Toxic analogues

Selection of these regulatory mutants is often done by using toxic analogues of amino adds for example p-fluoro-DL-phenylalanine is an analogue of phenylalanine. Mutants that have no feedback inhibition or repression to the amino add are also resistant to the analogue amino add. They are therefore selected for and can be used to overproduce the amino add. Some amino add analogues function as false co-repressors, false feedback inhibitors or inhibit the incorporation of foe amino acid into foe protein. 

Many nitrogen containing substances which cannot be used as metabolites (including toxic analogues of natural metabolites) are also transported, due to their likeness to natural permease substrates. 

Tsujimoto, M., Kotani, S., Okunaga, T., Kubo, T., Takada, H., Kubo, T., Shiba, T., Kusumoto, S., Takahashi, T., Goto, Y. Enhancement of humoral immune responses against viral vaccines by a non-pyrogenic 6-O-acylmuramyldipeptide and synthetic low toxicity analogues of lipid A. 

A substantial body of literature documents the side effects of platinum compounds. The nephrotoxicity of the parent compound cisplatin almost led to its abandonment, until Cvitkovic et al. introduced aggressive hydration, which prevented the development of acute renal failure [2] [3], As noted above, the toxicity of cisplatin was a driving force both in the search for less toxic analogues and for more effective treatments for its side effects, especially nausea and vomiting. 

For the aromatic pathway (Figure 30.20), the critical control points are the condensation of phosphoenolpyruvate and erythrose-4-phosphate to 3-deoxy-D-arabinoheptulosonate 7-phosphate, DAHP, by DAHP synthase. For tryptophan, the formation of anthranilic acid from chorismic acid by anthranilate synthase is the second critical control point. The transcriptional regulation was overcome through the use of alternative promoters and allosteric regulation was circumvented by the classical technique of selection for feedback-resistant mutants using toxic analogues of the repressing compounds. 

Paracetamol is now sold in smaller packs to make it more difficult for suicidal people to acquire sufficient drug for an overdose. An understanding of why the drug is toxic has stimulated the development of other possibly less toxic analogues of this drug. 

X 10 (the assay s limit of detection). This high level of selectivity is to be expected as the incorporation of serine may lead to the formation of the potentially toxic analogue oxy-CoA, and raises the question as to the mechanism whereby this selectivity is achieved. One proposal has it that, by using pathway a, PPCS enzymes may select cysteine by using the difference in pi), values between thiols and alcohols and the higher nucleophilicity of thiolates to form the thioester 16 first, which subsequently rearranges to the thermodynamically more stable amide. Unfortunately, no experimental validation of this proposed mode of selection has been achieved as yet. 

It has been used for the treatment of local intestinal infections, specifically bacillary dysentry, but it has mostly been replaced by comparatively less toxic analogues, namely phthalylsulphatiazole and succinylsulphathiazole. 

Cisplatin was introduced into clinical practice in 1971 (only some five years after the initial discovery of its cell-killing properties), and the less toxic analogue, carboplatin, in 1981. To date, carboplatin is the only platinum analogue to have received worldwide registration. Comparative clinical properties of cisplatin and carboplatin are summarised in Table 1. 

However, when the methods of analysis are shifted from MBAs to alternative methods, there is need for information about relative toxicities (TEFs) of all toxic analogues within each toxin group. With that information, the total toxicity of each toxin group can be expressed in equivalents (TEQs) by the signature toxin for the group, STX-eq., OA-eq., AZA-l-eq., and so on. For analogues where this information is lacking, a relative toxicity of 1 may be apphed in the interim. 

The anthracyclines are among the most important antitumour agents for the treatment of hmnan cancer due to their broad efficacy. However, their severe toxicity has limited their usefulness and consequently stimulated an intensive synthetic effort directed towards the synthesis of less toxic analogues. Nearly 300 papers have been published detailing the synthetic effort towards the anthracyclines. Of this number less than 10 percent (24) have resulted in optically active compounds while the remainder have produced racemic material. Since one enantiomer is usually the biologically active one there is a definite need for better synthetic routes to the anthracyclines. 

A large number of ansamacrolides, exemplified by maytansine, 8, have potent antitumor activity. Maytansine has been subjected to clinical studies in the NCI program and has been disappointing as an anticancer agent. Furthermore, it has been shown to be quite toxic. Analogue development may produce a more useful and less toxic antitumor agent in the future (881). 

The precursor of bleomycin, phleomycin, was too nephrotoxic for development and the search for less toxic analogues resulted in the discovery of bleomycin [4, 8]. The major dose-limiting toxicity is pulmonary fibrosis and other serious toxicides noted have been hyperpyrexia, acute hypotensive responses and mucositis. The pulmonary toxicity appears to be dose-related and has led to fatalities. Bleomycin is administered as the metal-free chelate and is absorbed when administered orally excretion is mainly by renal clearance. 

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