title: 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: Organic Materials Chemistry and Bioorganic Chemistry, Institute for Chemistry of New Materials, Department of Biology and Chemistry, University of Osnabrück, Barbarastr. 7, D-49069 Osnabrück.
authors: Edith
authors: E
authors: Malecki
authors: Anisa
authors: A
authors: Farhat
authors: Gabriel A
authors: GA
authors: Bonaterra
authors: Doris
authors: D
authors: Röthlein
authors: Martin
authors: M
authors: Wolf
authors: Jürgen
authors: J
authors: Schmitt
authors: Ralf
authors: R
authors: Kinscherf
authors: Helmut
authors: H
authors: Rosemeyer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D019073:HT29 Cells; D006801:Humans; D018613:Microscopy, Confocal; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; C001943:5-fluorouridine; D014529:Uridine
keywords: Antiproliferative activity; Antitumor activity; Cytotoxic activity; Drug delivery; Lipophilicity; Nucleolipids; Uridine, 5-fluoro-