Enzymatic resolution and evaluation of enantiomers of cis-5′-hydroxythalidomide

Abstract

The straightforward synthesis of both enantiomers of cis-5'-hydroxythalidomide, a major metabolite of thalidomide, has been accomplished by enzymatic kinetic resolution of a racemic substrate catalyzed by Pseudomonas stutzeri lipase TL. cis-5'-Hydroxythalidomide shows resistance to racemization (and epimerization) at physiological pH. A tube formation assay to assess the ability to inhibit angiogenesis revealed that cis-5'-hydroxythalidomides are inactive.

Synthesis and Configurational Stability of (S)- and (R)-Deuteriothalidomides

“…In the study, (S)-1 was racemized and decayed in all buffer solutions; the rates of racemization and hydrolysis were rather quick in neutral and alkaline buffer solutions, which were consistent with the earlier studies by Hashimoto as well as by us. 11,28,29) As expected, the stability of (S)-3 toward racemization is higher than that of (S)-1 under all conditions. The half-life to racemization of (S)-1 was estimated by a plot of the experimental data, t 0.5 ϭR/Sϭ0.5 while the racemization half-lives of (S)-1 were found to be 31.8 h at 6.18 pH, 29.9 h at 7.78 and 3.5 h at 8.76 in buffer solution at 37°C, those of (S)-3 were 156.3 h at pH 6.18, 59.5 h at pH 7.78 and 17.9 h at pH 8.76 (Fig.…”

“…This result implies that the rate of racemization of 3 is slower than that of 1 because the half-life of racemization of 1 is reported to be about 10 h under neutral conditions. 11,28,29) These observations encouraged us to investigate the stability of optically active 1 and 3 toward racemization and hydrolysis (decay). Optically pure (S)-1 and (S)-3 were incubated at 37°C and varying pH values, and monitored by HPLC.…”

“…[20][21][22][23][24][25] They have basically the same properties as hydrogenated compounds, but are resistant to metabolism due to the higher stability of the carbon-deuterium (C-D) bond than that of the carbon-hydrogen (C-H) bond. As a result of our research designed to produce an analogue of thalidomide that is resistant to racemization and is also a close structural mimic, [26][27][28][29] we describe herein the design and synthesis of 3Ј-deuteriothalidomide (3), the most closed isostere of thalidomide (Fig. 1).…”

Lipase from Pseudomonas stutzeri: Purification, homology modelling and rational explanation of the substrate binding mode

“…co.jp/meito/kaseihin/index e.html) has proven to be an attractive alternative for the recognition of alcohols possessing large groups at the asymmetric carbon atom, such as wood sterols [10], benzoins [11][12][13] and other bulky secondary alcohols [14][15][16]. On the other hand, this enzyme has been shown to be very active in hydrophobic solvents, such as toluene [15], or polar ones, such as acetone, 1,4-dioxane [16] or THF [11][12][13][14], also displaying an increase in activity and stability upon immobilization [17]. Furthermore, Lipase TL has proven to be also useful for N-acetylalanine deprotection [18], stereoselective acylation of 2-chloro-1-(2,4-difluorophenyl)ethanol [19] or aminolysis reactions [20] in 2-methyltetrahydrofuran (2-MeTHF), a greener substitute for THF displaying very interesting properties.…”

Hydrolases in the Stereoselective Synthesis of N-Heterocyclic Amines and Amino Acid Derivatives

“…76 A great excess of the acyl donor (125 equiv) was necessary for the formation of the enantiopure alcohol (3S,5R)-80 after a reasonable reaction time (69 h). The biological evaluation of optically active (3S,5R)-and (3R,5S)-80 showed that these derivatives failed to show the antiangiogenesis activity that is closely related with the teratogenicity of thalidomide.…”