/10.1007/BF02303785] [PMID: 9607631] 
[17] 
Lai L, Liu J, Zhai D, et al. Plumbagin inhibits tumour angiogenesis and tumour growth through the Ras signalling pathway following activation of the VEGF receptor-2. Br J Pharmacol  2012; 165(4b): 1084-96.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01532.x] [PMID: 21658027] 
[18] 
Miller KD, Trigo JM, Wheeler C, et al. A multicenter phase II trial of ZD6474, a vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with previously treated metastatic breast cancer. Clin Cancer Res  2005; 11(9): 3369-76.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-1923] [PMID: 15867237] 
[19] 
Gianni L, Lladó A, Bianchi G, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol  2010; 28(7): 1131-7.
[http://dx.doi.org/10.1200/JCO.2009.24.1661] [PMID: 20124183] 
[20] 
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol  2011; 29(25): 3366-73.
[http://dx.doi.org/10.1200/JCO.2011.35.0868] [PMID: 21768458] 
[21] 
Bhargava R, Gerald WL, Li AR, et al. EGFR gene amplification in breast cancer: Correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations. Mod Pathol  2005; 18(8): 1027-33.
[http://dx.doi.org/10.1038/modpathol.3800438] [PMID: 15920544] 
[22] 
Sasaki T, Hiroki K, Yamashita Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. BioMed Res Int  2013; 2013: 546318.
[http://dx.doi.org/10.1155/2013/546318] [PMID: 23986907] 
[23] 
Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol  2005; 23(16): 3676-85.
[http://dx.doi.org/10.1200/JCO.2005.07.032] [PMID: 15738535] 
[24] 
Real PJ, Benito A, Cuevas J, et al. Blockade of epidermal growth factor receptors chemosensitizes breast cancer cells through up-regulation of Bnip3L. Cancer Res  2005; 65(18): 8151-7.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1134] [PMID: 16166289] 
[25] 
Langelier MF, Ruhl DD, Planck JL, Kraus WL, Pascal JM. The Zn3 domain of human poly(ADP-ribose) polymerase-1 (PARP-1) functions in both DNA-dependent poly(ADP-ribose) synthesis activity and chromatin compaction. J Biol Chem  2010; 285(24): 18877-87.
[http://dx.doi.org/10.1074/jbc.M110.105668] [PMID: 20388712] 
[26] 
Dai Q, Chen J, Gao C, Sun Q, Yuan Z, Jiang Y. Design, synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents. Chin Chem Lett  2019; 31(2): 404-8.
[http://dx.doi.org/10.1016/j.cclet.2019.06.019] 
[27] 
Yuan Z, Chen S, Chen C, Chen J, Chen C, Dai Q. Chunmei Gao, Yuyang Jiang. Design, synthesis and biological evaluation of 4-amidobenzimidazoleacridine derivatives as dual PARP and Topoinhibitors for cancer therapy. Eur J Med Chem  2017; 138: 1135-46.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.050] [PMID: 28763648] 
[28] 
Murai J, Zhang Y, Morris J, et al. Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic inhibition. J Pharmacol Exp Ther  2014; 349(3): 408-16.
[http://dx.doi.org/10.1124/jpet.113.210146] [PMID: 24650937] 
[29] 
Bai P, Cantó C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab  2012; 16(3): 290-5.
[http://dx.doi.org/10.1016/j.cmet.2012.06.016] [PMID: 22921416] 
[30] 
Lee JM, Hays JL, Annunziata CM, et al. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J Natl Cancer Inst  2014; 106(6): dju089.
[http://dx.doi.org/10.1093/jnci/dju089] [PMID: 24842883] 
[31] 
Qin T, Huang G, Chi L, et al. Exceptionally high UBE2C expression is a unique phenomenon in basal-like type breast cancer and is regulated by BRCA1. Biomed Pharmacother  2017; 95: 649-55.
[http://dx.doi.org/10.1016/j.biopha.2017.08.095] [PMID: 28881292] 
[32] 
Yun MH, Hiom K. CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature  2009; 459(7245): 460-3.
[http://dx.doi.org/10.1038/nature07955] [PMID: 19357644] 
[33] 
Zarrizi R, Menard J, Belting M, Massoumi R. Deubiquitination of γ -tubulin by BAP1 prevents chromosome instability in breastcancer cells. Cancer Res  2014; 0221-7.
[34] 
Papoutsis AJ, Lamore SD, Wondrak GT, Selmin OI, Romagnolo DF. Resveratrol prevents epigenetic silencing of BRCA-1 by the aromatic hydrocarbon receptor in human breast cancer cells. J Nutr  2010; 140(9): 1607-14.
[http://dx.doi.org/10.3945/jn.110.123422] [PMID: 20631324] 
[35] 
Ocaña A, Amir E. Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: Current status and future directions. Cancer Treat Rev  2009; 35(8): 685-91.
[http://dx.doi.org/10.1016/j.ctrv.2009.08.001] [PMID: 19733440] 
[36] 
Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther  2005; 315(3): 971-9.
[http://dx.doi.org/10.1124/jpet.105.084145] [PMID: 16002463] 
[37] 
Pentassuglia L, Graf M, Lane H, et al. Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes. Exp Cell Res  2009; 315(7): 1302-12.
[http://dx.doi.org/10.1016/j.yexcr.2009.02.001] [PMID: 19331811] 
[38] 
Samir HR, Ratn  DS, Dilip VJ, Hitesh TM, Shailesh KM. Recent developments in receptor tyrosine kinases targeted anticancer therapy. Vet World  2016; 9: 80-90.
[http://dx.doi.org/10.14202/vetworld.2016.80-90] 
[39] 
O’Sullivan CC. CDK4/6 inhibitors for the treatment of advanced hormone receptor positive breast cancer and beyond: 2016 update. Expert Opin Pharmacother  2016; 17(12): 1657-67.
[http://dx.doi.org/10.1080/14656566.2016.1201072] [PMID: 27322766] 
[40] 
Prall OW, Sarcevic B, Musgrove EA, Watts CK, Sutherland RL. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J Biol Chem  1997; 272(16): 10882-94.
[http://dx.doi.org/10.1074/jbc.272.16.10882] [PMID: 9099745] 
[41] 
Meric-Bernstam F, Hung MC. Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin Cancer Res  2006; 12(21): 6326-30.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1732] [PMID: 17085641] 
[42] 
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science  1987; 235(4785): 177-82.
[http://dx.doi.org/10.1126/science.3798106] [PMID: 3798106] 
[43] 
Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol  2009; 27(34): 5838-47.
[http://dx.doi.org/10.1200/JCO.2009.22.1507] [PMID: 19884552] 
[44] 
Tagliabue E, Balsari A, Campiglio M, Pupa SM. HER2 as a target for breast cancer therapy. Expert Opin Biol Ther  2010; 10(5): 711-24.
[http://dx.doi.org/10.1517/14712591003689972] [PMID: 20214497] 
[45] 
Gutierrez C, Schiff R. HER2: Biology, detection, and clinical implications. Arch Pathol Lab Med  2011; 135(1): 55-62.
[http://dx.doi.org/10.5858/2010-0454-RAR.1] [PMID: 21204711] 
[46] 
Kallioniemi OP, Kallioniemi A, Kurisu W, et al. ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci USA  1992; 89(12): 5321-5.
[http://dx.doi.org/10.1073/pnas.89.12.5321] [PMID: 1351679] 
[47] 
Swetha P, Bhagavan RRM, Rajendra PVVS. Synthesis, characterization, and anticancer activity of some novel acridine derivatives. Asian J Pharm Clin Res  2020; 13(6): 166-9.
[48] 
Sun Y-W, Chen KY, Kwon CH, Chen KM. CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells. Mol Med Rep  2016; 13(1): 933-8.
[http://dx.doi.org/10.3892/mmr.2015.4604] [PMID: 26648164] 
[49] 
Wakelin LPG, Bu X, Eleftheriou A, Parmar A, Hayek C, Stewart BW. Bisintercalating threading diacridines: relationships between DNA binding, cytotoxicity, and cell cycle arrest. J Med Chem  2003; 46(26): 5790-802.
[http://dx.doi.org/10.1021/jm030253d] [PMID: 14667232] 
[50] 
Solomon VR, Pundir S, Le HT, Lee H. Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity. Eur J Med Chem  2018; 143: 1028-38.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.097] [PMID: 29232580] 
[51] 
Bacherikov VA, Chang JY, Lin YW, et al. Synthesis and antitumor activity of 5-(9-acridinylamino)anisidine derivatives. Bioorg Med Chem  2005; 13(23): 6513-20.
[http://dx.doi.org/10.1016/j.bmc.2005.07.018] [PMID: 16140018] 
[52] 
Yang P, Yang Q, Qian X. Novel DNA bis-inteclators of isoquinolino [4,5-bc] acridines: Design, synthesis and evaluation of cytotoxic activities. Tetrahedron  2005; 61: 11895-901.
[http://dx.doi.org/10.1016/j.tet.2005.09.065] 
[53] 
Kumar R, Sharma A, Sharma S, Silakari O, Singh M, Kaur M. Synthesis, characterization and antitumor activity of 2-methyl-9-substituted acridines. Arab J Chem  2017; 10: 5956-63.
[http://dx.doi.org/10.1016/j.arabjc.2012.12.035] 
[54] 
Plouvier B, Houssin R, Hecquet B, et al. Antitumor combilexin. A thiazole-containing analogue of netropsin linked to an acridine chromophore. Bioconjug Chem  1994; 5(5): 475-81.
[http://dx.doi.org/10.1021/bc00029a016] [PMID: 7849080] 
[55] 
Surbhi A, Anuj K, Nikhil K, Partha R, Sondhi SM. Synthesis and anticancer activity evaluation of some acridine derivatives. Med Chem Res  2015; 24: 1942-51.
[http://dx.doi.org/10.1007/s00044-014-1268-6] 
[56] 
de Almeida SM, Lafayette EA, da Silva LP, et al. Synthesis, DNA binding, and antiproliferative activity of novel Acridine-Thiosemicarbazone derivatives. Int J Mol Sci  2015; 16(6): 13023-42.
[http://dx.doi.org/10.3390/ijms160613023] [PMID: 26068233] 
[57] 
Tabarrini O, Cecchetti V, Fravolini A, et al. Design and synthesis of modified quinolones as antitumoral acridones. J Med Chem  1999; 42(12): 2136-44.
[http://dx.doi.org/10.1021/jm980324m] [PMID: 10377219] 
[58] 
Antonini I, Polucci P, Jenkins TC, et al. 1-[(ω-aminoalkyl)amino]-4-[N-(ω-aminoalkyl)carbamoyl]-9-oxo-9, 10-dihydroacridines as intercalating cytotoxic agents: Synthesis, DNA binding, and biological evaluation. J Med Chem  1997; 40(23): 3749-55.
[http://dx.doi.org/10.1021/jm970114u] [PMID: 9371240] 
[59] 
Gao C, Zhang W, He S, Li S, Liu F, Jiang Y. Synthesis and antiproliferative activity of 2,7-diamino l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives as potent telomeric G-quadruplex DNA ligands. Bioorg Chem  2015; 60: 30-6.
[http://dx.doi.org/10.101ao6/j.bioorg.2015.04.002] 
[60] 
Nadaraj V, Selvi ST, Mohan S. Microwave-induced synthesis and anti-microbial activities of 7,10,11,12-tetrahydrobenzo[c]acridin-8(9H)-one derivatives. Eur J Med Chem  2009; 44(3): 976-80.
[http://dx.doi.org/10.1016/j.ejmech.2008.07.004] [PMID: 18718695] 
[61] 
Kalirajan R. Mohammed rafick MH, Sankar S, Gowramma B. Green synthesis of some novel chalcone and isoxazole substituted 9-anilinoacridine derivatives and evaluation of their antimicrobial and larvicidal activities. Indian J Chem  2018; 57B: 583-90.
[62] 
Kalirajan R, Muralidharan V. Selvaraj Jubie and Sankar S. Microwave assisted synthesis, characterization and evaluation for their antimicrobial activities of some novel pyrazole substituted 9-Anilino Acridine Derivatives. Int J Health Allied Sci  2013; 2(2): 81-7.
[http://dx.doi.org/10.4103/2278-344X.115682] 
[63] 
Dickens BF, Weglicki WB, Boehme PA, Mak TI. Antioxidant and lysosomotropic properties of acridine-propranolol: protection against oxidative endothelial cell injury. J Mol Cell Cardiol  2002; 34(2): 129-37.
[http://dx.doi.org/10.1006/jmcc.2001.1495] [PMID: 11851353] 
[64] 
Kalirajan R, Muralidharan V, Jubie S, et al. Synthesis of some novel pyrazole substituted 9-anilinoacridine derivatives and evaluation for their antioxidant and cytotoxic activities. J Heterocycl Chem  2012; 49: 748-54.
[http://dx.doi.org/10.1002/jhet.848] 
[65] 
Kalirajan R, Rafick MH, Sankar S, Jubie S. Docking studies, synthesis, characterization and evaluation of their antioxidant and cytotoxic activities of some novel isoxazole-substituted 9-anilinoacridine derivatives. Scientific World J  2012; 2012: 165258.
[http://dx.doi.org/10.1100/2012/165258] [PMID: 22593663] 
[66] 
Gamage SA, Tepsiri N, Wilairat P, et al. Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum. J Med Chem  1994; 37(10): 1486-94.
[http://dx.doi.org/10.1021/jm00036a014] [PMID: 8182707] 
[67] 
Anderson MO, Sherrill J, Madrid PB, et al. Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum. Bioorg Med Chem  2006; 14(2): 334-43.
[http://dx.doi.org/10.1016/j.bmc.2005.08.017] [PMID: 16216519] 
[68] 
Sondhi SM, Johar M, Nirupama S, Sukla R, Raghubir R, Dastidar SG. Synthesis of sulpha drug acridine derivatives and their evaluation for anti-anflammatory, analgesic and anticancer acvity. Indian J Chem  2002; 41B: 2659-66.
[69] 
Gamage SA, Figgitt DP, Wojcik SJ, et al. Structure-activity relationships for the antileishmanial and antitrypanosomal activities of 1′-substituted 9-anilinoacridines. J Med Chem  1997; 40(16): 2634-42.
[http://dx.doi.org/10.1021/jm970232h] [PMID: 9258370] 
[70] 
Di Giorgio C, Shimi K, Boyer G, Delmas F, Galy JP. Synthesis and antileishmanial activity of 6-mono-substituted and 3,6-di-substituted acridines obtained by acylation of proflavine. Eur J Med Chem  2007; 42(10): 1277-84.
[http://dx.doi.org/10.1016/j.ejmech.2007.02.010] [PMID: 17418916] 
[71] 
Llama EF, Campo CD, Capo M, Anadon M. Synthesis and antinociceptive activity of 9-phenyl-oxy or 9-acyl-oxy derivatives of xanthene, thioxanthene and acridine. Eur J Med Chem  1989; 24: 391-6.
[http://dx.doi.org/10.1016/0223-5234(89)90083-4] 
[72] 
Recanatini M, Cavalli A, Belluti F, et al. SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. J Med Chem  2000; 43(10): 2007-18.
[http://dx.doi.org/10.1021/jm990971t] [PMID: 10821713] 
[73] 
Goodell JR, Madhok AA, Hiasa H, Ferguson DM. Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity. Bioorg Med Chem  2006; 14(16): 5467-80.
[http://dx.doi.org/10.1016/j.bmc.2006.04.044] [PMID: 16713270] 
[74] 
Hemalatha V, Sakila L, Balaji M. Molecular modelling and in silico drug docking studies on breast cancer target protein (TNRC9) using cheminformatics software and tools. Int J Novel Trends Pharm Sci  2015; 5(3): 55-63.
[75] 
Rastogi K, Chang JY, Pan WY, et al. Antitumor AHMA linked to DNA minor groove binding agents: Synthesis and biological evaluation. J Med Chem  2002; 45(20): 4485-93.
[http://dx.doi.org/10.1021/jm0200714] [PMID: 12238927] 
[76] 
Baruah H, Wright MW, Bierbach U. Solution structural study of a DNA duplex containing the guanine-N7 adduct formed by a cytotoxic platinum-acridine hybrid agent. Biochemistry  2005; 44(16): 6059-70.
[http://dx.doi.org/10.1021/bi050021b] [PMID: 15835895] 
[77] 
Harrison RJ, Cuesta J, Chessari G, et al. Trisubstituted acridine derivatives as potent and selective telomerase inhibitors. J Med Chem  2003; 46(21): 4463-76.
[http://dx.doi.org/10.1021/jm0308693] [PMID: 14521409] 
[78] 
Kalirajan R, Sivakumar SU, Jubie S, Gowramma B, Suresh B. Synthesis and biological evaluation of some heterocyclic derivatives of chalcones. Int J Chem Sci  2009; 1(1): 27-34.
[79] 
Padmaja A, Payani T, Reddy GD, Padmavathi V. Synthesis, antimicrobial and antioxidant activities of substituted pyrazoles, isoxazoles, pyrimidine and thioxopyrimidine derivatives. Eur J Med Chem  2009; 44(11): 4557-66.
[http://dx.doi.org/10.1016/j.ejmech.2009.06.024] [PMID: 19631423] 
[80] 
Kalirajan R, Leela Rathore, Jubie S, Gowramma B, Gomathy S, Sankar S. Microwave assisted synthesis of some novel pyrazole substituted benzimidazoles and evaluation of their biological activities. Indian J Chem  2011; 50B: 1794-801.
[81] 
Kalirajan R, Jubie S, Gowramma B. Microwave irradated synthesis, characterization and evaluation for their antibacterial and larvicidal activities of some novel Chalcone and Isoxazole substituted 9-Anilino Acridines. Open J Chem  2015; 1(1): 001-7.
[82] 
Panda S, chowdary P, jayashree B. Synthesis, anti-inflammatory and antibacterial activity of novel indolyl-isoxazoles. Indian J Pharm Sci  2009; 71(6): 684-7.
[http://dx.doi.org/10.4103/0250-474X.59554] [PMID: 20376225] 
[83] 
Kalirajan R, Kulshrestha V, Sankar S, Jubie S. Docking studies, synthesis, characterization of some novel oxazine substituted 9-anilinoacridine derivatives and evaluation for their anti oxidant and anticancer activities as topo isomerase II inhibitors. Eur J Med Chem  2012; 56: 217-24.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.025] [PMID: 22982526] 
[84] 
Kalirajan R. Rathore L, Jubie S, Gowramma B, Gomathy S, Sankar S, Microwave assisted synthesis of some novel pyrazole substituted benzimidazoles and evaluation of their biological activities. Indian J Chem  2011; 50B: 1794-801.
[85] 
Kalirajan R, Sankar S, Jubie S, Gowramma B. Molecular Docking studies and in-silico ADMET screening of some novel Oxazine substituted 9-Anilinoacridines as Topoisomerase II Inhibitors. Indian J Pharm Educ Res  2017; 51(1): 110-5.
[http://dx.doi.org/10.5530/ijper.51.1.15] 
[86] 
Kalirajan R, Gowramma B, Jubie S, Sankar S. Molecular docking studies and in silico admet screening of some novel heterocyclic substituted 9-Anilinoacridines as Topoisomerase II inhibitors. JSM Chem  2017; 5(1): 1039-44.
[87] 
Kalirajan R, Gaurav K, Pandiselvi A, Gowramma B, Sankar S. Novel thiazine substituted 9-Anilinoacridines: synthesis, antitumour activity and structure activity relationships. Anticancer Agents Med Chem  2019; 19(11): 1350-8.
[http://dx.doi.org/10.2174/1871520619666190408134224] [PMID: 30961512] 
[88] 
Gowramma B, Praveen TK, Gomathy S, Kalirajan R, Babu B, Nagappan K Veni. Synthesis of 2-(Bis (2-Chloroethyl) Amino)-N- (5-substituedphenyl)-1,3,4- Thiadiazol- 2-Yl) Aceto hydrazide and evaluation of anticancer activity. Current Bioactive comp  2018; 14(3): 309-16.
[89] 
Kalirajan R, Vivek kulshrestha, Sankar S. Synthesis, characterization and evaluation for antitumour activity of some novel oxazine substituted 9-Anilinoacridines and their 3D-QSAR studies. Indian J Pharm Sci  2018; 80(5): 921-9.
[http://dx.doi.org/10.4172/pharmaceutical-sciences.1000439] 
[90] 
Kalirajan R, Rathore L, Jubie S, et al. Microwave assisted synthesis and biological evaluation of pyrazole derivatives of Benzimidazoles. Indian J Pharm Educ Res  2010; 44(4): 358-62.
[91] 
Kalirajan R, Chitra, Jubie S, Gowramma B. Synthesis and biological evaluation of Mannich bases of 2-substituted Benzimidazoles. Asian J Chem  2009; 21(7): 5207-11.
[92] 
Jubie S, Gayathri R, Srividya AR, et al. Synthesis and characterization of some novel quinoxaline-2, 3-dione derivatives: a preliminary investigation on their activity against a human epithelial carcinoma cell line. Lett Drug Des Discov  2011; 8: 317-20.
[http://dx.doi.org/10.2174/157018011794839385] 
[93] 
Jubie S, Patil , P,  R,  N,  A. Nilesh Ramesh, Dhanabal P, Kalirajan R, Muruganantham N, Shanish Antony A. Synthesis, antidepressant and antimicrobial activities of some novel stearicacid analogues. Eur J Med Chem  2012; 54: 931-5.
[http://dx.doi.org/10.1016/j.ejmech.2012.06.025] [PMID: 22770606] 
[94] 
Jubie S, Dhanabal P, Afzal Azam M, Muruganantham N, Kalirajan R, Elango K. Synthesis and characterization of some novel fatty acid analogues: a preliminary investigation on their activity against human lung carcinoma cell line. Lipids Health Dis  2013; 12: 45-52.
[http://dx.doi.org/10.1186/1476-511X-12-45] [PMID: 23537396] 
[95] 
Kalirajan R, Pandiselvi A, Gowramma B. In-silico drug design by docking studies, ADMET screening, MM-GBSA binding free energy of some chalcone substituted 9-Anilinoacridines as HER2 inhibitors targeting breast cancer. Int J Comp Theo Chem  2019; 7(1): 6-13.
[http://dx.doi.org/10.11648/j.ijctc.20190701.12] 
[96] 
Kalirajan R, Pandiselvi A, Gowramma B, Balachandran P. In-silico design, ADMET screening, MM-GBSA binding free energy of some novel isoxazole substituted9-anilinoacridines as HER2 inhibitors targeting breast cancer. Curr Drug Res Rev  2019; 11(2): 118-28.
[http://dx.doi.org/10.2174/2589977511666190912154817] [PMID: 31513003] 
[97] 
Halperin I, Ma B, Wolfson H, Nussinov R. Principles of docking: an overview of search algorithms and a guide to scoring functions. Proteins  2002; 47(4): 409-43.
[http://dx.doi.org/10.1002/prot.10115] [PMID: 12001221] 
[98] 
Tripuraneni NS, Azam MA. Pharmacophore modelling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors. J Theor Biol  2016; 394: 117-26.
[http://dx.doi.org/10.1016/j.jtbi.2016.01.007] [PMID: 26804643] 
[99] 
Lengaur T, Rarey M. Computational method for bio molecular docking. Curr Opin Strut Biol  1996; 6(3): 402-6.
[http://dx.doi.org/10.1016/S0959-440X(96)80061-3] 
[100] 
Kalirajan R, Pandiselvi A, Sankar S, Gowramma B. Molecular docking studies and in silico ADMET screening of some novel chalcone substituted 9-Anilinoacridines as Topoisomerase II inhibitors. SF J Pharm Anal Chem  2018; 1(1): 1004-9.
[101] 
Reetu VK. Computer aided design of selective calcium channel blockers: Using pharmacophore - based and docking simulations. Indian J Pharm Sci Res  2012; 3(3): 805-10.
[102] 
Furrer D, Paquet C, Jacob S, Diorio C. The Human Epidermal Growth Factor Receptor 2 (HER2) as a prognostic and predictive biomarker: molecular insights into HER2 activation and diagnostic implications. Intech Open 2018.
[http://dx.doi.org/10.5772/intechopen.78271] 
[103] 
Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W. Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the opls force field. J Chem Theory Comput  2010; 6(5): 1509-19.
[http://dx.doi.org/10.1021/ct900587b] [PMID: 26615687] 
[104] 
Li J, Abel R, Zhu K, Cao Y, Zhao S, Friesner RA. The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling. Proteins  2011; 79(10): 2794-812.
[http://dx.doi.org/10.1002/prot.23106] [PMID: 21905107] 
[105] 
Pal Shilpi. An in silico drug designing approach to target the BRCA1 protein involved in Breast cancer. Helix  2016; l6(1): 761-5.
[106] 
Mehta S, Seema R. Pathak. in silico drug design and molecular docking studies of novel coumarin derivatives as anticancer agents. Asian J Pharm Clin Res (Alex)  2017; 10(4): 335-40.
[107] 
Sahu M, Nerkar AG. In silico design, synthesis and pharmacological screening of some Quinazolinone metal complexes as dihydrofolate reductase inhibitors for anticancer activity: Part-II. Int J Pharm Pharm Sci  2014; 6(5): 509-14.
[108] 
Alejandro Speck-Planche, MNatália D S Cordeiro. Fragment-based in silico modeling of multi-target inhibitors against breast cancer-related proteins. Mol Divers  2017; 21: 511-23.
[http://dx.doi.org/10.1007/s11030-017-9731-1] 
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DOI https://dx.doi.org/10.2174/2589977513666210617160302	Print ISSN 2589-9775
Publisher Name Bentham Science Publisher	Online ISSN 2589-9783
Current Drug Research Reviews

Pyrazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer - An in-silico approach

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