Synthesis and pharmacological properties of N-(3-{3-(1-piperidinylmethyl)phenoxy}propyl)-2-(2-hydroxyethylthio)acetamide and related compounds as antiulcer agents. I.

Ueda, I.; Ishii, Kuniyoshi; Shinozaki, Katsuo; Seiki, Masao; Arai, Heihachiro; Hatanaka, Minoru

doi:10.1248/cpb.38.3035

Cited by 6 publications

(4 citation statements)

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“…In this case, however, TDG was incompletely utilized by SH91, however, with a large fraction of TDG biotransformed to HETA and TDG. Because both HETA and TDGA are useful chemicals [8,9,10,11], the second objective has added value, that is, it produces HETA and TDGA. Based on the metabolic pathway (TDG®HETA® TDGA®Cell Mass), a metabolic model was successfully constructed to describe the TDG mineralization process for SH91.…”

Section: Discussionmentioning

confidence: 99%

A metabolic model for thiodiglycol degradation: capacity constraint leads to byproduct accumulation

Lee

Chan

Weigand

et al. 2001

Bioprocess and Biosystems Engineering

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A metabolic model was developed to describe the degradation of thiodiglycol (TDG) by Alcaligenes xylosoxydans ssp. xylosoxydans (SH91). Experimental evidence has suggested there is a metabolic capacity constraint that limits the speci®c thiodiglycol utilization rate, leads to metabolic byproducts, and ultimately inhibits the overall degradation process. A global inhibition function, g, was introduced to mathematically characterize this constraint based on thiodiglycol consumption. The resulting model described well the dynamic response of cells consuming thiodiglycol in several reactor con®gurations (batch, repeated batch, repeated fed batch) and was used to optimize overall thiodiglycol degradation as well as de®ne conditions for optimizing conversion to byproducts [(2-hydroxyethyl)thio]acetic acid (HETA) and thiodiglycolic acid (TDGA), which are of commercial interest. IntroductionA gram-negative bacterium, Alcaligenes xylosoxydans ssp. xylosoxydans (SH91), was used to degrade thiodiglycol (TDG) in a sulfur mustard mineralization process. In our previous work [1], an Andrews inhibition model was used to describe the SH91 growth and TDG uptake in media containing less than 100 mM TDG. Subsequently, in experiments with high initial concentration (up to 600 mM), we identi®ed and quanti®ed several metabolites including [(2-hydroxyethyl)thio] acetic acid (HETA) and thiodiglycolic acid (TDGA), that were produced by SH91 [2, 3]. TDG is converted to HETA by an NAD + -dependent butanol dehydrogenase [4], which is also used to convert HETA to TDGA, resulting in two NADH produced per processed TDG. The pathway is depicted in Fig. 1. Accordingly, a model is presented here to describe SH91 growth in TDG medium that yields metabolic byproducts, HETA and TDGA. The model comprises three principal¯uxes, TDG®HETA, HETA®TDGA, and TDGA®Cell Mass. A global inhibition factor, g, is employed to describe the inhibition phenomena we have observed at high TDG concentration. This model describes a capacity constraint for the assimilation of TDG by the cell mass that, in turn, results in HETA and TDGA accumulation as an over¯ow phenomenon. The resulting model successfully described experimental results for batch (initial TDG concentration varied from 8 to 170 mM), repeated-batch (TDG feed concentration 270 mM), as well as repeated fed-batch experiments with linear feed (TDG feed concentration 290 mM). Materials and methods2.1 Microorganism, media, and culture conditions SH91, a gram-negative bacterium, consumes TDG as the sole carbon source for growth. Stock cultures were maintained on TDG medium of the following composition (per liter): TDG, 30 mM; ammonium sulfate, 2 g; potassium phosphate dibasic, 2 g; and modi®ed Wolin salts solution (WS42, [1]), 10 mL. Incubated cells ($0.3 OD) were added to the fermenters (1.5 L working volume, New Brunswick Scienti®c) as inocula (1.5% v/v). The best growth conditions were 30°C and pH 8 [3, 5]. Analytical methodsCell concentration was determined by optical density (OD 600 , Milton Roy, Spec21). Dry ...

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Section: Discussionmentioning

confidence: 99%

A metabolic model for thiodiglycol degradation: capacity constraint leads to byproduct accumulation

Lee

Chan

Weigand

et al. 2001

Bioprocess and Biosystems Engineering

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“…The organic solution is treated with ethyl acetate saturated with oxalate at 0-5°C. The phenoxypropylamine derivatives oxalate 6a -6f are obtain as white precipitates [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

“…Roxatidine acetate ( 4 ) was synthesized by a series of reaction including Leukart reductive amination, acylation and substitution [ 2 ]. On the basis of the bioisosterism principle phenoxypropylamines were prepared from compound 3 using primary amines [ 3 ]. The process is simple and moderate.…”

Section: Introductionmentioning

confidence: 99%

Phenoxypropylamines: Synthesis and Antiulcer Evaluation

Zhou

Zhang

et al. 2009

Molecules

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“…[(2‐Hydroxyethyl)thio]acetic acid (HETA) has been used as a raw material for the synthesis of several chemicals. Nishitani et al used HETA as raw material to produce antibiotics (1), Ueda et al used it to synthesize an antiulcer agent (2), and it was also used directly as a photothermographic photosensitive material (3). HETA is typically synthesized by the reaction of thioglycolic acid with 2‐chloroethanol, 2‐bromoethanol, ethylene oxide, or vinyl acetate (4, 5).…”

Section: Introductionmentioning

confidence: 99%

Biocatalytic Transformation of [(2-Hydroxyethyl)thio]acetic Acid and Thiodiglycolic Acid from Thiodiglycol by Alcaligenes xylosoxydans ssp. xylosoxydans (SH91)

et al. 2000

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A Gram-negative bacterium, Alcaligenes xylosoxydans ssp. xylosoxydans (SH91), consumed thiodiglycol (TDG), the nontoxic hydrolysis product of sulfur mustard, as a primary carbon source and transformed TDG to commercially relevant chemical precursors, [(2-hydroxyethyl)thio]acetic acid (HETA) and thiodiglycolic acid (TDGA). Aerobic fed batch and repeated batch experiments were run to compare the molar yields of HETA and TDGA that result under different operating policies. In repeated batch experiments, 35% of the TDG was converted to HETA. Under the conventional batch process and a repeated fed batch process, the HETA yields were reduced (21% and 18%, respectively), while the yield of TDGA was increased (47% and 31%,respectively). This work demonstrated that cell growth associated biocatalytic transformations were manipulated to achieve a desired byproducts profile through an understanding of the specific reaction and cell growth kinetics and by altering the reaction operating policy accordingly.

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Synthesis and pharmacological properties of N-(3-{3-(1-piperidinylmethyl)phenoxy}propyl)-2-(2-hydroxyethylthio)acetamide and related compounds as antiulcer agents. I.

Cited by 6 publications

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A metabolic model for thiodiglycol degradation: capacity constraint leads to byproduct accumulation

A metabolic model for thiodiglycol degradation: capacity constraint leads to byproduct accumulation

Phenoxypropylamines: Synthesis and Antiulcer Evaluation

Biocatalytic Transformation of [(2-Hydroxyethyl)thio]acetic Acid and Thiodiglycolic Acid from Thiodiglycol by Alcaligenes xylosoxydans ssp. xylosoxydans (SH91)

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