Glycoconjugate Journal

, Volume 33, Issue 2, pp 137–146 | Cite as

Enzymatic synthesis of lactosylated and sialylated derivatives of epothilone A

  • Prakash Parajuli
  • Ramesh Prasad Pandey
  • Rit Bahadur Gurung
  • Ju Yong Shin
  • Hye Jin Jung
  • Dae Hee Kim
  • Jae Kyung Sohng
Original Article


Epothilone A is a derivative of 16-membered polyketide natural product, which has comparable chemotherapeutic effect like taxol. Introduction of sialic acids to these chemotherapeutic agents could generate interesting therapeutic glycoconjugates with significant effects in clinical studies. Since, most of the organisms biosynthesize sialic acids in their cell surface, they are key mediators in cellular events (cell-cell recognition, cell-matrix interactions). Interaction between such therapeutic sugar parts and cellular polysaccharides could generate interesting result in drugs like epothilone A. Based on this hypothesis, epothilone A glucoside (epothilone A 6-O-β-D-glucoside) was further decorated by conjugating enzymatically galactose followed by sialic acids to generate epothilone A 7-O-β-D-glucopyranosyl, 4′-O-α-D-galactoside i.e., lactosyl epothilone A (lac epoA) and two sialosides of epothilone A namely epothilone A 7-O-β-D-glucopyranosyl, 4′-O-α-D-galactopyranosyl 3″-O-α-N-acetyl neuraminic acid and epothilone A 7-O-β-D-glucopyranosyl, 4′-O-α-D-galactopyranosyl 6″-O-α-N-acetylneuraminic acid i.e., 3′sialyllactosyl epothilone A: 3′SL-epoA, and 6′sialyllactosyl epothilone A: 6′SL-epoA, respectively. These synthesized analogs were spectroscopically analyzed and elucidated, and biologically validated using HUVEC and HCT116 cancer cell lines.


Chemotherapeutic agent Epothilone A 6-O-β-D-glucoside 3′Sialyllactosyl epothilone A 6′sialyllactosyl epothilone A Epothilones 



This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2014R1A2A2A01002875).

Supplementary material

10719_2015_9646_MOESM1_ESM.docx (19.6 mb)
ESM 1 (DOCX 20066 kb)


  1. 1.
    Akbari, V., Moghim, S., Reza, M.M.: Comparision of epothilone and taxol binding in yeast tubulin using molecular modeling. Avicenna J. Med. Biotechnol. 3, 167–175 (2001)Google Scholar
  2. 2.
    Jordan, M.A., Wilson, L.: Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 4, 253–265 (2004)CrossRefPubMedGoogle Scholar
  3. 3.
    He, L., Orr, G.A., Horitz, S.B.: Novel molecules that interact with microtubules and have functional activity similar to Taxol. Drug Discov. Today 6, 1153–1164 (2001)CrossRefPubMedGoogle Scholar
  4. 4.
    Shi, G., Wang, Y., Jin, Y., Chi, S., Shi, Q., Ge, M., Wang, S., Zhang, X., Xu, S.: Structural insight into the mechanism of epothilone A bound to beta-tubulin and its mutants at Arg282Gln and Thr274lle. J. Biomol. Struct. Dyn. 30, 559–573 (2002)CrossRefGoogle Scholar
  5. 5.
    Rogalska, A., Marczak, A., Gajek, A., Swed, M., Sliwinska, A., Drzewoski, J., Jozwiak, Z.: Induction of apoptosis in human ovarian cancer cells by new anticancer compounds, epothilone A and B. Toxicol. In Vitro 27, 239–249 (2013)CrossRefPubMedGoogle Scholar
  6. 6.
    Altmann, K.H., Pfeiffer, B., Arseniyadis, S., Pratt, B.A., Nicolaou, K.C.: The chemistry and biology of epothilones- the wheel keeps turning. ChemMedChem 2, 396–423 (2007)CrossRefPubMedGoogle Scholar
  7. 7.
    Bollag, D.M., McQueney, P.A., Zhu, J., Hensens, O., Koupal, L., Liesch, J., Goetz, M., Lazarides, E., Woods, C.M.: Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 55, 2325–2333 (1995)PubMedGoogle Scholar
  8. 8.
    Brabec, V., Kasparkova, J.: Modifications of DNA by platinum complexes. Relation to resistance of tumors to platinum antitumor drugs. Drug Resist. Updat. 8, 131–146 (2005)CrossRefPubMedGoogle Scholar
  9. 9.
    Xie, X.K., Yang, D.S., Ye, Z.M., Tao, H.M.: Enhancement effect of adenovirus-mediated antisense c-myc and caffeine on the cytotoxicity of cisplatin in osteosarcoma cell lines. Chemotherapy 55, 433–440 (2008)CrossRefGoogle Scholar
  10. 10.
    Tanaka, M., Kataoka, H., Mabuchi, M., Sakuma, S., Takahishi, S., Tujii, R., Akashi, H., Ohi, H., Yano, S., Morita, A., Joh, T.: Anticancer effects of novel photodynamic therapy with glycoconjugated chlorin for gastric and colon cancer. Anticancer Res. 31, 763–769 (2011)PubMedGoogle Scholar
  11. 11.
    Tanaka, M., Kataoka, H., Yano, S., Ohi, H., Kawamoto, K., Shibahara, T., Mizoshita, T., Mori, Y., Tanida, S., Kamiya, T., Joh, T.: Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells. BMC Cancer 13, 237 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Tiwari, V.K., Mishra, R.C., Sharma, A., Tripathi, R.P.: Carbohydrate based potential chemotherapeutic agents: recent developments and their scope in future drug discovery. Mini. Rev. Med. Chem. 12, 1497–519 (2012)CrossRefPubMedGoogle Scholar
  13. 13.
    Traving, C., Schauer, R.: Structure, function and metabolism of sialic acids. Cell. Mol. Life Sci. 54, 1330–1349 (1998)CrossRefPubMedGoogle Scholar
  14. 14.
    Yu, H., Chokhwala, H.A., Huang, S., Chen, X.: One-pot three-enzyme chemoenzymatic approach to the synthesis of sialosides containing natural and non-natural functionalities. Nat. Protoc. 1, 2485–2492 (2006)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Varki, A., Schauer, R., Sialic acids. In: Verki, A., Cummings, R. D., Esko, J. D.; et al.: editors. Essentials of glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Chapter 14. Available from:
  16. 16.
    Parajuli, P., Pandey, R.P., Koirala, N., Yoon, Y.J., Kim, B.G., Sohng, J.K.: Enzymatic synthesis of epothilone A glycosides. AMB Express 4, 31 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Choi, Y.H., Kim, J.H., Park, J.H., Lee, N., Kim, D.H., Jang, K.S., Park, I.H., Kim, B.G.: Protein engineering of α2,3/2,6-sialyltransferase to improve the yield and productivity of in vitro sialyllactose synthesis. Glycobiology 24, 159–169 (2014)CrossRefPubMedGoogle Scholar
  18. 18.
    Oh, T.J., Kim, D.H., Kang, S.Y., Yamaguchi, T., Sohng, J.K.: Enzymatic synthesis of vancomycin derivatives using galactosyltransferase and sialyltransferase. J. Antibiot (Tokyo) 64, 103–109 (2011)CrossRefGoogle Scholar
  19. 19.
    Parajuli, P., Pandey, R.P., Pokhrel, A.R., Ghimire, G.P., Sohng, J.K.: Enzymatic glycosylation of the topical antibiotics mupirocin. Glycoconj. J. 31, 563–572 (2014)CrossRefPubMedGoogle Scholar
  20. 20.
    Pandey, R.P., Gurung, R.B., Parajuli, P., Koirala, N., le Tuoi, T., Sohng, J.K.: Assessing acceptor substrate promiscuity of YjiC-mediated glycosylation towards flavonoids. Carbohydr. Res. 393, 26–31 (2014)CrossRefPubMedGoogle Scholar
  21. 21.
    Pandey, R.P., Parajuli, P., Koirala, N., Park, J.W., Sohng, J.K.: Probing 3-hydroxyflavone for in vitro glycorandomization of flavonols by YjiC. Appl. Environ. Microbiol. 79, 6833–6838 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Antoine, T., Priem, B., Heyraud, A., Greffe, L., Gilbert, M., Wakarchuk, W.W., Lam, J.S., Samain, E.: Large-scale in vivo synthesis of the carbohydrate moieties of gangliosides GM1 and GM2 by metabolically engineered Escherichia coli. Chembiochem 4, 406–412 (2003)CrossRefPubMedGoogle Scholar
  23. 23.
    Wang, J., Zhang, H., Ying, L., Wang, C., Jiang, N., Zhou, Y., Wang, H., Bai, H.: Five new epothilone metabolites from Sorangium cellulosum strain So0157-2. J. Antibiot (Tokyo) 62, 483–487 (2009)CrossRefGoogle Scholar
  24. 24.
    Park, H.J., Zhang, Y., Georgescu, S.P., Johnson, K.L., Kong, D., Galper, J.B.: Human umbilical vein endothelial cells and human dermal microvascular endothelial cells offer new insight into the relationship between lipid metabolism and angiogenesis. Stem Cell Rev. 2, 93–102 (2006)CrossRefPubMedGoogle Scholar
  25. 25.
    Raiput, A., Dominquez San Martin, I., Rose, R., Beko, A., Levea, C., Sharratt, E., Mazurchuk, R., Hoffman, R.M., Brottain, M.G., Wang, J.J.: Characterization of HCT116 human colon cancer cells in an orthotopic model. Surg. Res. 147, 276–281 (2008)CrossRefGoogle Scholar
  26. 26.
    Cazet, A., Julien, S., Bobowski, M., Krzewinski-Recchi, M.A., Harduin-Lepers, A., Groux-Degroote, S., Delannoy, P.: Consequences of the expression of sialylated antigens in breast cancer. Carbohydr. Res. 345, 1377–1388 (2010)CrossRefPubMedGoogle Scholar
  27. 27.
    Audry, M., Jeanneau, C., Imberty, A., Harduin-Lepers, A., Delannoy, P., Breton, C.: Current trends in the structure-activity relationships of sialyltransferases. Glycobiology 21, 716–726 (2010)CrossRefPubMedGoogle Scholar
  28. 28.
    Cheng, H., Cao, X., Xian, M., Cai, T.B., Ji, J.J., Tunac, J.B., Sun, D., Wang, P.G.: Synthesis and enzyme-specific activation of carbohydrate-geldanamycin conjugates with potent anticancer activity. J. Med. Chem. 48, 645–652 (2005)CrossRefPubMedGoogle Scholar
  29. 29.
    Schulte, T.W., Akinaga, S., Soga, S., Sullivan, W., Stensgard, B., Toft, D., Neckers, L.M.: Antibiotic radicicol binds to the N-terminal domain of HSP90 and shares important biologic activities with geldanamycin. Cell Stress Chaperones 3, 100–108 (1998)CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Vahdat, L. T.: Slinical studies with epothlones for the treatment of metastatic breast cancer. Semin. Oncol. 35, S22-30Google Scholar
  31. 31.
    Heuser, E., Lipp, K., Wiegandt, H.: Detection of sialic acid containing compounds and the behavior of gangliosides in polyacrylamide disc electrophoresis. Anal. Biochem. 60, 382–388 (1974)CrossRefPubMedGoogle Scholar
  32. 32.
    Bisel, B., Pavone, F.S., Calamai, M.: GM1 and GM2 gangliosides: recent developments. Biomol. Concepts. 5, 87–93 (2014)CrossRefPubMedGoogle Scholar
  33. 33.
    Bagriacik, E.U., Miller, K.S.: Cell surface sialic acid and the regulation of immunie cell interactions: the neuraminidase effect reconsidered. Glycobiology 3, 267–275 (1999)CrossRefGoogle Scholar
  34. 34.
    Varki, A., Gagneux, P.: Multifarious roles of sialic acids in immnity. Ann. N. Y. Acad. Sci. 1253, 16–36 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang, B., Brand-Miller, J.: The role and potential of sialic acid in human nutrition. Eur. J. Clin. Nutr. 57, 1351–1369 (2003)CrossRefPubMedGoogle Scholar
  36. 36.
    Hata, K., Koseki, K., Yamaguchi, K., Moriya, S., Suzuki, Y., Yingsakmongkon, S., Hirai, G., Sodeoka, M., von Itzstein, M., Miyagi, T.: Limited inhibitory effects of oseltamivir and zanamivir on human sialidases. Antimicrob. Agents Chemother. 52, 3484–3481 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Cowan, C. B., Patel, D.A., Good, T. A.: Exploring the mechanism of beta-amyloid toxicity attenuation by multivalent sialic acid polymers through the use of mathematical models. J. Theor. Biol. 258, 189–197Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Prakash Parajuli
    • 1
  • Ramesh Prasad Pandey
    • 1
  • Rit Bahadur Gurung
    • 1
  • Ju Yong Shin
    • 1
  • Hye Jin Jung
    • 1
  • Dae Hee Kim
    • 2
  • Jae Kyung Sohng
    • 1
  1. 1.Institute of Biomolecule Reconstruction, Department of BT-convergent Pharmaceutical EngineeringSunMoon UniversityAsan-SiSouth Korea
  2. 2.GeneChemDaejeonSouth Korea

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