Design, synthesis and antiproliferative activity evaluation of EGFR inhibitors containing 3-hydroxy-4-pyridinone fragment

LIU Shen1 SHAO Jia-an2 YU Yong-ping1

(1.Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University, Hangzhou, China 310058)
(2.Department of Chemistry, College of Science, Zhejiang Sci-Tech University, Hangzhou, China 310018)

【Abstract】The development of multi-targeted tyrosine kinase inhibitors is of great significance for anti-cancer therapy. Epidermal growth factor receptor (EGFR) signaling pathway plays a crucial role in the apoptosis, proliferation, differentiation, migration and cell cycle of cancer cells. Meanwhile, Fe chelators are effective antitumor agents. By incorporating 3-hydroxy-4-pyridinone fragment (a Fe chelator motif) into the conventional quinazoline scaffold of EGFR inhibitors, 12 compounds which may target multiple drug targets were synthesized. The general procedure for the synthesis of target compounds was described and all of them were characterized by 1H-NMR, MS and melting point. In the tumor cell lines tested, most of the compounds exhibit efficient antiproliferative activity on the human epidermal carcinoma cell A431 (with EGFR overexpression) and HeLa, albeit a moderate inhibition in gefitinib-resistant NSCLC cell H1975 (bearing EGFR[L858R/T790M]).

【Keywords】 EGFR tyrosine kinase inhibitor; 4-anilinoquinazoline; 3-hydroxy-4-pyridinone; multiple-target; antiproliferative activity;

【DOI】

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    References

    [1] XIA G X, CHEN W T, ZHANG J, et al. A chemical tuned strategy to develop novel irreversible EGFRTK inhibitors with improved safety and pharmacokinetic profiles [J]. J M ed Chem, 2014, 57 (23): 9889–9900.

    [2] THOMAS S M, GRANDIS J R. Pharmacokinetic and pharmacodynamic properties of EGFR inhibitors under clinical investigation[J]. Cancer Treat Rev, 2004, 30 (3): 255–268.

    [3] MOULDER S L, YAKES F M, MUTHUSWAMY S K, et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo[J]. Cancer Res, 2001, 61 (24): 8887–8895.

    [4] DANCEY J E, FREIDLIN B. Targeting epidermal growth factor receptor—are we missing the mark?[J]. Lancet, 2003, 362 (9377): 62–64.

    [5] RANSON M. Epidermal growth factor receptor tyrosine kinase inhibitors [J]. Br J Cancer, 2004, 90 (12): 2250–2255.

    [6] KONECNY G E, PEGRAM M D, VENKATESAN N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab–treated breast cancer cells [J]. Cancer Res, 2006, 66 (3): 1630–639.

    [7] NOLTING M, SCHNEIDER M T, TREPEL M. Lapatinib recent results [J]. Cancer Res, 2014, 201 (201): 125–143.

    [8] RACHID Z, BRAHIMI F, KATSOULAS A, et al. The combitargeting concept: chemical dissection of the dual targeting properties of a series of “CombiTriazenes” [J]. J M ed Chem, 2003, 46 (20): 4313–4321.

    [9] DOMARKAS J, DUDOUIT F, WILLIAMS C, et al. The combitargeting concept: synthesis of stable nitrosoureas designed to inhibit the epidermal growth factor receptor (EGFR) [J]. J M ed Chem, 2006, 49 (12): 3544–3552.

    [10] CAI X, ZHAI H X, FORRESTER J, et al. Discovery of 7-(4- (3-ethylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer [J]. J M ed Chem, 2010, 53 (5): 2000–2009.

    [11] MAHBOOBI S, SELLMER A, WINKLER M, et al. Novel chimeric histone deacetylase inhibitors: a series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity [J]. J Med Chem, 2010, 53 (24): 8546–8555.

    [12] YU Y, KOVACEVIC Z, RICHARDSON D R. Tuning cell cycle regulation with an iron key [J]. Cell Cycle, 2007, 6 (16): 1982–1994.

    [13] DARIUS J R, THOMAS M M, SHAFIE N H, et al. Expanding horizons in iron chelation and the treatment of cancer: role of iron in the regulation of ER stress and the epithelial-mesenchymal transition [J]. Biochim Biophys Acta, 2014, 1845 (2): 166–181.

    [14] YU Y, DANUTA S, KALINOWS K, et al. Thiosemicarbazones from the old to new: iron chelators that are more than just ribonucleotide reductase inhibitors [J]. J Med Chem, 2009, 52 (17): 5271–5294.

This Article

ISSN:1005-0108

CN:21-1313/R

Vol 27, No. 01, Pages 1-7

February 2017

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Article Outline

Abstract

  • 1 Design of target compounds and synthetic routes
  • 2 Synthetic experiments
  • 3 Antiproliferative activity assay in vitro
  • References