To design and synthesize a novel class of antitumor agents, featuring the 3, 5-substituted indolin-2-one framework.
Based on enzyme binding features of (Z)-SU5402, introducing a β-pyrrole group at the 3-position of the indolin-2-one core, a series of novel 3,5-substituted indolin-2-ones were designed and synthesized. Four human carcinoma cell lines of A-431, A-549, MDA-MB-468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay.
Twenty new compounds (1a–t) with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra, and confirmed by X-ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor tyrosine kinases, the cell-based antitumor activity was promising. Compounds 1g and 1h showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC50 of 0.065–9.4 umol/L.
This study provides a new template for further development of potent antitumor drugs.
Ullrich A, Schlessinger J . Signal transduction by receptors with tyrosine kinase activity. Cell 1990; 61: 203–12.
Aaronson SA . Growth factors and cancer. Science 1991; 254: 1146–53.
Boschelli DH, Wu Z, Klutchko SR, Showalter HDH, Hamby JM, Lu GH, et al. Synthesis and tyrosine kinase inhibitory activity of a series of 2-amino-8 H-pyrido[2,3- d]pyrimidines: identification of potent, selective platelet-derived growth factor receptor tyrosine kinase inhibitors. J Med Chem 1998; 41: 4365–77.
Alexander JB . Chemical inhibitors of protein kinases. Chem Rev 2001; 101: 2541–72.
Traxler P, Furet P . Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. Pharmacol Ther 1999; 82: 195–206.
Cance WG, Liu ET . Protein kinase in human breast cancer. Breast Cancer Res Treat 1995; 35: 105–14.
Chrysogelos SA, Dickson RB . Egf receptor expression, regulation, and function in breast cancer. Breast Cancer Res Treat 1994; 29: 29–40.
Yang EB, Wang DF, Cheng Y, Mack P . Expression and functions of growth-factors and growth-factor receptors in liver-cancer. Cancer J 1997; 10: 319–24.
Yang EB, Guo YJ, Zhang K, Chen YZ, Mack P . Inhibition of epidermal growth factor receptor tyrosine kinase by chalcome derivatives. Biochim Biophys Acta 2001; 1550: 144–50.
Traxler P, Bold G, Buchdunger E, Caravatti G, Furet P, Manley P, et al. Tyrosine kinase inhibitors: from rational design to clinical trials. J Med Res Rev 2001; 21: 499–512.
Kurup A, Garg R, Hansch C . Comparative QSAR study of tyrosine kinase inhibitors. Chem Rev 2001; 101: 2573–600.
Khazaie K, Schirrmacher V, Lichtner RB . EGF receptor in neo-plasia and metastasis. Cancer Metast Rev 1993; 12: 255–74.
Fry DW, Kraker AJ, McMichael A, Ambroso LA, Nelson JM, Leopold WR, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 1994; 265: 1093–5.
Smaill JB, Rewcastle GW, Loo JA, Greis KD, Chan OH, Reyner, EL, et al. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino) quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 2000; 43: 1380–97.
Traxeler P, Bold G, Frei J, Lang M, Lydon N, Mett H, et al. Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4- d]pyrimidines. J Med Chem 1997; 40: 3601–16.
Wissner A, Overbeek E, Reich MF, Floyd MB, Johnson BD, Mamuya N, et al. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3- carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem 2003; 46: 49–63.
Palmer BD, Trumpp-Kallmeyer S, Fry DW, Nelson JM, Showalter HDH, Denny WA . Tyrosine kinase inhibitors. 11. Soluble analogues of pyrrolo- and pyrazoloquinazolines as epidermal growth factor receptor inhibitors: synthesis, biological evaluation, and modeling of the mode of binding. J Med Chem 1997; 40: 1519–29.
Sun L, Tran N, Liang C, Tang F, Rice A, Schreck R, et al. Design, synthesis, and evaluations of substituted 3-[(3-or4-carboxyethyl-pyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases. J Med Chem 1999; 42: 5120–30.
Sun L, Tran N, Tang F, App H, McMahon G, Tang C . Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J Med Chem 1998; 41: 2588–603.
Mohammadi M, McMahon G . Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 1997; 276: 955–60.
Battersby AR, Hunt E, McDonald E, Paine III JB, Saunders J . Biosynthesis of porphrins and related macrocycles. Part VIII. Enzymic decarboxylation of uroporphyrinogen-III: structure of an intermediate, phyriaporphyrinogen-III, and synthesis of the corresponding porphyrin and of two isomeric porphrins. J Chem Soc Perk I 1976; 1008–21.
Guo XN, Zhong L, Zhang XH, Zhao WM, Zhang XW, Lin LP, et al. Evaluation of active recombinant catalytic domain of human ErbB-2 tyrosine kinase, and suppression of activity by a naturally derived inhibitor, ZH-4B. Biochim Biophys Acta 2004; 1673: 186–93.
Wang S, Yang D, Enyedy I . Erbb-2 selective small molecule kinase inhibitors. US patent 2004023957-A1. 2004.
Mosmann T . An in vitro murine model of a penicillin specific IgE anamnestic response. J Immunol Methods 1983; 139: 55–60.
Origin. Version 7.0. Northampton, MA: Microcal Software Inc, 2002. [ cited 2005 Jul 20]. Available from: http://www.microcal.com.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucleic Acids Res 2000; 28: 235–42.
Sybyl molecular modeling package (Computer program). Version 6.8. St Louis, MO: Tripos Associates, 2000.
Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C, Alagona G, et al. A new force field for molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 1984; 106: 765–84.
Gasteiger J, Marsili M . Iterative partial equalization of orbital electronegativity — a rapid access to atomic charges. Tetrahedron 1980; 36: 3219–88.
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998; 19: 1639–62.
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Autodock (Version 3.0.3), Molecular Graphics Laboratory, Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA. 1999.
Case DA, Pearlman DA, Caldwell JW, Cheatham TE III, Ross WS, Simmerling CL, et al. AMBER 5.1, 5th ed, San Francisco, CA: University of California; 1997.
Liu H, Li Y, Song M, Tan X, Cheng F, Zheng S, et al. Structure-based discovery of potassium channel blockers from natural products: virtual screening and electrophysiological assay testing. Chem Biol 2003; 10: 1103–13.
POV-ray. Version 3. POV-ray-Team, 1999. [ cited 2005 Jul 20]. Available from: http://www.povray.org.
Usack KP, Arnold LD, Barberis CE, Chen HP, Ericsson AM, Gaza-Bulseco GS, et al. A 13C NMR approach to categorizing potential limitations of a, b-unsaturated carbonyl systems in drug-like molecules. Bioorg Med Chem Lett 2004; 14: 5503–7.
John B, Dolphin D . Pyrrole chemistry. An improved synthesis of ethyl pyrrole-2-carboxylate esters from diethyl aminomalonate. J Org Chem 1985; 50: 5598–604.
Sheldrick GM . SHELXS-97: Program for the solution of crystal structure. Germany: Goettingen Univ; 1997.
Beurskens PT, Admiraal B, Beurskens G, Bosman WP, Garcia-Granda S, Gould RO, et al. The DIRIDIF-94 program system. Technical report of the crystallography laboratory. The Netherlands: University of Nijmegen, 1994.
Cromer DT, Waber JT . International tables for X-ray crystallography. Vol 4. Kynoch Press and Birmingham: England, 1974.
Ibers JA, Hamilton WC . Dispersion corrections and crystal structure refinements. Acta Cryst 1964; 17: 781–2.
Creagh DC, Hubbell JH . International tables for crystallography. In: Wilson AJC editor. Boston: Kluwer Academic Publishers: 1992.
Project supported by the State Key Program of Basic Research of China (No 2002CB512802), the 863 Hi-Tech Program (No 2002AA233061 and 2003AA235011), the National Natural Science Foundation of China (No 20372069, 29725203 and 20472094).
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Li, Hh., Zhang, Xh., Tan, Jz. et al. Design, synthesis, antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives. Acta Pharmacol Sin 28, 140–152 (2007). https://doi.org/10.1111/j.1745-7254.2007.00473.x
- protein-tyrosine kinase
- antitumor drug screening assays
- drug design
- molecular models
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