Metabolic neutral transformation

With regard to metabolic stability bioisosteric replacements, that is, substituents that are interchangeable with minimal effect on metabolism, one could look at the most neutral transformations, that is, the ones that did not result in a favorable or unfavorable effect on metabolic stability, at least within the defined tolerance threshold of 25%. The substituents of these transformations are therefore, by definition, isosteres. The 12 most neutral transformations in terms of the percentage of examples that led to no significant change are listed in Table 6.4. 

Table 6.4 The 12 most neutral transformations (with >30 examples each) in terms of metabolic stability. 

A variety of approaches are routinely used to qualitatively and/or quantitatively assess toxicant-induced cell death in vitro. For example, dye-based cytotoxicity assays are widely employed to assess the viability of cells in culture. While initially developed for use in mammalian cell lines, these approaches have been successfully applied in toxicological studies using fish cell lines27. The principle behind many of these assays is the ability of metabolically active cells to either exclude (e.g. trypan blue), incorporate (e.g. neutral red), and/or metabolically transform (e.g. 3-[4,5-dimethylthiazol-3-yl]-2,5-diphenyltetrazolium bromide (MTT)) colorimetric... 

Identification of the overall neutral, least detrimental, and least favorable transformations with regard to metabolic stability and identification of interesting isosteres. 

Umbellate pore-fungus, Zhuling in Chinese, is the pore-fungus of Polyporus umbellatus (Pers.) Fr. (Polyporaceae), This drug is widly used in traditional Chinese medicine. The properties and taste are sweet or without taste and neutral. It enters the kidney and urinary meridians. The functions are to transform dampness and promote water metabolism. The indications for use of Umbellate pore fungus are dysuria, turbid urine, edema, diarrhoea and profuse leukorrhea [87]. 

Several prodrugs of Hourouracil were obtained by acylation or carbamoylation of N-1 and/or N-3 atoms of the pyrimidine ring of 1. In particniar, an oral drug Carmofur (2) which is 1-hexylcarbamoyl derivative of 1 was launched in Japan in 1981 and later - in other countries [35], The carbamate moiety in 2 decomposes gradually in neutral water or in basic conditions, but it is strongly resistant to acidic hydrolysis and hence can survive acid in the stomach. The 1-hexylcarbamoyl moiety also facilitates the rapid uptake of 2 through the cell membrane [36]. The metabolic activation of Carmofur involves oxidation and scission of the side-chain with slow release of 1 [37]. Two main routes of the side chain transformation are (o-oxidation and ((o-l)-oxidation metabolites 40-43 were detected after adnunis-tration of Carmofur (Fig. 3) [38]. Non-enzymatic hydrolytic decomposition of 2 and its metabolites also contributes to release of 1. 

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