Synthesis and antiproliferative properties of ibuprofen–oligo(3-hydroxybutyrate) conjugates

• Published in: European journal of medicinal chemistry Vol. 45; no. 5; pp. 1833 - 1842
• Main Authors: Zawidlak-Węgrzyńska, Barbara, Kawalec, Michał, Bosek, Izabela, Łuczyk-Juzwa, Maria, Adamus, Grażyna, Rusin, Aleksandra, Filipczak, Piotr, Głowala-Kosińska, Magdalena, Wolańska, Katarzyna, Krawczyk, Zdzisław, Kurcok, Piotr
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01-05-2010; Elsevier
• Subjects: 3-Hydroxybutyric Acid - chemical synthesis; 3-Hydroxybutyric Acid - chemistry; 3-Hydroxybutyric Acid - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal cancer cells; Dose-Response Relationship, Drug; Drug conjugates; Drug Evaluation, Preclinical; Female; Fluorescein; General aspects; Humans; Ibuprofen; Ibuprofen - chemical synthesis; Ibuprofen - chemistry; Ibuprofen - pharmacology; Medical sciences; Molecular Structure; Non-steroidal anti-inflammatory drugs; Oligo(3-hydroxybutyrates); Pharmacology. Drug treatments; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship; Colorectal cancer cells; Drug conjugates; Oligo(3-hydroxybutyrates); Ibuprofen; Fluorescein; Non-steroidal anti-inflammatory drugs; Antineoplastic agent; Solid tumor; Rat; Toxicity; Cytotoxicity; Oligomer; Arylpropionic acid derivatives; Colon; Mechanism of action; Chemical synthesis; Tumor cell; Human; Rodentia; Oral administration; Butyrate(hydroxy)polymer; In vitro; Biological activity; Non steroidal antiinflammatory agent; In vivo; Vertebrata; Mammalia; Cell line; Animal; Conjugated compound
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.01.020

Synthesis of novel conjugates of the non-steroidal anti-inflammatory drug – ibuprofen with nontoxic oligo(3-hydroxybutyrate) (OHB) is described. Presented results indicate that anionic ring-opening polymerization of (
R,
S)-β-butyrolactone initiated with an alkali metal salt of (
S)-(+)-2-(4-isobutylphenyl)propionic acid (ibuprofen) may constitute a convenient method of conjugation of selected drugs with biodegradable OHB. Furthermore using the MTT cell proliferation assay we demonstrated that ibuprofen conjugated with OHB exhibited significantly increased, as compared to free ibuprofen, potential to inhibit proliferation of HT-29 and HCT 116 colon cancer cells. However, the conjugates of ibuprofen and OHB are less toxic as was shown in oral acute toxicity test in rats. Although the mechanism of antiproliferative activity of ibuprofen–OHB conjugates (Ibu–OHB) has to be established, we suggest that partially it can be related to more effective cellular uptake of the conjugate than the free drug. This assumption is based on the observation of much more efficient accumulation of a marker compound – OHB conjugated with fluorescein, in contrast to fluorescein sodium salt, which entered cells inefficiently. Further characterization of biological properties of the ibuprofen–OHB conjugates would provide insight into the mechanism of their antiproliferative effect and assess the potential relevance of their anticancer activity.
The synthesis of ibuprofen conjugates with oligo(3-hydroxybutyrate) is described. These conjugates were found to exert significantly higher antiproliferative activity against colon cancer cells than the free ibuprofen.
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