Synthesis of Antimitotic Thioglycosides: In Vitro and in Vivo Evaluation of Their Anticancer Activity

The synthesis and biological activity of oleylN-acetyl-α- and β-d-glucosaminides (1 and 2, respectively) and their thioglycosyl analogues (3 and 4, respectively) are reported. The compounds exhibited antimitotic activity on rat glioma (C6) and human lung carcinoma (A549) cell cultures in the micromo...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-10, Vol.54 (19), p.6949-6955
Main Authors: García-Álvarez, Isabel, Groult, Hugo, Casas, Josefina, Barreda-Manso, M. Asunción, Yanguas-Casás, Natalia, Nieto-Sampedro, Manuel, Romero-Ramírez, Lorenzo, Fernández-Mayoralas, Alfonso
Format: Article
Language:English
Subjects:
Animals
Antimitotic Agents - chemical synthesis
Antimitotic Agents - chemistry
Antimitotic Agents - pharmacology
beta-N-Acetylhexosaminidases - chemistry
Cancer
Cell Line, Tumor
Chemical Sciences
Drug Screening Assays, Antitumor
Glycolipids - chemical synthesis
Glycolipids - chemistry
Glycolipids - pharmacology
Humans
Hydrolysis
Life Sciences
Medicinal Chemistry
Mice
Mice, Nude
Neoplasm Transplantation
Organic chemistry
Rats
Structure-Activity Relationship
Thioglucosides - chemical synthesis
Thioglucosides - chemistry
Thioglucosides - pharmacology
Thioglycosides - chemical synthesis
Thioglycosides - chemistry
Thioglycosides - pharmacology
Transplantation, Heterologous
Tumor Burden - drug effects
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Summary:The synthesis and biological activity of oleylN-acetyl-α- and β-d-glucosaminides (1 and 2, respectively) and their thioglycosyl analogues (3 and 4, respectively) are reported. The compounds exhibited antimitotic activity on rat glioma (C6) and human lung carcinoma (A549) cell cultures in the micromolar range. Analysis of cell extracts using ultra performance liquid chromatography–mass spectrometry showed that the synthetic glycosides produce alterations in glycosphingolipid metabolism, with variable effect on the level of glucosylceramide depending on the configuration of the antimitotic used. In vivo experiments in nude mice bearing an implanted C6 glioma showed that the α-thioglycoside 3 reduced tumor volume, while the O-glycosyl derivative was inactive, highlighting the importance of using enzyme resistant glycosides.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm200961q