Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors

Satō, Yoshiyuki; Onozaki, Yu; Sugimoto, Tatsuho; Kurihara, Hideki; Kamijo, Kaori; Kadowaki, Chie; Tsujino, Toshiaki; Watanabe, Akiko; Otsuki, Sachie; Mitsuya, Morihiro; Iida, Masato; Haze, Kyosuke; Machida, Takumitsu; Nakatsuru, Yoko; Komatani, Hideya; Kotani, Hidehito; Iwasawa, Yoshikazu

doi:10.1016/j.bmcl.2009.06.084

Cited by 50 publications

(29 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This approach allows to circumvent the use of undesired metal catalysts for enantioselective synthesis as well as kinetic resolution steps, which lead to loss of material. For example, ( S )‐1‐(2′‐chloro phenyl) 1‐ethanol ( 13 ) has recently been used as chiral key intermediate for the synthesis of thiophene‐benzimidazole and thiophene‐imidazopyridine derivatives, which are promising serine/threonine kinase PLK1 inhibitor candidates . PLK1 is a regulator of mitotic progression and cell division in eukaryotes and has a good antitumor efficacy .…”

Section: Resultsmentioning

confidence: 99%

“…We describe the application of xylose reductase [E.C.1.1.1.175] from Candida tenuis ( Ct XR) to enantioselectively synthesize chiral intermediates for the formation of two different groups of drugs . This enzyme reduces its natural substrate xylose to xylitol using NADPH or NADH as cofactor .…”

Section: Introductionmentioning

confidence: 99%

“…The resulting chiral key intermediates gained are exemplarily used to obtain oxetines, which are potent selective serotonin reuptake inhibitors . These secondary alcohols can also be applied to synthesize promising serine/threonine kinase polo‐like kinase 1 (PLK1) inhibitor candidates …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Candida tenuis Xylose Reductase Catalyzed Reduction of Aryl Ketones for Enantioselective Synthesis of Active Oxetine Derivatives

et al. 2012

View full text Add to dashboard Cite

Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1-phenyl-1-propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two-phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)-Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo-like kinase 1 inhibitor are discussed.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Candida tenuis Xylose Reductase Catalyzed Reduction of Aryl Ketones for Enantioselective Synthesis of Active Oxetine Derivatives

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Enzyme yield per liter culture volume was increased tenfold that is overall enzyme yield obtained from a 5‐L fermentation is sufficient for the production of 60 g ( S )‐1‐(2‐chlorophenyl)ethanol. The product is a required key intermediate in the synthesis of polo‐like kinase 1 inhibitors, a class of attractive cancer therapy candidates (Santamaria et al, 2007; Sato et al, 2009). The amount of ( S )‐1‐(2‐chlorophenyl)ethanol produced in this study would cover the demand of 100 patients for two treatment courses, assuming a product loss of 50% in synthesis of the API (calculated from the clinical phase studies I and II of the structurally and functionally related inhibitor BI2536 (Mross et al, 2008; Von Pawel et al, 2008)).…”

Section: Physiological Parameters Of E Coli Cultivations In a Batch mentioning

confidence: 99%

Scale‐up and intensification of (S)‐1‐(2‐chlorophenyl)ethanol bioproduction: Economic evaluation of whole cell‐catalyzed reduction of o‐Chloroacetophenone

Eixelsberger

Woodley

Nidetzky

et al. 2013

Biotech & Bioengineering

View full text Add to dashboard Cite

Escherichia coli cells co-expressing genes coding for Candida tenuis xylose reductase and Candida boidinii formate dehydrogenase were used for the bioreduction of o-chloroacetophenone with in situ coenzyme recycling. The product, (S)-1-(2-chlorophenyl)ethanol, is a key chiral intermediate in the synthesis of polo-like kinase 1 inhibitors, a new class of chemotherapeutic drugs. Production of the alcohol in multi-gram scale requires intensification and scale-up of the biocatalyst production, biotransformation, and downstream processing. Cell cultivation in a 6.9-L bioreactor led to a more than tenfold increase in cell concentration compared to shaken flask cultivation. The resultant cells were used in conversions of 300 mM substrate to (S)-1-(2-chlorophenyl)ethanol (e.e. >99.9%) in high yield (96%). Results obtained in a reaction volume of 500 mL were identical to biotransformations carried out in 1 mL (analytical) and 15 mL (preparative) scale. Optimization of product isolation based on hexane extraction yielded 86% isolated product. Biotransformation and extraction were accomplished in a stirred tank reactor equipped with pH and temperature control. The developed process lowered production costs by 80% and enabled (S)-1-(2-chlorophenyl)ethanol production within previously defined economic boundaries. A simple and efficient way to synthesize (S)-1-(2-chlorophenyl)ethanol in an isolated amount of 20 g product per reaction batch was demonstrated.

show abstract

“…In vivo studies have shown that competitive inhibition of PLK1 has good antitumor efficacy in xenograft tumor models (Santamaria et al, 2007). Thiophene-benzimidazole andimidazopyridine are currently among the most promising PLK1 inhibitor candidates and S-1-(o-chlorophenyl)-ethanol is used as chiral key intermediate in their synthesis (Sato et al, 2009). Asymmetric reduction of the ketone precursor o-chloroacetophenone is a preferred synthetic route towards chiral alcohol products.…”

Section: Introductionmentioning

confidence: 99%

Enzyme identification and development of a whole‐cell biotransformation for asymmetric reduction ofo‐chloroacetophenone

Kratzer

Pukl

Egger

et al. 2010

Biotech & Bioengineering

View full text Add to dashboard Cite

Chiral 1-(o-chlorophenyl)-ethanols are key intermediates in the synthesis of chemotherapeutic substances. Enantioselective reduction of o-chloroacetophenone is a preferred method of production but well investigated chemo- and biocatalysts for this transformation are currently lacking. Based on the discovery that Candida tenuis xylose reductase converts o-chloroacetophenone with useful specificity (kcat/Km=340 M(-1) s(-1)) and perfect S-stereoselectivity, we developed whole-cell catalysts from Escherichia coli and Saccharomyces cerevisiae co-expressing recombinant reductase and a suitable system for recycling of NADH. E. coli surpassed S. cerevisiae sixfold concerning catalytic productivity (3 mmol/g dry cells/h) and total turnover number (1.5 mmol substrate/g dry cells). o-Chloroacetophenone was unexpectedly "toxic," and catalyst half-life times of only 20 min (E. coli) and 30 min (S. cerevisiae) in the presence of 100 mM substrate restricted the time of batch processing to maximally ∼5 h. Systematic reaction optimization was used to enhance the product yield (≤60%) of E. coli catalyzed conversion of 100 mM o-chloroacetophenone which was clearly limited by catalyst instability. Supplementation of external NAD+ (0.5 mM) to cells permeabilized with polymyxin B sulfate (0.14 mM) resulted in complete conversion providing 98 mM S-1-(o-chlorophenyl)-ethanol. The strategies considered for optimization of reduction rate should be generally useful, however, especially under process conditions that promote fast loss of catalyst activity.

show abstract

Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors

Cited by 50 publications

References 16 publications

Candida tenuis Xylose Reductase Catalyzed Reduction of Aryl Ketones for Enantioselective Synthesis of Active Oxetine Derivatives

Candida tenuis Xylose Reductase Catalyzed Reduction of Aryl Ketones for Enantioselective Synthesis of Active Oxetine Derivatives

Scale‐up and intensification of (S)‐1‐(2‐chlorophenyl)ethanol bioproduction: Economic evaluation of whole cell‐catalyzed reduction of o‐Chloroacetophenone

Enzyme identification and development of a whole‐cell biotransformation for asymmetric reduction ofo‐chloroacetophenone

Contact Info

Product

Resources

About