Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2363–2374 | Cite as

Synthesis and molecular docking study of novel alizarin derivatives containing phosphoryl amino acid moiety as potential antitumor agents

Original Research


Series of novel alizarin and phosphoryl amino acid scaffold (4a4d, 8a8d) were synthesized and evaluated for the suppression of cancer cell proliferation in vitro against MGC-803, HepG2, T24, NCI-H460, and SK-OV-3 cell lines by standard 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay compared with commercial anticancer drug doxorubicin. Interestingly, all newly synthesized compounds exhibited relatively high cytotoxicity compared with alizarin and low cytotoxicity against human normal liver cell line HL-7702 cells. Especially, compound 8d showed the best cytotoxicity against SK-OV-3 cells with IC50 7.09 µM, which was slightly worse than that of drug doxorubicin. The cell apoptosis-inducing activity of representative compound 8d in SK-OV-3 cells revealed that the anticancer activity of this compound depended on apoptosis of cancer cells via regulation of Bcl-2 family members, activation of caspase-9 and caspase-3. Cell cycle analysis confirmed that compound 8d mainly arrested SK-OV-3 cells in G2 stage. In addition, molecular docking studies were performed to position compound 8d into the telomerase (5CQG) active site to determine the probable binding model.


Alizarin Phosphoryl amino acid Antitumor Apoptosis Molecular docking 



This study was supported by the National Natural Science Foundation of China (No. 81260472, 21101035 and 21362002), Special Research Found for the Doctoral Program of Higher Education (NO. 20134504110002), the State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China (CMEMR2016-B06), a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. 1107047002).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1938_MOESM1_ESM.docx (594 kb)
Supplementary Information


  1. Bryan C, Rice C, Hoffman H, Harkisheimer M, Sweeney M, Skordalakes E (2015) Structural basis of Telomerase inhibition by the highly specific BIBR1532. Structure 23:1934–1942CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chen CL, Chang DM, Chen TC, Lee CC, Hsieh HH, Huang FC, Huang KF, Guh JH, Lin JJ, Huang HS (2013) Structure-based design, synthesis and evaluation of novel anthra[1,2-d]imidazole-6,11-dione derivatives as telomerase inhibitors and potential for cancer polypharmacology. Eur J Med Chem 60:29–41CrossRefPubMedGoogle Scholar
  3. Dass CR, Choong PF (2006) Carrier-mediated delivery of peptidic drugs for cancer therapy. Peptides 27:3020–3028CrossRefPubMedGoogle Scholar
  4. Deng JX, Sanchez T, Neamati N, Briggs JM (2006) Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors. J Med Chem 49:1684–1692CrossRefPubMedGoogle Scholar
  5. Dreicer R, Manola J, Roth BJ, See WA, Kuross S, Edelman MJ, Hudes GR, Wilding G (2004) Phase III trial of Methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the Urothelium. Cancer 100:1639–1645CrossRefPubMedGoogle Scholar
  6. Fang LY, Zhang GS, Li CL, Zheng XC, Zhu LZ, Xiao JJ, Szakacs G, Nadas J, Chan KK, Wang PG, Sun DX (2006) Discovery of a Daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance. J Med Chem 49:932–941CrossRefPubMedGoogle Scholar
  7. Huang HS, Huang KF, Li CL, Huang YY, Chiang YH, Huang FC, Lin JJ (2008) Synthesis, human telomerase inhibition and anti-proliferative studies of a series of 2,7-bis-substituted amido-anthraquinone derivatives. Bioor Med Chem 16:6976–6986CrossRefGoogle Scholar
  8. Jacquemin G, Margiotta D, Kasahara A, Bassoy EY, Walch M, Thiery J, Lieberman J, Martinvalet D (2015) Granzyme B-induced mitochondrial ROS are required for apoptosis. Cell Death Differ 22:862–874CrossRefPubMedGoogle Scholar
  9. Kamal A, Ramu R, Tekumalla V, Khanna GBR, Barkume MS, Juvekar AS, Zingde SM (2007) Synthesis, DNA binding, and cytotoxicity studies of pyrrolo[2,1-c][1,4]benzodiazepine-anthraquinone conjugates. Bioorg Med Chem 15:6868–6875CrossRefPubMedGoogle Scholar
  10. Kaneshiro T, Morioka T, Inamine M, Kinjo T, Arakaki J, Chiba I, Sunagawa N, Suzui M, Yoshimi N (2006) Anthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation. Eur J Pharmacol 553:46–53CrossRefPubMedGoogle Scholar
  11. Kharlamova TV (2009) Synthesis and HIV-1 RNase H-activity of new alizarin acetonyl derivatives. Chem Nat Compd 45:629–633CrossRefGoogle Scholar
  12. Kingston DGI, Snyder JP (2014) The quest for a simple bioactive analog of paclitaxel as a potential anticancer agent. Acc Chem Res 47:2682–2691CrossRefPubMedPubMedCentralGoogle Scholar
  13. Kluza J, Marchetti P, Gallego MA, Lancel S, Fournier C, Loyens A, Beauvillain JC, Bailly C (2004) Mitochondrial proliferation during apoptosis induced by anticancer agents: effects of doxorubicin and mitoxantrone on cancer and cardiac cells. Oncogene 23:7018–7030CrossRefPubMedGoogle Scholar
  14. Kortylewicz ZP, Galardy RE (1990) Phosphoramidate peptide inhibitors of human skin fibroblast collagenase. J Med Chem 33:263–273CrossRefPubMedGoogle Scholar
  15. Kukowska-Kaszuba M, Dzierzbicka K (2007) Synthesis and structure–activity studies of peptideacridine/acridone conjugates. Curr Med Chem 14:3079–3104CrossRefPubMedGoogle Scholar
  16. Kukowska-Kaszuba M, Dzierzbicka K, Serocki M, Skladanowski A (2011) Solid phase synthesis and biological activity of tuftsin conjugates. J Med Chem 54:2447–2454CrossRefPubMedGoogle Scholar
  17. Lee JH, Kim NW, Her E, Kim BK, Choi WS, Hwang KH, Choi DK, Lim BO, Han JW, Kim YM (2006) Rubiae radix suppresses the activation of mast cells through the inhibition of Syk kinase for anti-allergic activity. J Pharm Pharmacol 58:503–512CrossRefPubMedGoogle Scholar
  18. Lee YR, Yu DS, Liang YC, Huang KF, Chou SJ, Chen TC, Lee CC, Chen CL, Chiou SH, Huang HS (2013) New approaches of PARP-1 inhibitors in human lung cancer cells and cancer stem-like cells by some selected anthraquinone-derived small molecules. PLoS One 8:e56284CrossRefPubMedPubMedCentralGoogle Scholar
  19. Liang ZJ, Ai J, Ding X, Peng X, Zhang DY, Zhang RH, Wang Y, Liu F, Zheng MY, Jiang HL, Liu H, Geng MY, Luo C (2013) Anthraquinone derivatives as potent inhibitors of c‑met kinase and the extracellular signaling pathway. ACS Med Chem Lett 4:408–413CrossRefPubMedPubMedCentralGoogle Scholar
  20. Liu H, Dong A, Gao C, Tan C, Liu H, Zu X, Jiang Y (2008) The design, synthesis, and anti-tumor mechanism study of N-phosphoryl amino acid modified resveratrol analogues. Bioorg Med Chem 16:10013–10021CrossRefPubMedGoogle Scholar
  21. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229CrossRefPubMedGoogle Scholar
  22. Molavian HR, Goldman A, Phipps CJ, Kohandel M, Wouters BG, Sengupta S, Sivaloganathan S (2015) Drug-induced reactive oxygen species (ROS) rely on cell membrane properties to exert anticancer effects. Sci Rep 6:27439CrossRefGoogle Scholar
  23. Monneret C (2001) Recent developments in the field of antitumour anthracyclines. Eur J Med Chem 36:483–493CrossRefPubMedGoogle Scholar
  24. Morier-Teissier E, Boitte N, Helbecque N, Bernier JL, Pommery N, Duvalet JL, Fournier C, Hecquet B, Catteau JP, Henichart JP (1993) Synthesis and antitumor properties of an anthraquinone bisubstituted by the copper chelating peptide Gly-Gly-L-His. J Med Chem 36:2084–2090CrossRefPubMedGoogle Scholar
  25. Ottewell PD, Woodward JK, Lefley DV, Evans CA, Coleman RE, Holen I (2009) Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone. Mol Cancer Ther 8:2821–2832CrossRefPubMedGoogle Scholar
  26. Singh R, Chauhan SM, Geetanjali (2005) Anthraquinones and other biologically active compounds from the genus Rubia. J Chem Biodivers 1:1241–1264CrossRefGoogle Scholar
  27. Sridhar J, Liu J, Foroozesh M, Stevens CLK (2012) Inhibition of Cytochrome P450 enzymes by quinones and anthraquinones. Chem Res Toxicol 25:357–365CrossRefPubMedPubMedCentralGoogle Scholar
  28. Sun XB, Feng YP, Guo XF (2003) A green synthesis of diisopropyl phosphoryl amino acid. Chin Chem Lett 14:121–124Google Scholar
  29. Wang B, Jiang L, Wang J, Ma JB, Liu M, Yu HW (2009) A tandem and fully enzymatic procedure for the green resolution of chiral alcohols: acylation and deacylation in non-aqueous media. Tetrahedron 22:980–985CrossRefGoogle Scholar
  30. Ye MY, Yao GY, Pan YM, Liao ZX, Zhang Y, Wang HS (2014) Synthesis and antitumor activities of novel α-aminophosphonate derivatives containing an alizarin moiety. Eur J Med Chem 83:116–128CrossRefPubMedGoogle Scholar
  31. Yim H, Lee YH, Lee CH, Lee SK (1999) Emodin, an anthraquinone derivative isolated from the rhizomes of Rheum palmatum, selectively inhibits the activity of Casein kinase II as a competitive inhibitor. Planta Med 65:9–13CrossRefPubMedGoogle Scholar
  32. Zagotto G, Sissi C, Lucatello L, Pivetta C, Cadamuro SA, Fox KR, Neidle S, Palumbo M (2008) Aminoacyl-anthraquinone conjugates as telomerase inhibitors: synthesis, biophysical and biological evaluation. J Med Chem 51:5566–5574CrossRefPubMedGoogle Scholar
  33. Zheng GW, Yu HL, Zhang JD, Xu JH (2009) Enzymatic production of l-menthol by a high substrate concentration tolerable esterase from newly isolated Bacillus subtilis ECU0554. Adv Synth Catal 35:405–414CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Ri-zhen Huang
    • 1
  • Le Jin
    • 1
  • Gui-yang Yao
    • 1
  • Wei-long Dai
    • 2
  • Xiao-chao Huang
    • 1
  • Zhi-Xin Liao
    • 1
  • Heng-shan Wang
    • 2
  1. 1.Department of Pharmaceutical Engineering, School of Chemistry and Chemical EngineeringSoutheast UniversityNanjingPeople’s Republic of China
  2. 2.State Key Laboratory Cultivation Base for the Chemistry and Molecular Engineering of Medicinal ResourcesSchool of Chemistry & Pharmaceutical Sciences of Guangxi Normal UniversityGuilinPeople’s Republic of China

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