Next Article in Journal
Extraction and Modification of Macroalgal Polysaccharides for Current and Next-Generation Applications
Next Article in Special Issue
Synthesis and Evaluation of Artificial Nucleic Acid Bearing an Oxanorbornane Scaffold
Previous Article in Journal
Stereoselective Bioreduction of α-diazo-β-keto Esters
Previous Article in Special Issue
Synthesis of Oligonucleotides Containing 2′-N-alkylaminocarbonyl-2′-amino-LNA (2′-urea-LNA) Moieties Using Post-Synthetic Modification Strategy
Open AccessArticle

Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations

1
Chair of Bioprocess Engineering, Faculty III Process Sciences, Institute of Biotechnology, Technische Universität Berlin, Straße des 17. Juni 135, 10623 Berlin, Germany
2
Chemistry of Natural and Microbial Products Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, 12622 Cairo, Egypt
3
BioNukleo GmbH, Ackerstr. 76, 13355 Berlin, Germany
4
Chair of Applied Biochemistry, Faculty III Process Sciences, Institute of Biotechnology, Technische Universität Berlin, Straße des 17. Juni 135, 10623 Berlin, Germany
5
Faculty II Mathematics and Natural Sciences, Institute of Chemistry, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2020, 25(4), 934; https://doi.org/10.3390/molecules25040934
Received: 30 January 2020 / Revised: 16 February 2020 / Accepted: 18 February 2020 / Published: 19 February 2020
(This article belongs to the Special Issue Recent Development of Nucleic Acid Analogs)
The enzymatic synthesis of nucleoside analogues has been shown to be a sustainable and efficient alternative to chemical synthesis routes. In this study, dihalogenated nucleoside analogues were produced by thermostable nucleoside phosphorylases in transglycosylation reactions using uridine or thymidine as sugar donors. Prior to the enzymatic process, ideal maximum product yields were calculated after the determination of equilibrium constants through monitoring the equilibrium conversion in analytical-scale reactions. Equilibrium constants for dihalogenated nucleosides were comparable to known purine nucleosides, ranging between 0.071 and 0.081. To achieve 90% product yield in the enzymatic process, an approximately five-fold excess of sugar donor was needed. Nucleoside analogues were purified by semi-preparative HPLC, and yields of purified product were approximately 50% for all target compounds. To evaluate the impact of halogen atoms in positions 2 and 6 on the antiproliferative activity in leukemic cell lines, the cytotoxic potential of dihalogenated nucleoside analogues was studied in the leukemic cell line HL-60. Interestingly, the inhibition of HL-60 cells with dihalogenated nucleoside analogues was substantially lower than with monohalogenated cladribine, which is known to show high antiproliferative activity. Taken together, we demonstrate that thermodynamic calculations and small-scale experiments can be used to produce nucleoside analogues with high yields and purity on larger scales. The procedure can be used for the generation of new libraries of nucleoside analogues for screening experiments or to replace the chemical synthesis routes of marketed nucleoside drugs by enzymatic processes. View Full-Text
Keywords: cytostatics; dihalogenated nucleoside analogue; yield prediction; thermostable nucleoside phosphorylase; thermodynamic calculations; leukemic cell line cytostatics; dihalogenated nucleoside analogue; yield prediction; thermostable nucleoside phosphorylase; thermodynamic calculations; leukemic cell line
Show Figures

Graphical abstract

MDPI and ACS Style

Yehia, H.; Westarp, S.; Röhrs, V.; Kaspar, F.; Giessmann, R.T.; Klare, H.F.T.; Paulick, K.; Neubauer, P.; Kurreck, J.; Wagner, A. Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations. Molecules 2020, 25, 934. https://doi.org/10.3390/molecules25040934

AMA Style

Yehia H, Westarp S, Röhrs V, Kaspar F, Giessmann RT, Klare HFT, Paulick K, Neubauer P, Kurreck J, Wagner A. Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations. Molecules. 2020; 25(4):934. https://doi.org/10.3390/molecules25040934

Chicago/Turabian Style

Yehia, Heba; Westarp, Sarah; Röhrs, Viola; Kaspar, Felix; Giessmann, Robert T.; Klare, Hendrik F.T.; Paulick, Katharina; Neubauer, Peter; Kurreck, Jens; Wagner, Anke. 2020. "Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations" Molecules 25, no. 4: 934. https://doi.org/10.3390/molecules25040934

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop