Synthesis of enantiomerically enriched drug precursors and an insect pheromone via reduction of ketones using commercially available carbonyl reductase screening kit “Chiralscreen® OH”

Nagai, Toshiya; Sakurai, Saki; Natori, Naoki; Hataoka, Manaka; Kinoshita, Takako; Inoue, Hirokazu; Hanaya, Kengo; Shoji, Mitsuru; Sugai, Takeshi

doi:10.1016/j.bmc.2017.03.067

Cited by 12 publications

(7 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In parallel, the bromobenzyl carbamate ( 15 ) was synthesized through the following sequence (Scheme 2). 3-Hydroxybenzaldehyde ( 16 ) was carbamoylated using ethylmethylcarbamic chloride to yield the carbamate 17 [10]. The aldehyde group of the latter was reduced by NaBH 4 , and the alcohol derivative 18 was brominated by PBr 3 to give 15 .…”

Section: Resultsmentioning

confidence: 99%

“…Compound 7 docks in the AChE active site with the carbamate group in proximity of Ser203, as imposed by the constraint, but it is positioned much higher in the AChE binding site in two clusters compared to the donepezil and/or the donecopride (Figure 3) [5,6,7,8,9,10,11,12,13]. Consequently, according to our molecular modeling results, compound 7 loses the characteristic interactions of the donecopride ligands family, i.e.,: i) interaction between NH + of piperidine ring through the water molecule lying between the hydroxy groups of two tyrosines (Tyr341 and Tyr337); ii) interaction via C=O group with the backbone NH of Phe295; and iii) the methoxyphenyl moiety is placed a little high but stacking with Trp286 remains possible.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

et al. 2019

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

et al. 2019

View full text Add to dashboard Cite

show abstract

“…However, no corresponding alcohols were obtained. 57 Several KREDs from Codexis are capable of reducing β-substituted tetralones and a rather bulky tetralone derivative, which can be used as a precursor for (S,S)sertraline. 58 Using 64 as a model substrate, a series of KREDs with different stereoselectivity (−72% to 100% ee, S) were obtained by screening KRED libraries from Biocatalytics (CA, USA) and Julich Chiral Solutions (Julich, Germany).…”

Section: Sources and Propertiesmentioning

confidence: 99%

Stereochemistry in Asymmetric Reduction of Bulky–Bulky Ketones by Alcohol Dehydrogenases

Zhou

2020

ACS Catal.

View full text Add to dashboard Cite

Biocatalyzed asymmetric reduction of ketones is one of the most cost-effective and environmentally friendly approaches for preparing chiral alcohols. However, few natural ketone reductases (KREDs) or alcohol dehydrogenase (ADHs) with high activity and stereoselectivity toward bulky–bulky ketones have yet been reported due to the strong steric hindrance of these substrates. Recent developments in protein engineering have led to biocatalysts capable of producing chiral alcohols with high efficiency and stereoselectivity. This review discusses recent advances in several approaches for the manipulation of stereoselectivity, including engineering of the binding pocket and active site loops to accommodate bulky–bulky ketones, modulating the electronic effects on attraction and repulsion between binding pocket residues and substituents of ketone substrates, and adding traceless directing groups to substrates to alter their orientation. Microbial sources of KREDs and ADHs, screening techniques, and future outlooks for the field are also discussed.

show abstract

“…( S )‐Rivastigmine synthesis has been reported in the literature in 7 steps, but ( S )‐rivastigmine could be synthesized starting from the ( R )‐ 2h compound in both less steps and cheaper. In addition, a chiral molecule was synthesized in small scale with 99% enantioselectivity for the synthesis of ( S )‐rivastigmine with the commercially purchased pure enzyme in the literature . Despite the use of pure enzyme, this compound, which is obtained in the literature, has both a low conversion and yield.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, a chiral molecule was synthesized in small scale with 99% enantioselectivity for the synthesis of (S)-rivastigmine with the commercially purchased pure enzyme in the literature. [24] Despite the use of pure enzyme, this compound, which is obtained in the literature, has both a low conversion and yield. For the synthesis of (S)-rivastigmine, we obtained in scale-up with high conversion and yield of 2h in 99% enantiomeric purity using Lactobacillus paracasei BD87E6 biocatalyst as whole cell.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Enantiomerically Enriched Drug Precursors by Lactobacillus paracasei BD87E6 as a Biocatalyst

Öksüz

Şahin

Dertli

2018

Chemistry & Biodiversity

View full text Add to dashboard Cite

Global sales of single enantiomeric drug products are growing at an alarming rate every year. A total of 7 bacterial strains were screened for their ability to reduce acetophenones to its corresponding alcohol. Among these strains Lactobacillus paracasei BD87E6 was found to be the most successful biocatalyst to reduce the ketones to the corresponding alcohols. The reaction conditions were systematically optimized for the reducing agent Lactobacillus paracasei BD87E6, which showed high enantioselectivity and conversion for the bioreduction. The preparative scale asymmetric reduction of 3‐methoxyacetophenone (1h) by Lactobacillus paracasei BD87E6 gave (R)‐1‐(3‐methoxyphenyl)ethanol (2h) with 92% yield and 99% enantiomeric excess. Compound 2h could be used for the synthesis of (S)‐rivastigmine which has a great potential for the treatment of Alzheimer's disease. This study demonstrates that Lactobacillus paracasei BD87E6 can be used as a biocatalyst to obtain chiral carbinol with excellent yield and selectivity. The whole cell catalyzed the reductions of ketone substrates on the preparative scale, demonstrating that Lactobacillus paracasei BD87E6 would be a valuable biocatalyst for the preparation of chiral aromatic alcohols of pharmaceutical interest.

show abstract

Synthesis of enantiomerically enriched drug precursors and an insect pheromone via reduction of ketones using commercially available carbonyl reductase screening kit “Chiralscreen® OH”

Cited by 12 publications

References 47 publications

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

Stereochemistry in Asymmetric Reduction of Bulky–Bulky Ketones by Alcohol Dehydrogenases

Synthesis of Enantiomerically Enriched Drug Precursors by Lactobacillus paracasei BD87E6 as a Biocatalyst

Contact Info

Product

Resources

About