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

Autor: Knies C; Organic Chemistry I - Bioorganic Chemistry, Institute of Chemistry of New Materials, University of Osnabrück, Barbarastr. 7, D-49069, Osnabrück, Germany., Reuter H; Anorganische Chemie II, Strukturchemie, Institute of Chemistry of New Materials, University of Osnabrück, Barbarastr. 7, D-49069, Osnabrück, Germany., Hammerbacher K; Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, D-35032, Marburg, Germany., Bender E; Organic Chemistry I - Bioorganic Chemistry, Institute of Chemistry of New Materials, University of Osnabrück, Barbarastr. 7, D-49069, Osnabrück, Germany., Bonaterra GA; Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, D-35032, Marburg, Germany., Kinscherf R; Institute for Anatomy and Cell Biology, Department of Medical Cell Biology, Philipps-University of Marburg, Robert-Koch-Str. 8, D-35032, Marburg, Germany., Rosemeyer H; Organic Chemistry I - Bioorganic Chemistry, Institute of Chemistry of New Materials, University of Osnabrück, Barbarastr. 7, D-49069, Osnabrück, Germany.
Jazyk: angličtina
Zdroj: Chemistry & biodiversity [Chem Biodivers] 2019 Mar; Vol. 16 (3), pp. e1800497. Date of Electronic Publication: 2019 Feb 25.
DOI: 10.1002/cbdv.201800497
Abstrakt: 2-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 1 H- and 13 C-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.
(© 2019 Wiley-VHCA AG, Zurich, Switzerland.)
Databáze: MEDLINE
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