Synthesis of 5‐Fluorouridine Nucleolipid Derivatives and Their Cytostatic/Cytotoxic Activities on Human HT‐29 Colon Carcinoma Cells. Issue 12 (December 2013)

• Record Type: Journal Article
• Authors: Malecki, Edith; Farhat, Anisa; Bonaterra, Gabriel A.; Röthlein, Doris; Wolf, Martin; Schmitt, Jürgen; Kinscherf, Ralf; Rosemeyer, Helmut
• Is Part Of: Chemistry & biodiversity. Volume 10:Issue 12(2013:Dec.)
• Page Start: 2235
• Page End: 2246
• Publication Date: 2013-12
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Biodiversity -- Periodicals; 572
• DOI: 10.1002/cbdv.201300219
• Languages: English
• ISSNs: 1612-1872

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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; <bold>2a</bold>), carrying lipophilic moieties at N(3) and/or in the 2′, 3′‐<italic>O</italic>‐position (<italic>i.e.</italic>, <bold>3a</bold>–<bold>7a</bold> and <bold>3c</bold>), and tested their cytostatic/cytotoxic activities using HT‐29 human colon carcinoma cells, in comparison with, <italic>e.g.</italic>, 5‐FU (<bold>1</bold>) and 5‐FUrd (<bold>2a</bold>). Incorporation and intracellular localization of the substances under test were performed after conjugation with the fluorochrome <italic>Atto 425.</italic> We showed that all 5′‐<italic>O</italic>‐labelled <italic>Atto 425</italic> 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, <bold>1</bold> or <bold>2a</bold> (10, 20, 40, or 80 μ<sc>M</sc>) revealed a significant (14–23 or 33–45%, resp.) decrease of the viability in comparison with the (negative) control. Interestingly, derivatives <bold>3a</bold> and <bold>3c</bold> (40 and 80 μ<sc>M</sc>) led to a significant (77–95 or 89–96%, resp.) inhibition of survival of human HT29 cells, <italic>i.e.</italic>, these two substances were <italic>ca.</italic> 63–72% or <italic>ca.</italic> 75%, respectively more effective than 5‐FU (<bold>1</bold>; positive control). Furthermore, derivative <bold>5a</bold> showed a significant, <italic>i.e.</italic>, 30 and 86%, inhibition of the survival at 40 and 80 μ<sc>M</sc>, respectively in comparison with the (negative) control. Some synthesized 5‐FUrd derivatives turned out to be more effective than 5‐FU (<bold>1</bold>) or 5‐FUrd (<bold>2a</bold>).</p> </abstract>