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Synthesis of new indirubin derivatives and their in vitro anticancer activity

  • Dan Trong Nguyen
  • Giang Nguyen Truong
  • Truong Van Vuong
  • Tai Nguyen Van
  • Cuong Nguyen Manh
  • Cuong To Dao
  • Thuy Dinh Thi Thuy
  • Chinh Luu Van
  • Vu Tran Khac
Original Paper
  • 9 Downloads

Abstract

The opening of epoxy rings from (2′Z)-N-1-(oxiran-2-ylmethyl)indirubin (2) and (2′Z-3′E)-indirubin-3ʹ-[O-oxiran-2-ylmethyl)oxime] (6) with thiols gave 17 new derivatives of indirubin in good yields. Their structures were elucidated by 1D-, 2D-NMR and HRMS spectra. Screening for anticancer activity was performed with four human cancer cell lines: SW480, LU-1, HepG2 and HL-60 in comparison with indirubin, indirubin-3′-oxime and 6-mercaptopurine. The results showed that cytotoxic and anti-proliferative activities of five derivatives were found in the range of 1.35–19.24 µM. Among synthesized derivatives, 4f showed the strongest activity against all four tested cancer cell lines with IC50 values of 1.65, 2.21, 1.90 and 1.35 µM, respectively.

Keywords

Indirubin Indirubin-3′-oxime 6-mercaptopurine Cytotoxic 

Notes

Acknowledgements

The authors gratefully acknowledge Vietnam-Russia Tropical Center and Vietnam Academy of Science and Technology (VAST) for financial support via project VAST.HTQT.BELARUS.04/15-16.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.

References

  1. Bektas I, Karaman S, Diraz E, Celik M (2016) The role of natural indigo dye in alleviation of genotoxicity of sodium dithionite as reducing agent. Cytotechnology 63:2245–2255.  https://doi.org/10.1007/s10616-016-0018-7 CrossRefGoogle Scholar
  2. Choi OM, Cho YH, Choi S, Lee SH, Seo SH, Kim HY, Han G, Min DS, Park T, Choi KY (2014) The small molecule indirubin-3′-oxime activates Wnt/b-catenin signaling and inhibits adipocyte differentiation and obesity. Int J Obes 38:1044–1052.  https://doi.org/10.1038/ijo.2013.209 CrossRefGoogle Scholar
  3. Cuong NM, Thuy DTT, Ha NV, Tai BH (2007) Isolation of indirubin from the leaves of Strobilanthes cusia. J Sci Technol 45(3A):195–199Google Scholar
  4. Cuong NM, Tai BH, Hoan DH, Long PQ, Choi EM, Kim YH (2010a) Synthesis and anti-osteoporosis potential of two new indirubin-3-oxime derivatives. J Korean Soc Appl Biol Chem 53:22–26.  https://doi.org/10.3839/jksabc.2010.004 CrossRefGoogle Scholar
  5. Cuong NM, Tai BH, Hoan DH, Huong TT, Kim YH, Hyun JH, Kang HK (2010b) Inhibitory effects of indirubin derivatives on the growth of HL-60 leukemia cell. Nat Prod Commun 5:103–106PubMedGoogle Scholar
  6. Cuong NM, Tai BH, Hoan DH (2010c) Studies on acetylation and NMR reassignment of indirubin derivatives. Nat Prod Res 24:99–105.  https://doi.org/10.1080/14786410802300469 CrossRefPubMedGoogle Scholar
  7. Gilani SJ, Khan SA, Alam O, Siddiqui N (2011) Synthesis and in vitro antimicrobial evaluation of condensed heterocyclic 6-substituted 1,2,4-triazolo-[3.4-b]-1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives of isoniazid. Acta Pol Pharm 68:205–211PubMedGoogle Scholar
  8. Girard SK, Mialou V, Chebel A, Chien WW, Tigaud I, Mokdad F, Badiou C, Ffrench M (2007) Inhibition of normal lymphocyte proliferation by Indirubin-30-monoxime: a multifactorial process. Leukemia & Lymphoma 48:605–615.  https://doi.org/10.1080/10428190601059696 CrossRefGoogle Scholar
  9. Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P, Leost M, Damiens E, Marie D, Marko D, Niederberger E, Tang W, Eisenbrand G, Meijer L (1999) Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol 1:60–67.  https://doi.org/10.1038/9035 CrossRefPubMedGoogle Scholar
  10. Ichimaru Y, Saito H, Uchiyama T, Metori K, Tabata K, Suzuki T, Miyairi S (2015) Indirubin 3´-(O-oxiran-2-ylmethyl)oxime: a novel anticancer agent. Bioorg Med Chem Lett 25:1403–1406.  https://doi.org/10.1016/j.bmcl.2015.02.053 CrossRefPubMedGoogle Scholar
  11. Jung ME, Byun BJ, Kim HM, Lee JY, Park JH, Lee N, Son YH, Choi SU, Yang KM, Kim SJ, Lee KH, Kim YC, Choi G (2016) Discovery of indirubin derivatives as new class of DRAK2 inhibitors from high throughput screening. Bioorganic Med Chem Lett 26:2719–2723.  https://doi.org/10.1016/j.bmcl.2016.03.111 CrossRefGoogle Scholar
  12. Karapetyan G, Chakrabarty K, Hein M, Langer P (2011) Synthesis and Bioactivity of carbohydrate derivatives of indigo, its isomers and heteroanalogues. Med Chem Med 6:25–37.  https://doi.org/10.1002/cmdc.201000374 CrossRefGoogle Scholar
  13. Lectere S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernard J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L (2001) Indirubins inhibit glycogen synthase kinase-3β and CDK5/P25, two protein kinases involved abnormal tau phosphorylation in alzheimer’s disease. J Biol Chem 276:251–260.  https://doi.org/10.1074/jbc.M002466200 CrossRefGoogle Scholar
  14. Liao XM, Leung KN (2013) Indirubin-3-oxime induces mytochondrial dysfunction and triggers growth inhibition in cell cycle arrest in human neuroblastoma cells. Oncol Rep 29:371–379.  https://doi.org/10.3892/or.2012.2094 CrossRefPubMedGoogle Scholar
  15. Lo WY, Chang NW (2013) An indirubin derivative, indirubin-3′-monoxime suppresses oral cancer tumorigenesis through the down regulation of survivin. PLoS ONE.  https://doi.org/10.1371/journal.pone.0070198 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Meijer L, Skaltsounis AL, Magiatis P, Polychronopoulos P, Leost M, Ryan XP, Vonica CA, Brivanlou A, Dajani R, Crovace C, Tarricone C, Musacchio A, Roe SM, Pearl L, Greengard P (2003) GSK-3-Selective inhibitors derived from tyrian purple indirubins. Chem Biol 10:1255–1266.  https://doi.org/10.1016/j.chembiol.2003.11.010 CrossRefPubMedGoogle Scholar
  17. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst 83:757–766.  https://doi.org/10.1093/jnci/83.11.757 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Nam SK, Buettner R, Turkson J, Kim DH, Cheng JQ, Muehlbeyer S, Hippe F, Vatter S, Merz KH, Eisenbrand G, Jove R (2005) Indirubin derivatives inhibit stat3 signaling and induce apoptosis in human cancer cells. PNAS 102:5998–6003.  https://doi.org/10.1073/pnas.0409467102 CrossRefPubMedGoogle Scholar
  19. Perrin DD, Armarego WLF (1988) Purification of Laboratory Chemical, 3rd edn. Pergamon Press, OxfordGoogle Scholar
  20. Raju GN, Prathyusha TG, Sowmya PL, Mounika SJ, Nadendla RR (2015) Synthesis, characterization and biological activity of some 1,3,4-oxadiazole derivatives with benzothiazole moiety. Der Pharmacia Sinica 6:1–8Google Scholar
  21. Riepl HM, Urmann C (2012) Improved synthesis of indirubin derivatives by sequential Buid-up of indoxyl unit: first preparation of fluorescent indirubins. Helv Chim Acta 95:1461–1477.  https://doi.org/10.1002/hlca.201200042 CrossRefGoogle Scholar
  22. Sano M, Ichimaru Y, Kurita M, Hayashi E, Homma T, Saito H, Masuda S, Nemoto N, Hemmi A, Suzuki T, Miyairi S, Hao H (2017) Induction of cell death in pancreatic ductal adenocarcinoma by indirubin 3′-oxime and 5-methoxyindirubin 3′-oxime in vitro and in vivo. Can Lett 397:72–82.  https://doi.org/10.1016/j.canlet.2017.03.031 CrossRefGoogle Scholar
  23. Stasiak N, Koch WK, Glowniak K (2014) Modern industrial and pharmacological applications of indigo dye and its derivatives—a review. Acta Poloniae Pharmaceutica Drug Research 71:215–221Google Scholar
  24. Vaughan JR (1957) Heterocyclic sulphonamides. US patent 2783240Google Scholar
  25. Xiao Hao Y, Liu B, Qian L (2002) Indirubin and Mesoindigo in the Treatment of Chronic Myelogenous Leukemia in China. Leukemia and lymphoma 43:1763–1768CrossRefPubMedGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  • Dan Trong Nguyen
    • 1
  • Giang Nguyen Truong
    • 1
  • Truong Van Vuong
    • 1
  • Tai Nguyen Van
    • 2
  • Cuong Nguyen Manh
    • 2
  • Cuong To Dao
    • 2
  • Thuy Dinh Thi Thuy
    • 2
  • Chinh Luu Van
    • 2
    • 3
  • Vu Tran Khac
    • 4
  1. 1.Vietnam-Russia Tropical CenterHanoiVietnam
  2. 2.Institute of Natural Products ChemistryVietnam Academy of Science and TechnologyHanoiVietnam
  3. 3.Graduate University of Science and TechnologyHanoiVietnam
  4. 4.School of Chemical EngineeringHanoi University of Science and TechnologyHanoiVietnam

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