Synthesis, configurational stability and stereochemical biological evaluations of (S)- and (R)-5-hydroxythalidomides

Yamamoto, Takeshi; Shibata, Norio; Sukeguchi, Daisuke; Takashima, Masayuki; Nakamura, Shuichi; Toru, Takeshi; Matsunaga, Nozomu; Hara, Hideaki; Tanaka, Motohiro; Obata, Tohru; Sasaki, Takuma

doi:10.1016/j.bmcl.2009.02.108

Cited by 26 publications

(33 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Resultsmentioning

confidence: 51%

“…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.…”

Section: Resultsmentioning

confidence: 99%

“…[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).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Yamamoto

Tokunaga

Nakamura

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

A fundamental question is whether thalidomide (1) is stereospecifically teratogenic. The revival of 1 in the clinical field in the 21st century has re-activated an investigation of the molecular mechanism of the teratogenicity of 1. [1][2][3][4][5][6][7][8] Thalidomide (1) was popular especially for pregnant women as an effective antiemetic for morning sickness in the 1950-60s. The teratogenic side effects, leading to birth defects such as limb reduction, produced one of the most notorious medical disasters of modern medical history, and 1 was consequently withdrawn from the market in 1962. Thalidomide (1) possesses an asymmetric center in the glutarimide ring. Since 1 was marketed as a racemate, it was conceivable that sedative effects of 1 might be associated with one enantiomer and the unexpected teratogenic side effects might be ascribed to the other enantiomer. Twenty years after the thalidomide disaster, only (S)-thalidomide (1) was proved to be teratogenic.9) It was then concluded that the disaster could have been avoided if only the (R)-isomer of 1 had been marketed. However, it is presently unclear whether any of the actions of racemic 1 can be separated out using a pure enantiomer. According to the reports, considerable chiral inversion took place after incubation of enantiomerically pure 1. The strongly acidic hydrogen atom at the asymmetric center of 1 rapidly epimerizes under physiological conditions, rendering bioassay of the enantiomers difficult.10-12) Therefore, elucidation of the difference of biological activities between thalidomide enantiomers previously reported is said to be difficult. Therefore, the development of non-racemizable, chiral analogues of thalidomide has attracted much attention.13-16) 3Ј-Fluorothalidimide (2) was developed for this purpose several years ago by a member of our group and by others.17,18) Although the fluorine atom at the asymmetric center of 2 effectively obstructs racemization, the fluorine atom also introduces substantial electronic alterations into the molecule due to its highest electron negativity of 4.0, alterations that could be expected to significantly modulate biological activity. 19) Incidentally, deuterated drugs have been noted as a new strategy for drug discovery. [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). Deuterium at the 3Ј-position of 3 is expected to effectively block the racemization of thalidomide due to its isotopic effect without major alterations of biological activities. Results and DiscussionOptically pure 3Ј-deuteriothalidomide (3) was synthesized in four steps from ...

show abstract

Section: Resultsmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Yamamoto

Tokunaga

Nakamura

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

Self Cite

View full text Add to dashboard Cite

show abstract

“…5 Hydroxy and 5′- hydroxythalidomide were synthesized as reported previously. 17 Polyclonal anti human P450 3A4 antibodies were obtained from BD Biosciences (San Jose, CA). Other chemicals and reagents used in this study were obtained from the sources described previously 14 or were of the highest quality commercially available.…”

Section: Methodsmentioning

confidence: 99%

Thalidomide Increases Human Hepatic Cytochrome P450 3A Enzymes by Direct Activation of the Pregnane X Receptor

Murayama

Beuningen

Suemizu

et al. 2014

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Heterotropic cooperativity of human cytochrome P450 (P450) 3A4/3A5 by the teratogen thalidomide was recently demonstrated by H. Yamazaki et al. (2013) using the model substrate midazolam in various in vitro and in vivo models. Chimeric mice with humanized liver also displayed enhanced midazolam clearance upon pre treatment with orally administered thalidomide, presumably because of human P450 3A induction. In the current study, we further investigated the regulation of human hepatic drug metabolizing enzymes. Thalidomide enhanced levels of P450 3A4 and 2B6 mRNA, protein expression, and/or oxidation activity in human hepatocytes, indirectly suggesting activation of upstream transcription factors involved in detoxication, e.g. the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). A key event after ligand binding is an alteration of nuclear receptor conformation and recruitment of co regulator proteins that alter chromatin accessibility of target genes. To investigate direct engagement and functional alteration of PXR and CAR by thalidomide, we utilized a peptide microarray with 154 co regulator derived nuclear receptor interaction motifs and co regulator and nuclear receptor boxes, which serves as a sensor for nuclear receptor conformation and activity status as a function of ligand. Thalidomide and its human proximate metabolite 5 hydroxythalidomide displayed significant modulation of co regulator interaction with PXR and CAR ligand binding domains, similar to established agonists for these receptors. These results collectively suggest that thalidomide acts as a ligand for PXR and CAR and causes enzyme induction leading to increased P450 enzyme activity. The possibilities of drug interactions during thalidomide therapy in humans require further evaluation.

show abstract

“…9 It was initially believed that the R isomer is sedative, whereas the S isomer is teratogenic; however, the two enantiomers are readily interconvertible. 10 TD is metabolized in the liver to two major products, 5-hydroxythalidomide and 5´- hydroxythalidomide, by P450s. 11,12 We have previously shown that P450 3A4 and 3A5 also oxidize TD to the 5-hydroxy and dihydroxy metabolites.…”

Section: Introductionmentioning

confidence: 99%

The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage

Wani

Chakrabarty

Shibata

et al. 2017

Chem. Res. Toxicol.

Self Cite

View full text Add to dashboard Cite

Thalidomide [α-(N-phthalimido)glutarimide] (1) is a sedative and antiemetic drug originally introduced into the clinic in the 1950s for the treatment of morning sickness. Although marketed as entirely safe, more than 10,000 babies were born with severe birth defects. Thalidomide was banned and subsequently approved for the treatment of multiple myeloma and complications associated with leprosy. Although known for more than 5 decades, the mechanism of teratogenicity remains to be conclusively understood. Various theories have been proposed in the literature including DNA damage and ROS, inhibition of angiogenesis and inhibition of cereblon. All the theories have their merits and limitation. Although the recently proposed cereblon theory has gained wide acceptance, it fails to explain the metabolism and low dose requirement reported by a number of groups. Recently we have provided convincing structural evidence in support of the presences of arene oxide and the quinone reactive intermediates. However, the ability of these reactive intermediates to impart toxicity/teratogenicity needs investigation. Herein we report that the oxidative metabolite of thalidomide, di-hydroxythalidomide is responsible for generating ROS and DNA damage. We show using cell lines the formation of comet (DNA damage) and ROS. Using DNA cleavage assays we also show that catalase, radical scavengers and desferal is capable of inhibiting DNA damage. A mechanism of teratogenicity is proposed that not only explains the DNA damaging property but the metabolism, low concentration and species specificity requirements of thalidomide.

show abstract

Synthesis, configurational stability and stereochemical biological evaluations of (S)- and (R)-5-hydroxythalidomides

Cited by 26 publications

References 21 publications

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

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

Thalidomide Increases Human Hepatic Cytochrome P450 3A Enzymes by Direct Activation of the Pregnane X Receptor

The Dihydroxy Metabolite of the Teratogen Thalidomide Causes Oxidative DNA Damage

Contact Info

Product

Resources

About