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

Autor(en): Knies, Christine
Reuter, Hans 
Hammerbacher, Katharina
Bender, Eugenia
Bonaterra, Gabriel A.
Kinscherf, Ralf
Rosemeyer, Helmut 
Stichwörter: 2-CHLORO-2-DEOXYADENOSINE; 2-DEOXYADENOSINE; Biochemistry & Molecular Biology; biological activity; cancerostati; cancerotoxic activity; CELL; Chemistry; Chemistry, Multidisciplinary; cladribine; DEAMINASE DEFICIENCY; DEOXYADENOSINE ANALOGS; drug profiling; glioblastoma; IN-VITRO; multiple sclerosis; nucleolipids; PHOTOCHEMICAL CONVERSION; PURINE; SODIUM-SALT GLYCOSYLATION; TOXICITY
Erscheinungsdatum: 2019
Herausgeber: WILEY-V C H VERLAG GMBH
Journal: CHEMISTRY & BIODIVERSITY
Volumen: 16
Ausgabe: 3
Zusammenfassung: 
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 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.
ISSN: 16121872
DOI: 10.1002/cbdv.201800497

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