Theoretical aspects of the chemistry of the hydroxyl group

Mechanism of inhibition of rat liver bilirubin UDP-glucuronosyltransferase by triphenylalkyl derivatives

“…6-(Fluorenyl)hexanoic acid (31) and 6-(indenyl)hexanoic acid (32) were synthesized using the same protocol as described for 5Ј,5Ј,5Ј-triphenylpentyl-2-malonic acid (25), with fluorene and indene as starting materials, respectively. Monobenzyl diethylene glycol (33) was prepared by the action of the alcoolate of diethelene glycol on bromobenzyl, and the corresponding acid (34) was obtained after Jones oxidation. 5,5-diphenyl-1-pentanol (35) was prepared by condensation of diphenylmethyllithium and tetrahydropyranyl 4-chlorobutanylether in the same conditions used by Descoins et al (17).…”

“…N-(2,2,2-triphenylacetyl)-4-aminobutyric acid (26) has an optimal chain length for inhibition, but it did not inhibit bilirubin glucuronidation (IC 50 Ͼ 1 mM) ( Table 2). Molecular modeling (GEOMOS) showed that this compound led to a low-energy con-former that contains intramolecular hydrogen bonds (d ‫ס‬ 1.81 Å ), thus increasing the acidity of the carboxyl group (33).…”

“…Substitution of the triphenylmethyl moiety with benzyl (33,34) or diphenylmethyl (35) groups resulted in poor inhibitors (Table 3). By contrast, substitution by diphenyl-tert-butylsilyl (28) or triphenylsilyl (23) moieties produced potent inhibitors with IC 50 of 0.15 and 0.17 mM, respectively (Tables 2 and 3).…”