Medicinal Chemistry Research

, Volume 24, Issue 9, pp 3423–3436 | Cite as

Synthesis and anticancer activity of aminopropoxytriterpenoids

  • Gulnara V. Giniyatyllina
  • Irina E. Smirnova
  • Oxana B. Kazakova
  • Nadejda P. Yavorskaya
  • Irina S. Golubeva
  • Olga S. Zhukova
  • Rujena B. Pugacheva
  • Galina N. Apryshko
  • Vladimir V. Poroikov
Original Research


Triterpenoids with aminopropoxy groups in C-28 or C-3 and C-28 positions were synthesized from betulin, erythrodiol, uvaol, oleantriol and betulinic acid N-methylpiperazinylamide by cyanoethylation and the following catalytic hydrogenolysis. Computational estimating activity spectra of the designed compounds pointed out on their probable antineoplastic and proapoptotic activities. Their in vitro cytotoxic activity was evaluated at the National Cancer Institute, USA. Aminopropoxy derivatives of betulin, erythrodiol and oleantriol demonstrated the highest cytotoxic activity toward the most of 60 used tumor cell lines. Bisaminopropoxyerythrodiol revealed in vivo significant antineoplastic activity toward five mouse solid transplantable tumors. The results of in silico investigations and the efficacy of compounds in a broad panel of cell lines in vitro and the activity of bisaminopropoxyerythrodiol on the in vivo tumor models strongly suggest aminopropoxytriterpenoids as promising compounds for further investigation as anticancer agents.

Graphical Abstract


Synthesis Triterpenoids Cyanoethylation Aminopropoxy group Cytotoxicity Anticancer activity 



This work was supported by the grant to Russian Foundation for Basic Research (Project № 11-03-12144). We thank National Cancer Institute for screening of compounds 6, 7, 9, 10, 13, 14, 1618, 20 on human cancer cell lines. Spectroscopic studies were carried out using equipment available at the “Chemistry” User Facilities Center, Ufa Institute of Chemistry of Russian Academy of Sciences.


  1. Alley MC, Scudiero DA, Monks PA, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:589–601PubMedGoogle Scholar
  2. Antimonova AN, Uzenkova NV, Petrenko NI, Shakirov MM, Shul’ts EE, Tolstikov GA (2011) Synthetic transformations of higher terpenoids: XXIV. Synthesis of cyanoethyl derivatives of lupane triterpenoids and their transformation into 1,2,4-oxadiazoles. Russ J Organ Chem 47:589–601CrossRefGoogle Scholar
  3. Boyd MR, Paull KD (1995) Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Dev Res 34:91–109CrossRefGoogle Scholar
  4. Cassels BK, Asencio M (2011) Anti-HIV activity of natural triterpenoids and hemisynthetic derivatives 2004–2009. Phytochem Rev 10:545–564CrossRefGoogle Scholar
  5. Chen HL, Lin KW, Huang AM, Tu HY, Wei BL, Hour TC, Yen MH, Pu YS, Lin CN (2010) Terpenoids induce cell cycle arrest and apoptosis from the stems of Celastrus kusanoi associated with reactive oxygen species. J Agric Food Chem 58:3808–3812PubMedCrossRefGoogle Scholar
  6. Cheng KG, Su CH, Yang LD, Liu J, Chen Z (2015) Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity. Eur J Med Chem 89:480–489PubMedCrossRefGoogle Scholar
  7. Csuk R, Barthel A, Kluge R, Ströhl D (2010) Synthesis, cytotoxicity and liposome preparation of 28-acetylenic betulin derivatives. Bioorg Med Chem 18:7252–7259PubMedCrossRefGoogle Scholar
  8. Csuk R, Barthel A, Sczepek R, Siewert B, Schwarz S (2011) Improvement of the cytotoxicity and tumor selectivity of glycyrrhetinic acid by derivatization with bifunctional aminoacids. Arch Pharm 344:37–49CrossRefGoogle Scholar
  9. Csuk R, Nitsche C, Sczepek R, Schwarz S, Siewert B (2013a) Synthesis of antitumor-active betulinic acid-derived hydroxypropargylamines by copper-catalyzend mannich reactions. Arch Pharm Chem Life Sci 346:232–246CrossRefGoogle Scholar
  10. Csuk R, Sczepek R, Siewert B, Nitsche C (2013b) Cytotoxic betulin-derived hydroxypropargylamines trigger apoptosis. Bioorg Med Chem 21:425–435PubMedCrossRefGoogle Scholar
  11. Dzubak P, Hajduch M, Vydra D, Hustova A, Kvasnica M, Biedermann D, Markova L, Sarek J (2006) Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat Prod Rep 23:394–411PubMedCrossRefGoogle Scholar
  12. Filimonov DA, Poroikov VV (2006) Prediction of biological activity spectra for organic compounds. Zh Ross Khim J 50:66–75Google Scholar
  13. Filimonov DA, Poroikov VV (2008) Probabilistic approach in activity prediction. In: Varnek A, Tropsha A (eds) Chemoinformatics approaches to virtual screening. RSC Publishing, Cambridge (UK), pp 182–216CrossRefGoogle Scholar
  14. Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovsky DS, Pogodin PV, Poroikov VV (2014) Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem Heterocycl Comp 3:444–457CrossRefGoogle Scholar
  15. Flekhter OB, Karashurina LT, Nigmatullina LR, Sapozhnikova TA, Baltina LA, Zarudii FS, Galin FZ, Spirikhin LV, Tolstikov GA, Plyasunova OA, Pokrovskii AG (2000) Synthesis and pharmacological activity of betulin dinicotinate. Russ J Bioorg Chem 28:494–500CrossRefGoogle Scholar
  16. Flekhter OB, Medvedeva NI, Tolstikov GA, Galin FZ, Yunusov MS, Nguen HTM, Tien LV, Savinova OV, Boreko EI, Titov LP, Glukhov IV (2009) Synthesis of olean-18(19)-ene derivatives from betulin. Russ J Bioorg Chem 35:233–239CrossRefGoogle Scholar
  17. Geran RI, Greenberg NH, Macdonald MM, Schumacher AM, Abbott BS (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3:1–91Google Scholar
  18. Giniyatullina GV, Kazakova OB, Medvedeva NI, Sorokina IV, Zhukova NA, Tolstikova TG, Tolstikov GA (2013) Synthesis of aminopropylamino derivatives of betulinic and oleanolic acids. Russ J Bioorg Chem 39:329–337CrossRefGoogle Scholar
  19. Grever MR, Schepartz SA, Chabner BA (1992) The National Cancer Institute: cancer drug discovery and development program. Semin Oncol 19:622–638PubMedGoogle Scholar
  20. Hata K, Hori K, Ogasawara H, Takahashi S (2003) Anti-leukemia activities of Lup-28-al-20(29)-en-3-one, a lupane triterpene. Toxicol Lett 143:1–7PubMedCrossRefGoogle Scholar
  21. Jäger S, Winkler K, Pfüller U, Scheffler A (2007) Solubility studies of oleanolic acid and betulinic acid in aqueous solutions and plant extracts of Viscum album L. Planta Med 73:157–162PubMedCrossRefGoogle Scholar
  22. Juan ME, Wenzel U, Daniel H, Planas JM (2008) Erythrodiol, a natural triterpenoid from olives, has antiproliferative and apoptotic activity in HT-29 human adenocarcinoma cells. Mol Nutr Food Res 52:595–599PubMedCrossRefGoogle Scholar
  23. Kazakov DV, Kazakova OB, Ishmuratov GYu, Terent’ev AO, Nikishin GI, Tolstikov GA (2011) Chemiluminescence as a base for a new approach to the study of pharmacologically promising peroxide agents. Dokl Chem 436:34–38CrossRefGoogle Scholar
  24. Kazakov DV, Timerbaev AR, Safarov FE, Nazirov TI, Kazakova OB, Ishmuratov GY, Terent’ev AO, Borisov DA, Tolstikov AG, Tolstikov GA, Adam W (2012) Chemiluminescence from the biomimetic reaction of 1,2,4-trioxolanes and 1,2,4,5-tetroxanes with ferrous ions. RSC Adv 2:107–110CrossRefGoogle Scholar
  25. Kazakova OB, Giniyatullina GV, Tolstikov GA, Medvedeva NI, Utkina TM, Kartashova OL (2010a) Synthesis, modification, and antimicrobial activity of the N-methylpiperazinyl amides of triterpenic acids. Russ J Bioorg Chem 36:383–389CrossRefGoogle Scholar
  26. Kazakova OB, Tretyakova EV, Kukovinets OS, Abdrakhmanova AR, Kabalnova NN, Kazakov DV, Tolstikov GA, Gubaidullin AT (2010b) Synthesis of nontrivial quinopimaric acid derivatives by oxidation with dimethyldioxirane. Tetrahedron Lett 51:1832–1835CrossRefGoogle Scholar
  27. Kazakova OB, Yamansarov EYu, Kukovinets OS, Medvedeva NI, Kazakov DV, Kornilov OK, Suponitskii KYu (2011a) Anomalous ozonolysis product of 3β,28-di-O-acetyl-29-norlupan-20-one-O-methyloxime. Chem Nat Comp 47:738–740CrossRefGoogle Scholar
  28. Kazakova OB, Giniyatullina GV, Tolstikov GA (2011b) Synthesis of A-secomethylenamino- and substituted amidoximotriterpenoids. Russ J Bioorg Chem 37:619–625CrossRefGoogle Scholar
  29. Kazakova OB, Giniyatullina GV, Tolstikov GA, Baikova IP, Zaprutko L, Apryshko GN (2011c) Synthesis and antitumor activity of aminopropoxy derivatives of betulin, erythrodiol, and uvaol. Russ J Bioorg Chem 37:369–379CrossRefGoogle Scholar
  30. Kazakova OB, Kazakov DV, Yamansarov EYu, Medvedeva NI, Tolstikov GA, Suponitsky KYu, Arkhipov DE (2011d) Synthesis of triterpenoid-based 1,2,4-trioxolanes and 1,2,4-dioxazolidines by ozonolysis of allobetulin derivatives. Tetrahedron Lett 52:976–979CrossRefGoogle Scholar
  31. Kazakova OB, Smirnova IE, Do Tkhi Tkhu H, Nguen Tkhankh Tra, Apryshko GN, Zhukova OS, Medvedeva NI, Nazyrov TI, Tret’yakova EV, Chudov IV, Ismagilova AF, Suponitsky KY, Kazakov DV, Safarov FE, Tolstikov GA (2013) Synthesis, structure, and pharmacological activity of (7R,8S)-epoxy-(13R,17R)-trioxolane abietic acid. Russ J Bioorg Chem 39:202–211CrossRefGoogle Scholar
  32. Kim DS, Pezzuto JM, Pisha E (1998) Synthesis of betulinic acid derivatives with activity against human melanoma. Bioorg Med Chem Lett 8:1707–1712PubMedCrossRefGoogle Scholar
  33. Kommera H, Kaluderovic GN, Dittrich S, Kalbitz J, Dräger B, Müller T, Paschke R (2010) Carbamate derivatives of betulinic acid and betulin with selective cytotoxic activity. Bioorg Med Chem Lett 20:3409–3412PubMedCrossRefGoogle Scholar
  34. Kuo RY, Qian K, Morris-Natschke SL, Lee KH (2009) Plant derived tritepenes and analogues as antitumor anti HIV agents. Nat Prod Rep 26:1321–1344PubMedCentralPubMedCrossRefGoogle Scholar
  35. Laszczyk MN (2009) Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med 75:1549–1560PubMedCrossRefGoogle Scholar
  36. Laszczyk M, Jeger S, Simon-Haarhaus B, Scheffler A, Schempp CM (2006) Physical, chemical and pharmacological characterization of a new oleogel-forming triterpene extract from the outer bark of birch (betulae cortex). Planta Med 72:1389–1395PubMedCrossRefGoogle Scholar
  37. Liu X, Han X, Lin Y, Li Y, Li Q (2015) Influence of betulin in proliferation and apoptosis of human colon cancer SW480 cells. J Jilin Univ Med Edit 41:39–43Google Scholar
  38. Mahmoudi M, Rabe SZT, Balali-Mood M, Tabasi N, Riahi-Zanjani B (2015) Ursolic acid induced apoptotic cell death following activation of caspases in isolated human melanoma cells. Cell Biol Int 39:230–236PubMedCrossRefGoogle Scholar
  39. Martin R, Ibeas E, Carvalho-Tavares J, Hernandez M, Ruiz-Gutierrez V, Nieto ML (2009) Natural triterpenic diols promote apoptosis in astrocytoma cells through ROS-mediated mitochondrial depolarization and JNK activation. PLoS One 4:e5975PubMedCentralPubMedCrossRefGoogle Scholar
  40. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull KD, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, Campbell H, Mayo J, Boyd MJ (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Nat Cancer Inst 183:757–766CrossRefGoogle Scholar
  41. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Meth 65:55–63CrossRefGoogle Scholar
  42. Parra A, Martin-Fonseca S, Rivas F, Reyes-Zurita FJ, Medina-O’Donnell M, Rufino-Palomares EE, Martinez A, Garcia-Granados A, Lupiañez JA, Albericio F (2014) Solid-phase library synthesis of bi-functional derivatives of oleanolic and maslinic acids and their cytotoxicity on three cancer cell lines. ACS Comb Sci 16:428–447PubMedCrossRefGoogle Scholar
  43. Pyo JS, Roh SH, Kim DK, Lee JG, Lee YY (2009) Anti-cancer effect of betulin on a human lung cancer cell line: a pharmacoproteomic approach using 2 D SDS Page coupled with nano-HPLC tandem mass spectrometry. Planta Med 75:127–131PubMedCrossRefGoogle Scholar
  44. Salvador JAR, Moreira VM, Gonçalves BMF, Leal AS, Jing Y (2012) Ursane-type pentacyclic triterpenoids as useful platforms to discover anticancer drugs. Nat Prod Rep 29:1463–1479PubMedCrossRefGoogle Scholar
  45. Shanmugam MK, AnH Nguyen, Kumar AP, Tan BKH, Sethi G (2012) Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: potential role in prevention and therapy of cancer. Cancer Lett 320:158–170PubMedCrossRefGoogle Scholar
  46. Sheng H, Sun H (2010) Synthesis, biology and clinical significance of pentacyclic triterpenes: a multi-target approach to prevention and treatment of metabolic and vascular diseases. Nat Prod Rep 28:543–593CrossRefGoogle Scholar
  47. Shoemaker RH (2006) The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer 6:813–826PubMedCrossRefGoogle Scholar
  48. Smirnova IE, Kazakova OB, Huong DTT, Minnibaeva EM, Lobov AN, Suponitsky KYu (2014) One–pot synthesis of hollongdione from dipterocarpol. Nat Prod Commun 9:1417–1420PubMedGoogle Scholar
  49. Smirnova IE, Kazakova OB, Viet DQ, Nguyen TT, Linh PT, Huong DTT (2015) Synthesis and evaluation of 29-norcycloartane triterpenoids as α-glucosidase inhibitors. Med Chem Res. doi: 10.1007/s00044-014-1292-6 Google Scholar
  50. Thibeault D, Legault J, Bouchard J, Pichette A (2007) Useful approach to access germanicanes from Betulin. Tetrahedron Lett 48:8416–8419CrossRefGoogle Scholar
  51. Treshalina EM, Jukova OS, Gerasimova GK, Andronova NV, Garin AM (2012) In: Guide to carrying out preclinical researches of medicines. Part 1. Ed. A.N. Mironov. Moscow, Grif and Ko, 640Google Scholar
  52. Tret’yakova EV, Smirnova IE, Kazakova OB, Yavorskaya NP, Golubeva IS, Zhukova OS, Pugacheva RB, Apryshko GN, Poroikov VV (2014) Synthesis and anticancer activity of quinopimaric and maleopimaric acid’s derivatives. Bioorg Med Chem 22:6481–6489CrossRefGoogle Scholar
  53. Wang SR, Fang WS (2009) Pentacyclic triterpenoids and their saponins with apoptosis-inducing activity. Curr Topics Med Chem 9:1581–1596CrossRefGoogle Scholar
  54. Weinstein JN, Myers TG, O’Connor PM, Friend SH, Fornace AJ Jr, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, van Osdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE, Paull KD (1997) An information-intensive approach to the molecular pharmacology of cancer. Science 275:343–349PubMedCrossRefGoogle Scholar
  55. Yamansarov EYu, Kazakova OB, Lobov AN, Kazakov DV, Suponitskii KYu (2015) Synthesis of a triterpenoid with a 1,2,4,5-tetraoxane fragment. Chem Nat Comp 51:97–102CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Gulnara V. Giniyatyllina
    • 1
  • Irina E. Smirnova
    • 1
  • Oxana B. Kazakova
    • 1
  • Nadejda P. Yavorskaya
    • 2
  • Irina S. Golubeva
    • 2
  • Olga S. Zhukova
    • 2
  • Rujena B. Pugacheva
    • 2
  • Galina N. Apryshko
    • 2
  • Vladimir V. Poroikov
    • 3
  1. 1.Ufa Institute of ChemistryRussian Academy of SciencesUfaRussian Federation
  2. 2.N.N. Blokhin Russian Cancer Research CenterMoscowRussian Federation
  3. 3.V.N. Orekhovich Institute of Biomedical ChemistryMoscowRussian Federation

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