Document Type: Original Research Article

Authors

1 Institute of Microbiology, National Academy of Sciences of Belarus, Minsk-220141, Belarus

2 Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Minsk-220141, Belarus

10.33945/SAMI/PCBR.2020.1.8

Abstract

A series of conjugates of pharmacologically promising modified nucleosides with phospholipid was synthesized. Some liponucleotides were originally produced. Soybean lecithin served as the donor of phosphatidyl residue. Phospholipase D from strain Streptomyces netropsis BIM B-428D was engaged as biocatalyst in transphosphatidylation reaction. The yield of liponucleotide synthesis reaction varied in the range 44–95 mol% depending on the acceptor of phosphatidyl residue. 65 mg (about 68 µmoles) of pure phosphatidylclofarabine was recovered by chromatography on silica gel column, resulting in 68 mol% yield calculated from the amount of modified nucleoside supplied into the reaction mixture.

Graphical Abstract

Keywords

Main Subjects

[1] M.L. Ashdown, A.P. Robinson, S.L. Yatomi-Clarke, M.L. Ashdown, A. Allison, D. Abbott, S.N. Markovic and B.J. Coventry, Chemotherapy for late-stage cancer patients: meta-analysis of complete response rates. F1000Research,  4 (2015)  232.

[2] P. Zubor, P. Kubatka, I. Kapustova, L. Miloseva, Z. Dankova, A. Gondova, T. Bielik, S. Krivus, J. Bujnak and Z. Laucekova, Current approaches in the clinical management of pregnancy-associated breast cancer—pros and cons. EPMA Journal,  9 (2018)  257-270.

[3] N. Tsesmetzis, C.B. Paulin, S.G. Rudd and N. Herold, Nucleobase and nucleoside analogues: resistance and re-sensitisation at the level of pharmacokinetics, pharmacodynamics and metabolism. Cancers,  10 (2018)  240.

[4] I. Mender, S. Gryaznov, Z.G. Dikmen, W.E. Wright and J.W. Shay, Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2′-deoxyguanosine. Cancer discovery,  5 (2015)  82-95.

[5] S. Sengupta, M. Sobo, K. Lee, S.S. Kumar, A.R. White, I. Mender, C. Fuller, L.M. Chow, M. Fouladi and J.W. Shay, Induced telomere damage to treat telomerase expressing therapy-resistant pediatric brain tumors. Molecular cancer therapeutics,  17 (2018)  1504-1514.

[6] S.P. McDermott, K. Eppert, F. Notta, M. Isaac, A. Datti, R. Al-awar, J. Wrana, M.D. Minden and J.E. Dick, A small molecule screening strategy with validation on human leukemia stem cells uncovers the therapeutic efficacy of kinetin riboside. Blood, The Journal of the American Society of Hematology,  119 (2012)  1200-1207.

[7] M. Rajabi, E. Gorincioi and E. Santaniello, Antiproliferative activity of kinetin riboside on HCT-15 colon cancer cell line. Nucleosides, Nucleotides and Nucleic Acids,  31 (2012)  474-481.

[8] H. Ghanem, E. Jabbour, S. Faderl, V. Ghandhi, W. Plunkett and H. Kantarjian, Clofarabine in leukemia. Expert review of hematology,  3 (2010)  15-22.

[9] C. Fozza, The role of Clofarabine in the treatment of adults with acute myeloid leukemia. Critical reviews in oncology/hematology,  93 (2015)  237-245.

[10] N.K. Van Eijkelenburg, M. Rasche, E. Ghazaly, M.N. Dworzak, T. Klingebiel, C. Rossig, G. Leverger, J. Stary, E.S. De Bont and D.A. Chitu, Clofarabine, high-dose cytarabine and liposomal daunorubicin in pediatric relapsed/refractory acute myeloid leukemia: a phase IB study. Haematologica,  103 (2018)  1484-1492.

[11] R.L. Alexander and G.L. Kucera, Lipid nucleoside conjugates for the treatment of cancer. Current pharmaceutical design,  11 (2005)  1079-1089.

[12] M. Markovic, S. Ben-Shabat, S. Keinan, A. Aponick, E.M. Zimmermann and A. Dahan, Prospects and challenges of phospholipid-based prodrugs. Pharmaceutics,  10 (2018)  210.

[13] M. Markovic, S. Ben-Shabat, S. Keinan, A. Aponick, E.M. Zimmermann and A. Dahan, Molecular modeling-guided design of phospholipid-based prodrugs. International journal of molecular sciences,  20 (2019)  2210.

[14] I. Tsybulskaya, T. Kulak, E. Kalinichenko, A. Baranovsky, S. Bogushevich, M. Golubeva and B. Kuzmitsky, Phospholipid derivatives of cladribine and fludarabine: Synthesis and biological properties. Bioorganic & medicinal chemistry,  23 (2015)  3287-3296.

[15] R.L. Alexander, S.L. Morris-Natschke, K.S. Ishaq, R.A. Fleming and G.L. Kucera, Synthesis and cytotoxic activity of two novel 1-dodecylthio-2-decyloxypropyl-3-phosphatidic acid conjugates with gemcitabine and cytosine arabinoside. Journal of medicinal chemistry,  46 (2003)  4205-4208.

[16] S.F. Yang, S. Freer and A. Benson, Transphosphatidylation by phospholipase D. Journal of Biological Chemistry,  242 (1967)  477-484.

[17] L. Birichevskaya, L. Eroshevskaya, M. Kisel' and A. Zinchenko, Substrate requirements of phospholipase D from Streptomyces netropsis in the transphosphatidylation synthesis of phospolipids. Chemistry of natural compounds,  42 (2006)  32-35.

[18] L.L. Birichevskaya, S.V. Kvach, G.G. Sivets, E.N. Kalinichenko, A.I. Zinchenko and I.A. Mikhailopulo, A comparison of enzymatic phosphorylation and phosphatidylation of β-l-and β-d-nucleosides. Biotechnology letters,  29 (2007)  585-591.

[19] K. Cao, Y. Liu, Y. Tian, Q. Zhang, P. Cong, H. Li, J. Xu, Z. Li, J. Wang and X. Mao, Reaction Specificity of Phospholipase D Prepared from Acinetobacter radioresistens a2 in Transphosphatidylation. Lipids,  53 (2018)  517-526.

[20] B. Li, D. Duan, J. Wang, H. Li, X. Zhang and B. Zhao, Improving phospholipase D activity and selectivity by bio-imprinting-immobilization to produce phosphatidylglycerol. Journal of biotechnology,  281 (2018)  67-73.

[21] J.O. Rich and Y.L. Khmelnitsky, Phospholipase D‐catalyzed transphosphatidylation in anhydrous organic solvents. Biotechnology and bioengineering,  72 (2001)  374-377.

[22] H.-J. Hou, J.-S. Gong, Y.-X. Dong, J. Qin, H. Li, H. Li, Z.-M. Lu, X.-M. Zhang, Z.-H. Xu and J.-S. Shi, Phospholipase D engineering for improving the biocatalytic synthesis of phosphatidylserine. Bioprocess and biosystems engineering,  42 (2019)  1185-1194.

[23] Z.R. Zad, S.S.H. Davarani, A. Taheri and Y. Bide, A yolk shell Fe3O4 @PA-Ni@Pd/Chitosan nanocomposite -modified carbon ionic liquid electrode as a new sensor for the sensitive determination of fluconazole in pharmaceutical preparations and biological fluids. Journal of Molecular Liquids,  253 (2018)  233-240.

[24] A. Nagao, N. Ishida and J. Terao, Synthesis of 6-phosphatidyl-L-ascorbic acid by phospholipase D. Lipids,  26 (1991)  390-394.

[25] T. Koga, A. Nagao, J. Terao, K. Sawada and K. Mukai, Synthesis of a phosphatidyl derivative of vitamin E and its antioxidant activity in phospholipid bilayers. Lipids,  29 (1994)  83-89.

[26] S. Shuto, H. Itoh, A. Sakai, K. Nakagami, S. Imamura and A. Matsuda, Nucleosides and nucleotides—CXXXVII. Antitumor phospholipids with 5-fluorouridine as a cytotoxic polar-head: Synthesis of 5′-phosphatidyl-5-fluorouridines by phospholipase d-catalyzed transphosphatidylation. Bioorganic & medicinal chemistry,  3 (1995)  235-243.

[27] L.E. Iglesias, E.S. Lewkowicz, R. Medici, P. Bianchi and A.M. Iribarren, Biocatalytic approaches applied to the synthesis of nucleoside prodrugs. Biotechnology advances,  33 (2015)  412-434.

[28] M. Hossen and E. Hernandez, Phospholipase D-catalyzed synthesis of novel phospholipid-phytosterol conjugates. Lipids,  39 (2004)  777-782.

[29] S. Hama, C. Ogino and A. Kondo, Enzymatic synthesis and modification of structured phospholipids: recent advances in enzyme preparation and biocatalytic processes. Applied microbiology and biotechnology,  99 (2015)  7879-7891.

[30] K.Y. Hostetler, D.D. Richman, C. Sridhar, P.L. Felgner, J. Felgner, J. Ricci, M.F. Gardner, D.W. Selleseth and M.N. Ellis, Phosphatidylazidothymidine and phosphatidyl-ddC: assessment of uptake in mouse lymphoid tissues and antiviral activities in human immunodeficiency virus-infected cells and in Rauscher leukemia virus-infected mice. Antimicrobial agents and chemotherapy,  38 (1994)  2792-2797.