Synthesis of New Potential Lipophilic Co-Drugs of 2-Chloro-2 `-deoxyadenosine (Cladribine, 2-CdA, Mavenclad (R), Leustatin (R)) and 6-Azauridine (z(6)U) with Valproic Acid

DC FieldValueLanguage
dc.contributor.authorKnies, Christine
dc.contributor.authorReuter, Hans
dc.contributor.authorHammerbacher, Katharina
dc.contributor.authorBender, Eugenia
dc.contributor.authorBonaterra, Gabriel A.
dc.contributor.authorKinscherf, Ralf
dc.contributor.authorRosemeyer, Helmut
dc.date.accessioned2021-12-23T16:09:27Z-
dc.date.available2021-12-23T16:09:27Z-
dc.date.issued2019
dc.identifier.issn16121872
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/8802-
dc.description.abstract2-Chloro-2 `-deoxyadenosine (cladribine, 1) was acylated with valproic acid (2) under various reaction conditions yielding 2-chloro-2 `-deoxy-3 `,5 `-O-divalproyladenosine (3) as well as the 3 `-O- and 5 `-O-monovalproylated derivatives, 2-chloro-2 `-deoxy-3 `-O-valproyladenosine (4) and 2-chloro-2 `-deoxy-5 `-O-valproyladenosine (5), as new co-drugs. In addition, 6-azauridine-2 `,3 `-O-(ethyl levulinate) (8) was valproylated at the 5 `-OH group (-> 9). All products were characterized by H-1- and C-13-NMR spectroscopy and ESI mass spectrometry. The structure of the by-product 6 (N-cyclohexyl-N-(cyclohexylcarbamoyl)-2-propylpentanamide), formed upon valproylation of cladribine in the presence of N,N-dimethylaminopyridine and dicyclohexylcarbodiimide, was analyzed by X-ray crystallography. Cladribine as well as its valproylated co-drugs were tested upon their cancerostatic/cancerotoxic activity in human astrocytoma/oligodendroglioma GOS-3 cells, in rat malignant neuro ectodermal BT4Ca cells, as well as in phorbol-12-myristate 13-acetate (PMA)-differentiated human THP-1 macrophages. The most important result of these experiments is the finding that only the 3 `-O-valproylated derivative 4 exhibits a significant antitumor activity while the 5 `-O- as well as the 3 `,5 `-O-divalproylated cladribine derivatives 3 and 5 proved to be inactive.
dc.description.sponsorshipelemental analyses by Mrs. A. Schuster Funding Source: Medline; HR-ESI-MS measurements by Dr. S. Walter Funding Source: Medline; NMR measurements by Mrs. M. Gather Steckhan Funding Source: Medline
dc.language.isoen
dc.publisherWILEY-V C H VERLAG GMBH
dc.relation.ispartofCHEMISTRY & BIODIVERSITY
dc.subject2-CHLORO-2-DEOXYADENOSINE
dc.subject2-DEOXYADENOSINE
dc.subjectBiochemistry & Molecular Biology
dc.subjectbiological activity
dc.subjectcancerostati
dc.subjectcancerotoxic activity
dc.subjectCELL
dc.subjectChemistry
dc.subjectChemistry, Multidisciplinary
dc.subjectcladribine
dc.subjectDEAMINASE DEFICIENCY
dc.subjectDEOXYADENOSINE ANALOGS
dc.subjectdrug profiling
dc.subjectglioblastoma
dc.subjectIN-VITRO
dc.subjectmultiple sclerosis
dc.subjectnucleolipids
dc.subjectPHOTOCHEMICAL CONVERSION
dc.subjectPURINE
dc.subjectSODIUM-SALT GLYCOSYLATION
dc.subjectTOXICITY
dc.titleSynthesis of New Potential Lipophilic Co-Drugs of 2-Chloro-2 `-deoxyadenosine (Cladribine, 2-CdA, Mavenclad (R), Leustatin (R)) and 6-Azauridine (z(6)U) with Valproic Acid
dc.typejournal article
dc.identifier.doi10.1002/cbdv.201800497
dc.identifier.isiISI:000461868000014
dc.description.volume16
dc.description.issue3
dc.contributor.researcheridAAV-7164-2021
dc.identifier.eissn16121880
dc.publisher.placePOSTFACH 101161, 69451 WEINHEIM, GERMANY
dcterms.isPartOf.abbreviationChem. Biodivers.
crisitem.author.deptInstitut für Chemie neuer Materialien-
crisitem.author.deptInstitut für Chemie neuer Materialien-
crisitem.author.deptidinstitute11-
crisitem.author.deptidinstitute11-
crisitem.author.parentorgFB 05 - Biologie/Chemie-
crisitem.author.parentorgFB 05 - Biologie/Chemie-
crisitem.author.grandparentorgUniversität Osnabrück-
crisitem.author.grandparentorgUniversität Osnabrück-
crisitem.author.netidReHa636-
crisitem.author.netidRoHe783-
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