Retinoic acid conjugation

Base-induced elimination of sulphinate from homoallylic sulphones , from y-ketosulphones , and from 1,2-bissulphones has been used in synthetic sequences ranging from the preparation of retinoic acid and of its methyl ester , to a novel pentannulation sequence that leads to a range of cross-conjugated dienes , as exemplified by equation (69). The overall yield for the two steps was 63%. 

Xiang, J., F. S. Rondonuwu, Y. Kakitani, R. Fujii, Y. Watanabe, Y. Koyama, H. Nagae, Y. Yamano, and M. Ito. 2005. Mechanisms of electron injection from retinoic acid and carotenoic acids to Ti02 nanoparticles and charge recombination via the T, state as determined by subpicosecond to microsecond time-resolved absorption spectroscopy Dependence on the conjugation length. J. Phys. Chem. B 109 17066-17077. 

It was found that formation of the 6-cyclodextrin inclusion complex improved the compound solubility from less than 0.5 mg/mL to 160 mg/mL, eliminating the formulation problems associated with solubility concerns [65]. Although retinoic acid does exhibit intrinsic CD when dissolved in dimethyl sulfoxide, the CD spectrum is drastically upon formation of the cyclodextrin inclusion complex (see Figure 10). That CD can be measured in the absorption bands located at 350 and 400 nm can be taken as evidence that it is the conjugated sidechain of the retinoic acid solute which becomes included in the cavity of the cyclodextrin host system. 

In addition to bile acid conjugation, a variety of other compounds may also be excreted as taurine conjugates, including retinoic acid (Section 2.2.1.3) and a number of xenobiotics. 

Evidence for the preferential formation of the rraRS-substituted product of selenium dioxide allylic oxidation is seen in the synthesis of part of (13Z)-retinoic acid (equation 48). Reaction took place exclusively at the exocyclic double bond without rearrangement. Allylic oxidation of this nature has also been used in the synthesis of 6-conjugated 2-pyrones (equation 49). This intermediate was employed in the total synthesis of natural pyrones such as yangonin. 

The toxicity and bioavailability can be varied by conjugation to form new derivatives such as glu-curonides that are metabolized differently than the parent compound. An example is a glucuronide derivative of the aminophenol amide of dX -trans retinoic acid, fenretinamide (A-(4-hydroxyphenyl)-retinamide, 4-HPR) (117). 

The mechanism of action for retinoid glucuronides is not established [192]. A novel action of the conjugates is suggested, because the glucuronides do not bind to cellular retinoic acidbinding proteins or to nuclear receptors for retinoic acid, although they are active prior to their... 

Future work includes defining endogenous plasma levels of 13-cis and all trans retinoic acid in an expanded population and determining whether normal plasma levels are affected by disease or nutritional state. Finally, the assay will be expanded to measure the major metabolites of retinoic acid (4-hydroxy, 4-oxo, glucuronide conjugates, etc.). 

Retinoic acid from the intestinal mucosa is transported bound to serum albumin via the portal vein. Retinoic acid cannot be significantly reduced to retinal but is rapidly metabolized in tissue, such as Uver, to yield more polar catabohtes (e.g., 5,6-epoxyretinoic acid) and conjugates, such as retinoyl p-glucuronide, that are excreted. A small amount of retinoic acid undergoes enterohepatic circulation after intestinal hydrolysis of the glucuronide is excreted in the bile. 

Shirley, M.A. Bennani, Y.L. Boehm, M.F. Breau, A.P. Pathirana, C. Ulm, E.H. Oxidative and reductive metabolism of 9- s-retinoic acid in the rat. Identification of the 13,14-dihydro-9-cis-retinoic acid and its taurine conjugate. Drug Metab.Dispos., 1996, 24, 293-302... 

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