Design, synthesis and antitumor activity of novel indolin-2-one derivatives containing 4-thiazolidinone moiety

Abstract

A series of novel indolin-2-one derivatives containing 4-thiazolidinone moiety(7a–7r) were synthesized and evaluated for their in vitro antitumour activities against MDA-MB-231(human breast cancer), H460(human lung cancer) and HT-29(human colon cancer) cell lines by standard 3-(4,5-dimethylthiazae-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Representative compounds(7d, 7k, 7m, 7p) with higher cytotoxicity were further examined against one normal cell line(WI-38, human fetal lung fibroblasts). The preliminary investigation shows that most of the compounds display moderate to excellent potency and high selectivity against different human cancer cell lines. In particular, the most potent compound 7m shows promising cytotoxicity against MDA-MB-231, H460 and HT-29 cell lines with IC₅₀ values of 0.78, 0.056 and 0.018 μmol/L, respectively. The potency is much higher than that of Sunitinib(IC₅₀=3.46 μmol/L against MDA-MB-231, IC₅₀=2.59 μmol/L against H460, IC₅₀=1.50 μmol/L against HT-29) by 4.4, 46.3 and 83.3 fold.

Keywords

Indolin-2-one / 4-Thiazolidinone / Antitumour activity

References

[1] LiaoH M, ChongL E, TanL, ChenX D, YouR, GongPChem. Res. Chinese Universities, 2014, 305759.

[2] KrugM, HilgerothAMini-Rev. Med. Chem., 2008, 8: 1312.

[3] JinK, ZhangX P, MaC H, XuY Y, YuanY M, XuW FBioorg. Med. Chem., 2013, 21: 2663.

[4] EbosJ M L, LeeC R, Cruz-MunozW, BjamasonG A, ChristensenJ G, KerbelR SCancer Cell, 2009, 15: 232.

[5] PanditB, SunY, ChenP, SackettD L, HuZ, RichW, LiC, LewisA, SchaeferK, LiP KBioorg. Med. Chem., 2006, 14: 6492.

[6] RothG J, HeckelA, ColbatzkyF, HandschuhS, KleyJ, Lehmann-LintzT, LotzR, Tontsch-GruntU, WalterR, HilbergFJ. Med. Chem., 2009, 52: 4466.

[7] ElbarbaryA A, KhodairA I, PedersenE B, NielsenCMonatsh. Chem., 1994, 125: 593.

[8] OttanaR, MaccariR, BarrecaM L, BrunoG, RotondoA, RossiA, ChiricostaG, di PaolaR, SautebinL, CuzzocreaS, VigoritaM GBioorg. Med. Chem., 2005, 13: 4243.

[9] ViciniP, GeronikakiA, AnastasiaK, IncertiM, ZaniFBioorg. Med. Chem., 2006, 14: 3859.

[10] OttanaR, CarottiS, MaccariR, LandiniI, ChiricostaG, CaciagliB, VigoritaM G, MiniEBioorg. Med. Chem. Lett., 2005, 15: 3930.

[11] ZhengW, DegterevA, HsuE, YuanJ, YuanCBioorg. Med. Chem. Lett., 2008, 18: 4932.

[12] SharathK, KothanahallyS, HanumappaA, HegdeM, NarasimhamurthyK H, RaghavanS C, RangappaK SEur. J. Med. Chem., 2014, 81: 341.

[13] CutshallN S, O’DayC, PrezhdoMBioorg. Med. Chem. Lett., 2005, 15: 3374.

[14] AhnJ H, KimS J, ParkW S, ChoS Y, HaJ D, KimS S, KangS K, JeongD G, JungS K, LeeS H, KimH M, ParkS K, LeeK H, LeeC W, RyuS E, ChoiJ KBioorg. Med. Chem. Lett., 2006, 16: 2996.

[15] DegterevA, LugovskoyA, CardoneM, MulleyB, WagnerG, MitchisonT, YuanJNat. Cell Biol., 2001, 3: 173.

[16] ZimenkovskyB, KazmirchukG, ZaprutkoL, ParaskiewiczA, MelzerE, LesykRAnn. Polish Chem. Soc., 2005, 1: 69

[17] WangS B, ZhaoY F, ZhangG G, LüY X, ZhangN, GongPEur. J. Med. Chem., 2011, 46: 3509.

[18] VartaleS P, PawarY D, HalikarN KHeterocyclic Letters, 2012, 2: 311

[19] HavrylyukD, MosulaL, ZimenkovskyB, VasylenkocO, GzellabA, LesykREur. J. Med. Chem., 2010, 45: 5012.

[20] BeauchardA, LaborieH, RouillardH, LozachO, FerandinY, GuévelR L, Guguen-GuillouzoC, MeijerL, BessonT, ThiéryVBioorg. Med. Chem., 2009, 17: 6257.

[21] MologniL, RostagnoR, BrussoloS, KnowlesP P, KjaerS, Murray-RustJ, RossoE, ZambonA, ScapozzaL, McDonaldN Q, LucchiniV, Gambacorti-PasseriniCBioorg. Med. Chem., 2010, 18: 1482.

[22] OhishiY, MukaiT, NagaharaM, YajimaM, KajikawaN, MiyaharaK, TakanoTChem. Pharm. Bull., 1990, 38: 1911.

[23] MomoseY, MeguroK, IkedaH, HatanakaC, OiS, SohdaTChem. Pharm. Bull., 1991, 39: 1440.

RIGHTS & PERMISSIONS

Jilin University, The Editorial Department of Chemical Research in Chinese Universities and Springer-Verlag GmbH