Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations

dc.contributor.authorYehia, Heba
dc.contributor.authorWestarp, Sarah
dc.contributor.authorRöhrs, Viola
dc.contributor.authorKaspar, Felix
dc.contributor.authorGiessmann, Robert T.
dc.contributor.authorKlare, Hendrik F. T.
dc.contributor.authorPaulick, Katharina
dc.contributor.authorNeubauer, Peter
dc.contributor.authorKurreck, Jens
dc.contributor.authorWagner, Anke
dc.date.accessioned2020-04-28T06:19:37Z
dc.date.available2020-04-28T06:19:37Z
dc.date.issued2020-02-19
dc.date.updated2020-03-05T20:53:09Z
dc.description.abstractThe 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.en
dc.description.sponsorshipDFG, 390540038, EXC 2008: UniSysCaten
dc.description.sponsorshipDFG, 414044773, Open Access Publizieren 2019 - 2020 / Technische Universität Berlinen
dc.identifier.eissn1420-3049
dc.identifier.urihttps://depositonce.tu-berlin.de/handle/11303/11041
dc.identifier.urihttp://dx.doi.org/10.14279/depositonce-9929
dc.language.isoenen
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subject.ddc540 Chemie und zugeordnete Wissenschaftende
dc.subject.othercytostaticsen
dc.subject.otherdihalogenated nucleoside analogueen
dc.subject.otheryield predictionen
dc.subject.otherthermostable nucleoside phosphorylaseen
dc.subject.otherthermodynamic calculationsen
dc.subject.otherleukemic cell lineen
dc.titleEfficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculationsen
dc.typeArticleen
dc.type.versionpublishedVersionen
dcterms.bibliographicCitation.articlenumber934en
dcterms.bibliographicCitation.doi10.3390/molecules25040934en
dcterms.bibliographicCitation.issue4en
dcterms.bibliographicCitation.journaltitleMoleculesen
dcterms.bibliographicCitation.originalpublishernameMDPIen
dcterms.bibliographicCitation.originalpublisherplaceBaselen
dcterms.bibliographicCitation.volume25en
tub.accessrights.dnbfreeen
tub.affiliationFak. 3 Prozesswissenschaften::Inst. Biotechnologie::FG Bioverfahrenstechnikde
tub.affiliation.facultyFak. 3 Prozesswissenschaftende
tub.affiliation.groupFG Bioverfahrenstechnikde
tub.affiliation.instituteInst. Biotechnologiede
tub.publisher.universityorinstitutionTechnische Universität Berlinen

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