Synthesis, Structure Activity Relationships and Biological Activity Evaluation of Novel Spirocyclic Thiazolidin-4-ones as Potential Anti-Breast Cancer and Epidermal Growth Factor Receptor Inhibitors

Abstract

A series of triazaspiro[4.5]dec-8-ene benzylidine derivatives containing thiazolidinone ring system (6–18) have been designed, synthesized and their biological activities evaluated as potential epidermal growth factor receptor inhibitors. Among them, 9-amino-2-(4-nitrobenzylidene)-3-oxo-4-phenyl-7-thioxo-1-thia-4,6,8-triazaspiro[4.5]dec-8-ene-10-carbonitrile (18) displayed the most potent inhibitory activity (IC₅₀=6.355 µM). Antiproliferative assay results indicated that compound 18 exhibited moderate antiproliferative activity against MCF-7 cell line in vitro; with GI₅₀ value of 30.6 µM. In addition, compounds 7 and 15 displayed the highest antiproliferative activity at a common GI₅₀ value of 10.8 µM. Docking simulation was performed to determine the probable binding model and to pursuit information regarding the activity of compound 18. Based on the preliminary results, compound 18 could be used as an attractive building block for designing potential epidermal growth factor receptor inhibitors.

Key words

spiro-thiazolidin-4-one - EGFR - antiproliferative - structure activity relationship

• References

• 1 American Cancer Society. “Breast Cancer Statistics on Incidence, Survival, and Screening,” http://www.imaginis.com/breast-health/breast-cancer-statistic
• 2 Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2: 127-137
• 3 Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1994; 1198: 165-184
• 4 Fleming TP, Saxena A, Clark WC et al. Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 1992; 52: 4550-4553
• 5 Jensen PB, Hunter T. Oncogenic kinase signalling. Nature 2001; 411: 355-365
• 6 Kim H, Muller W. The role of the epidermal growth factor receptor family in mammary tumorigenesis and metastasis. J Exp Cell Res 1999; 253: 78-87
• 7 Moscatello DK, Holgado-Mudruga M, Godwin AK et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. J Cancer Res 1995; 55: 5536-5539
• 8 Bridges AJ. The rationale and strategy used to develop a series of highly potent, irreversible, inhibitors of the epidermal growth factor receptor family of tyrosine kinases. Curr Med Chem 1999; 6: 825-843
• 9 Boschelli DH. Small molecule inhibitors of receptor tyrosine kinases. Drugs Future 1999; 24: 515-537
• 10 Hennequin L, Stokes ES, Thomas AP et al. Novel 4-anilino quinazolines 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
• 11 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
• 12 Dayam R, Aiello F, Deng JX et al. Discovery of small molecule integrin alphavbeta3 antagonists as novel anticancer agents. J Med Chem 2006; 49: 4526-4534
• 13 Lesyk RB, Zimenkovsky BS, Kaminskyy DV et al. Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group. Biopolym Cell 2001; 27: 107-117
• 14 Kaminskyy DV, Lesyk RB. Structure-anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives. Biopolym Cell 2010; 26: 136-145
• 15 Kaminskyy D, Kyhluk D, Vasylenko O et al. A Facile Synthesis and Anticancer Activity Evaluation of Spiro[Thiazolidinone-Isatin] Conjugates. Sci Pharm 2011; 79: 763-777
• 16 Yong R, Ung AT, Pyne SG et al. Synthesis of novel 30-spirocyclic-oxindole derivatives and assessment of their cytostatic activities. Tetrahedron 2007; 63: 5579-5586
• 17 Young-Won C, Angela S, Bao-Ning S et al. Potential anticancer activity of naturally occurring and semisynthetic derivatives of aculeatins a and b from amomum aculeatum. J Nat Prod 2008; 71: 390-395
• 18 Qiu KM, Wang H, Wang L et al. Design, synthesis and biological evaluation of pyrazolyl-thiazolinone derivatives as potential EGFR and HER-2 kinase inhibitors. Bioorg Med Chem 2012; 20: 2010-2018
• 19 Lv PC, Zhou CF, Chen J et al. Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors. Bioorg Med Chem 2010; 18: 314-319
• 20 Sakka OK, Fleita DH, Harrison TA. (2-(4-oxo-3-phenyl thiazolidin -2-ylidene) malononitrile. Act Cryst Sec E 2013; E69: o350
• 21 Halgren TA. Merck molecular force field: I. Basis, form, scope, parameterization and performance of MMFF94. J Comput Chem 1996; 17: 490-519
• 22 Dewar MJS, Zoobisch EG, Healy EF et al. AM1: A new general purpose quantum mechanical molecular model. J Am Chem Soc 1985; 107: 3902-3910
• 23 ArgusLab 4.0.1 Mark A. Thompson Planaria Software LLC, Seattle, WA. http://www.arguslab.com
• 24 Mohareb RM, El-Sayed NE, Abdelaziz MA. Uses of Cyanoacetylhydrazine in Heterocyclic Synthesis: Novel Synthesis of Pyrazole Derivatives with Anti-tumor Activities. Molecules 2012; 17: 8449-8463
• 25 Youssef MM, Amin MA. Microwave Assisted Synthesis of Some New Heterocyclic Spiro-Derivatives with Potential Antimicrobial and Antioxidant Activities. Molecules 2010; 15: 8827-8840
• 26 Fabbro D, Ruetz S, Buchdunger E et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther 2002; 93: 79-98
• 27 Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002; 277: 46265-46272
• 28 Matysiak J. Evaluation of electronic, lipophilic and membrane affinity effects on antiproliferative activity of 5-substituted-2-(2,4-dihydroxyphenyl)-1,3,4- thiadiazoles against various human cancer cells. Eur J Med Chem 2007; 42: 940-947
• 29 Schon U, Antel J, Bruckner R et al. Synthesis, pharmacological characterization, and quantitative structure-activity relationship analyses of 3,7,9,9- tetraalkylbispidines: derivatives with specific bradycardic activity. J Med Chem 1998; 41: 318-331
• 30 Roy DR, Pal N, Mitra A et al. An atom counting strategy towards analyzing the biological activity of sex hormones. Eur J Med Chem 2007; 42: 1365-1369
• 31 Raya A, Barrientos-Salcedo C, Rubio-Po’o C et al. Electronic structure evaluation through quantum chemical descriptors of 17b-aminoestrogens with an anticoagulant effect. Eur J Med Chem 2011; 46: 2463-2468
• 32 Fukui K. Role of frontier orbitals in chemical reactions. Science 1982; 218: 747-754
• 33 Lewis DFV, Loannides C, Parke DV. Interaction of a series of nitriles with the alcoholinducible isoform of P450: Computer analysis of structure-activity relationships. Xenobiotica 1994; 24: 401-408
• 34 Zhou Z, Parr RG. Activation hardness: new index for describing the orientation of electrophilic aromatic substitution. J Am Chem Soc 1990; 112: 5720-5724