N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol

Abstract

Abstract:Resveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH3-[OCH2CH2]n-) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption.

Resveratrol derivatives as a pharmacological tool

“…The use of methoxy‐OEGs as promoieties was helpful in modulating physicochemical and absorption properties of derivatives . Results of pharmacokinetics studies confirmed the observations already reported for acetal derivatives: variations in the length of the OEG sequence affect the absorption of the prodrug.…”

“…N ‐monosubstituted carbamate derivatives were thus developed and tested . They are stable in acidic solutions (resembling the gastric pH), but undergo hydrolysis at higher pH values (near‐neutral solutions, resembling the intestinal pH).…”

Insight into the mechanism of cytotoxicity of membrane-permeant psoralenic Kv1.3 channel inhibitors by chemical dissection of a novel member of the family

“…HPLC/ESI-MS analysis was used to confirm the purity (>95%) of isolated intermediates and products. PAP-OH [ 10 ], Ts-MTEG [ 24 ], Ts-MHEG [ 24 ], PAP-1 [ 18 ] and POP-OH [ 49 ], were prepared according to adapted literature procedures. The spectroscopic data for these compounds was consistent with the literature.…”

“…Since our active principle is a “small” organic molecule (PAP-1), using relatively short methoxy-oligoethylene glycol (MOEG) chains to modify its properties seems preferable to attaching macromolecules. Our group has previously utilized MOEGs to form prodrugs of the natural polyphenol Resveratrol [ 24 ] endowed with enhanced water solubility and protection from first-pass metabolism after oral administration. The compounds could freely permeate biomembranes, thus suggesting that their psoralenic analogs might as well.…”

The Design, Synthesis, and Characterization of Resveratrol Derivatives Modified by Different γ-Aminobutyric Acid Esters

“…N-Monosubstituted carbamate esters are usually synthesized through two steps: first, the desired primary amine is reacted with a phosgene or its equivalent to give a reactive isocyanate derivative; then, the intermediate is coupled with the phenolic functional group [12,27]. ese procedures, however, provide low yields of the desired trisubstituted resveratrol derivatives likely because the high reactivity of the isocyanate group promotes the polymerization side reaction that entrains the stilbene C-C double bond [28]. e final products were obtained with good yields through this route.…”