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Medicinal Chemistry Research

, Volume 26, Issue 3, pp 518–531 | Cite as

Triphenylphosphonium cations of betulinic acid derivatives: synthesis and antitumor activity

  • Anna Yu. Spivak
  • Darya A. Nedopekina
  • Rezeda R. Khalitova
  • Rinat R. Gubaidullin
  • Viktor N. Odinokov
  • Yuriy P. Bel’skii
  • Natalia V. Bel’skaya
  • Veniamin A. Khazanov
Original Research

Abstract

A series of lupane triterpenoid conjugates with the triphenylphosphonium cation, in which the terpenoid molecules are linked to one or two triphenylphosphonium moieties at the С-2, С-28, or С-30 positions by carbon–carbon or ester bonds, have been designed and synthesized as potential anti-cancer agents. The pharmacological results showed that all of the prepared triphenylphosphonium salts displayed considerable antitumor activities against the tested cancer murine tumor (Ehrlich ascites carcinoma, (Р-815), and human tumor (MCF-7) (IC50 < 2 μg/mL)) cell lines. The presence of the triphenylphosphonium cation in the triterpenoid conjugates markedly enhanced the cytotoxic action as compared to the parent compound (betulinic acid) (IC50 24.7 μg/mL for Ehrlich cells and 18.7 μg/mL for Р-815 cells), while the correlation between the cytotoxic activity and the chemical structure of phosphonium salts was not observed.

Keywords

Pentacyclic triterpenoids Betulin Betulinic acid Triphenylphosphonium derivatives Anticancer agents 

Notes

Acknowledgements

The authors are deeply thankful to the staff members of the analytical center “Agidel” at Institute of Petrochemistry and Catalysis of RAS for spectral measurement. This work was performed under financial support from the Russian Science Foundation (Grant 16-13-10051).

Compliance with ethical standards

Conflict of interest

The authors declare no Conflict of interest.

Supplementary material

44_2016_1771_MOESM1_ESM.doc (14.4 mb)
Supplementary Material

References

  1. Alkhaldi AAM, Martinek J, Panicucci B, Dardonville C, Zikova A, Koning HP (2016) Trypanocidal action of bisphosphonium salts through a mitochondrial target in bloodstream form Trypanosoma brucei. Int J Parasitol 6:23–34Google Scholar
  2. Biedermann D, Eignerova B, Hajduch M, Sarek J (2010) Synthesis and evaluation of biological activity of the quaternary ammonium salts of lupane-, oleanane-, and ursane-type acids. Synthesis (Mass) 18:3839–3848Google Scholar
  3. Chintharlapalli S, Papineni S, Lei P, Pathi S, Safe S (2011) Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer 11:371–383CrossRefPubMedPubMedCentralGoogle Scholar
  4. Cichewicz RA, Kouzi SA (2004) Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Med Res Rev 24:90–114CrossRefPubMedGoogle Scholar
  5. Csuk R (2014) Betulinic acid and its derivatives: a patent review (2008–2013). Expert Opin Ther Patents 24:913–923CrossRefGoogle Scholar
  6. Damle AA, Pawar YP, Narkar AA (2013) Anticancer activity of betulinic acid on MCF-7 tumors in nude mice. Indian J Exper Biol 51:485–491Google Scholar
  7. Fetisova EK, Avetisyan AV, Izyumov DS, Korotetskaya MV, Chernyak BV, Skulachev VP (2010) Mitochondria-targeted antioxidant SkQR1 selectively protects MDR (Pgp 170)-negative cells against oxidative stress. FEBS Lett 584:562–566CrossRefPubMedGoogle Scholar
  8. Fulda S (2008) Betulinic acid for cancer treatment and prevention. Int J Mol Sci 9:1096–1107CrossRefPubMedPubMedCentralGoogle Scholar
  9. Fulda S, Kroemer G (2009) Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov Today 14:885–890CrossRefPubMedGoogle Scholar
  10. Fulda S (2009) Betulinic acid: A natural product with anticancer activity. Mol Nutr Food Res 53:140–146CrossRefPubMedGoogle Scholar
  11. Fulda S, Galluzzi L, Kroemer G (2010) Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9:447–464CrossRefPubMedGoogle Scholar
  12. Fulda S, Kroemer G (2011) Mitochondria as therapeutic targets for the treatment of malignant disease. Antioxid Redox Signal 15:2937–2949CrossRefPubMedGoogle Scholar
  13. Han M, Vakili MR, Abyaneh HS, Molavi O, Lai R, Lavasanifar A (2014) Mitochondrial delivery of doxorubicin via triphenylphosphine modification for overcoming drug resistance in MDA-MB-435/DOX cells. Mol Pharm 11:2640–2649CrossRefPubMedGoogle Scholar
  14. Jara JA, Castro-Castillo V, Saavedra-Olavarría J, Peredo L, Pavanni M, Jana F, Letelier ME, Parra E, Becker MI, Morello A, Kemmerling U, Maya JD, Ferreira J (2014) Antiproliferative and uncoupling effects of delocalized, lipophilic, cationic gallic acid derivatives on cancer cell lines. Validation in vivo in singenic mice. J Med Chem 57:2440–2454CrossRefPubMedGoogle Scholar
  15. Jeong H-J, Chai HB, Park S-Y, Kim DSHL (1999) Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Bioorg Med Chem Lett 9:1201–1204CrossRefPubMedGoogle Scholar
  16. Kessler JH, Mullauer FB, Roo GM, Medema JP (2007) Broad in vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types. Cancer Lett 251:132–145CrossRefPubMedGoogle Scholar
  17. Kim DSHL, Chen Z, Ngugen VT, Pezzuto JM, Qui S, Lu Z-Z (1997) A concise semi-synthetic approach to betulinic acid from betulin. Synth Commun 27:1607–1612CrossRefGoogle Scholar
  18. Kovarova J, Bajzikova M, Vondrusova M, Stursa J, Goodwin J, Nguyen M, Zobalova R, Pesdar EA, Truksa J, Tomasetti M, Dong L-F, Neuzil J (2014) Mitochondrial targeting of α-tocopheryl succinate enhances its anti-mesothelioma efficacy. Redox Rep 19:16–25CrossRefPubMedGoogle Scholar
  19. Kuznetsova SA, Vasilèva NYu, Kalacheva GS, Titova NM, Red’kina ES, Skvortsova GP (2008) Obtaining betulin diacetate from the outer birch bark and studying it’s antioxidant activity. J Siberian Federal Univ Chem 2:151–165Google Scholar
  20. Kvasnica M, Sarek J, Klinotova E, Dzubak P, Hajduch M (2005) Synthesis of phthalates of betulinic acid and betulin with cytotoxic activity. Bioorg Med Chem 13:3447–3454CrossRefPubMedGoogle Scholar
  21. Marrache S, Pathak RK, Dhar S (2014) Detouring of cisplatin to access mitochondrial genome for overcoming resistance. PNAS 111:10444–10449CrossRefPubMedPubMedCentralGoogle Scholar
  22. Modica-Napolitano JS, Kulawiec M, Singh KK (2007) Mitochondria and human cancer. Curr Mol Med 7:121–131CrossRefPubMedGoogle Scholar
  23. Mukherjee R, Jaggi M, Rajendran P, Srivastava SK, Siddiqui MJAS, Vardhan A, Burman AC (2004) Synthesis of 3-O-acyl/3-benzylidene/3-hydrazone/3-hydrazine/17-carboxyacryloyl ester derivatives of betulinic acid as anti-angiogenic agents. Bioorg Med Chem Letters 14:3169–3172CrossRefGoogle Scholar
  24. Mukherjee R, Kumar V, Srivastava SK, Agarwal SK, Burman AC (2006) Betulinic acid derivatives as anticancer agents: structure activity relationship. Anti-Cancer Agents Med Chem 6:271–279CrossRefGoogle Scholar
  25. Mullauer FB, Bloois L, Daalhuisen JB, Brink MST, Storm G, Medema JP, Schiffelers RM, Kessler JH (2011) Betulinic acid delivered in liposomes reduces growth of human lung and colon cancers in mice without causing systemic toxicity. Anticancer Drugs 22:223–233CrossRefPubMedGoogle Scholar
  26. Mullauer FB, Kessler JH, Medema JP (2010) Betulinic acid, a natural compound with potent anti-cancer effects. Anticancer Drugs 21:215–227CrossRefPubMedGoogle Scholar
  27. Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CWW, Fong HHS, Kinghorn AD, Brown DM, Wani MC, Wall ME, Hieken TJ, Das Gupta TK, Pezzuto JM (1995) Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1:1046–1051CrossRefPubMedGoogle Scholar
  28. Qian K, Yu D, Chen Ch-H, Huang L, Morris-Natschke SL, Nitz TJ, Salzwedel K, Reddick M, Allaway GP, Lee K-H (2009) Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents. J Med Chem 52:3248–3258CrossRefPubMedPubMedCentralGoogle Scholar
  29. Reddy CA, Somepalli V, Golakoti T, Kanugula AK, Karnewar S, Rajendiran K, Vasagiri N, Prabhakar S, Kuppusamy P, Kotamraju S, Kutala VK (2014) Mitochondrial-targeted curcuminoids: a strategy to enhance bioavailability and anticancer efficacy of curcumin. PLoS One 9:89351CrossRefGoogle Scholar
  30. Ross MF, Ros T, Blaikie FH, Prime TA, Porteous CM, Severina II, Skulachev VP, Kjaergaard HG, Smith RAJ, Murphy MP (2006) Accumulation of lipophilic dications by mitochondria and cells. Biochem J 400:199–208CrossRefPubMedPubMedCentralGoogle Scholar
  31. Santos RC, Salvador JAR, Marin S, Cascante M, Moreira JN, Dinis TCP (2010) Synthesis and structure–activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid. Bioorg Med Chem 18:4385–4396CrossRefPubMedGoogle Scholar
  32. Sarek J, Kvasnica M, Vik M, Urban M, Dzubak P, Hajduch M (2011) The potential of triterpenoids in the treatment of melanoma. In: Murph M (ed) Research on melanoma—a glimpse into current directions and future trends. In Tech, Rijeka, pp 125–158Google Scholar
  33. Severina II, Vyssokikh MY, Pustovidko AV, Simonyan RA, Rokitskaya TI, Skulachev VP (2007) Effects of lipophilic dications on planar bilayer phospholipids membrane and mitochondria. Biochim Biophys Acta 1767:1164–1168CrossRefPubMedGoogle Scholar
  34. Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, Filenko OF, Kalinina NI, Kapelko VI, Kolosova NG, Kopnin BP, Korshunova GA, Lichinitser MR, Obukhova LA, Pasyukova EG, Pisarenko OI, Roginsky VA, Ruuge EK, Senin II, Severina II, Skulachev MV, Spivak IM, Tashlitsky VN, Tkachuk VA, Vyssokik My, Yaguzhinsky LS, Zorov DB (2009) An attempt to prevent senescence: A mitochondrial approach. Biochim Biophys Acta 1787:437–461CrossRefPubMedGoogle Scholar
  35. Smith RAJ, Hartley RC, Cocheme HM, Murphy MP (2012) Mitochondrial pharmacology. Trends Pharmacol Sci 33:341–352CrossRefPubMedGoogle Scholar
  36. Spivak AYu, Nedopekina DA, Shakurova ER, Khalitova RR, Gubaidullin RR, Odinokov VN, Dzhemilev UM, Bel´skii YuP, Bel´skaya NV, Stankevich SA, Korotkaya EV, Khazanov VA (2013) Synthesis of lupane triterpenoids with triphenylphosphonium substituents and studies of their antitumor activity. Russ Chem Bull 62:188–198CrossRefGoogle Scholar
  37. Spivak AYu, Keiser J, Vargas M, Gubaidullin RR, Nedopekina DA, Shakurova ER, Khalitova RR, Odinokov VN (2014) Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo. Bioorg Med Chem 22:6297–6304CrossRefPubMedGoogle Scholar
  38. Strobykina IYu, Belenok MG, Semenova MN, Semenov VV, Babaev VM, Rizvanov IK, Mironov VF, Kataev VE (2015) Triphenylphosphonium cations of the diterpenoid isosteviol:synthesis and antimitotic activity in a sea urchin embryo model. J Nat Prod 78:1300–1308CrossRefPubMedGoogle Scholar
  39. Uzenkova NV, Petrenko NI, Shakirov MM, Shul’ts EE, Tolstikov GA (2005) Synthesis of 30-amino derivatives of lupine triterpenoids. Chem Nat Comp 41:692–700CrossRefGoogle Scholar
  40. Yogeeswari P, Sriram D (2005) Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 12:657–666CrossRefPubMedGoogle Scholar
  41. Zuco V, Supino R, Righetti SC, Cleris L, Marchesi E, Gambacorti-Passerini C, Formelli F (2002) Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett 175:17–25CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Anna Yu. Spivak
    • 1
  • Darya A. Nedopekina
    • 1
  • Rezeda R. Khalitova
    • 1
  • Rinat R. Gubaidullin
    • 1
  • Viktor N. Odinokov
    • 1
  • Yuriy P. Bel’skii
    • 2
  • Natalia V. Bel’skaya
    • 2
  • Veniamin A. Khazanov
    • 2
  1. 1.Institute of Petrochemistry and Catalysis, Russian Academy of SciencesUfaRussian Federation
  2. 2.Innovative Pharmacology Research (IPHAR)TomskRussian Federation

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