Synthesis of 5-fluorouridine nucleolipid derivatives and their cytostatic/cytotoxic activities on human HT-29 colon carcinoma cells.

Abstract

One of the major drawbacks of chemotherapeutics is their insufficient penetration through cell membranes due to a high hydrophobicity. Thus, we have synthesized a series of selected nucleolipid derivatives of 5-fluorouridine (5-FUrd; 2a), carrying lipophilic moieties at N(3) and/or in the 2',3'-O-position (i.e., 3a-7a and 3c), and tested their cytostatic/cytotoxic activities using HT-29 human colon carcinoma cells, in comparison with, e.g., 5-FU (1) and 5-FUrd (2a). Incorporation and intracellular localization of the substances under test were performed after conjugation with the fluorochrome Atto 425. We showed that all 5'-O-labelled Atto 425 derivatives were incorporated by the human HT-29 cells and accumulated in their cytoplasm. Moreover, after 24-h treatment of HT-29 human colon carcinoma cells, 1 or 2a (10, 20, 40, or 80 μM) revealed a significant (14-23 or 33-45%, resp.) decrease of the viability in comparison with the (negative) control. Interestingly, derivatives 3a and 3c (40 and 80 μM) led to a significant (77-95 or 89-96%, resp.) inhibition of survival of human HT29 cells, i.e., these two substances were ca. 63-72% or ca. 75%, respectively more effective than 5-FU (1; positive control). Furthermore, derivative 5a showed a significant, i.e., 30 and 86%, inhibition of the survival at 40 and 80 μM, respectively in comparison with the (negative) control. Some synthesized 5-FUrd derivatives turned out to be more effective than 5-FU (1) or 5-FUrd (2a).

• Authors: Edith Malecki, Anisa Farhat, Gabriel A Bonaterra, Doris Röthlein, Martin Wolf, Jürgen Schmitt, Ralf Kinscherf, Helmut Rosemeyer
• Journal: Chemistry & biodiversity (Chem Biodivers) Vol. 10 Issue 12 Pg. 2235-46 (Dec 2013) ISSN: 1612-1880 [Electronic] Switzerland
• PMID: 24327444 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Verlag Helvetica Chimica Acta AG, Zürich.

Chemical References

• Antineoplastic Agents
• 5-fluorouridine
• Uridine

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, toxicity)
• Cell Survival (drug effects)
• Colonic Neoplasms (metabolism, pathology)
• HT29 Cells
• Humans
• Microscopy, Confocal
• Uridine (analogs & derivatives, chemical synthesis, chemistry, toxicity)