Introducing Lipophilicity to (Polyhydroxyalkyl)thiazolidine Carboxylic Acids Via Acylation.

The therapeutic efficacy of bioactive compounds is related to their bioavailability. In turn, the bioavailability depends on the equilibrium between the hydrophilicity and the lipophilicity. 2(R,S)-(Polyhydroxyalkyl)thiazolidine-4(R) carboxylic acids (TCAs), obtained from the condensation of l-cysteine and an aldose, have been recognized as nontoxic precursors of glutathione with important preventive and therapeutic effects. The bioavailability of these compounds can be improved by enhancing their lipophilicity. This can be achieved by the introduction of some acyl groups derived from fatty acids via esterification of the aldose hydroxyl groups. With this purpose four new compounds were synthesized through a selective palmitoyl acylation of d-(-)-ribose and d-(+)-glucose and subsequent condensation with l-cysteine. In addition, the log P of the new compounds was calculated as a measure of the lipophilicity, and in vitro 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) tests were performed as a measure of the antioxidant capability.

Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists.

The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.