Transition inhibitors

Chemical Reaction(s) Modeling and Design of Transition Inhibitors... 

Herbicidal Inhibition of Enzymes. The Hst of known en2yme inhibitors contains five principal categories group-specific reagents substrate or ground-state analogues, ie, rapidly reversible inhibitors affinity and photo-affinity labels suicide substrate, or inhibitors and transition-state, or reaction-intermediate, analogues, ie, slowly reversible inhibitors (106). 

Other miscellaneous compounds that have been used as inhibitors are sulfur and certain sulfur compounds (qv), picryUiydrazyl derivatives, carbon black, and a number of soluble transition-metal salts (151). Both inhibition and acceleration have been reported for styrene polymerized in the presence of oxygen. The complexity of this system has been clearly demonstrated (152). The key reaction is the alternating copolymerization of styrene with oxygen to produce a polyperoxide, which at above 100°C decomposes to initiating alkoxy radicals. Therefore, depending on the temperature, oxygen can inhibit or accelerate the rate of polymerization. 

Ubenimex, [(2(3),3(R))-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, was isolated as an inhibitor of aminopeptidases, on which it acts as a strong, reversible transition-state analogue inhibitor (293). Analogues of ubenimex have been made and some other aminopeptidase inhibitors, not all of them peptides, have been isolated from streptomycetes (294—296). 

The reaction is proposed to proceed from the anion (9) of A/-aminocatbonylaspattic acid [923-37-5] to dehydrooranate (11) via the tetrahedral activated complex (10), which is a highly charged, unstable sp carbon species. In order to design a stable transition-state analogue, the carboxylic acid in dihydrooronate (hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) [6202-10-4] was substituted with boronic acid the result is a competitive inhibitor of dibydroorotase witb a iC value of 5 ]lM. Its inhibitory function is supposedly due to tbe formation of tbe charged, but stable, tetrabedral transition-state intermediate (8) at tbe active site of tbe enzyme. 

A Tropsha, J Hermans. Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HIV protease. Protein Eng 51 29-34, 1992. 

A Li, V Daggett. Characterization of the transition state of protein unfolding by use of molecular dynamics Chymotrypsm inhibitor 2. Proc Natl Acad Sci USA 91 10430-10434, 1994. 

Deoxy-2-fluoroglucosides ( ) are mechanism-based glucosidase inhibitors Fluorine at C-2 slows the rate of the acetal C-OR (R = 2,4-dinitrophenyl) bond cleavage in S by destabilizing the proposed oxocarbonium lon-like transition state for glucosidase-catalyzed hydrolyses [28]... 

FIGURE 16.8 (a) Phosphoglycolohydroxamate is an analog of the enediolate transition state of the yeast aldolase reaction, (b) Purine riboside, a potent inhibitor of the calf intestinal adenosine deaminase reaction, binds to adenosine deaminase as the 1,6-hydrate. The hydrated form of purine riboside is an analog of the proposed transition state for the reaction. 

Radzicka, A., and Wolfenden, R., 1995. Transition state and mnltisnbstrate analog inhibitors. Methods in Enzymology 249 284-312. 

Wolfenden, R., and Frick, L., 1987. Transition state affinity and die design of enzyme inhibitors. Chapter 7 in Enzyme Mechanisms, edited by M. I. Page and A. Williams. London, England Royal Society of London. 

Wolfenden, R., and Kati, W. M., 1991. Testing the limits of protein-ligand binding discrimination widi transition-state analogue inhibitors. Accounts of Chemical Research 24 209-215. 

Lovastatin is administered as an inactive lactone. After oral ingestion, it is hydrolyzed to the active mevinolinic acid, a competitive inhibitor of the reductase with a Ki of 0.6 nM. Mevinolinic acid is thought to behave as a transition-state analog (Chapter 16) of the tetrahedral intermediate formed in the HMG-CoA reductase reaction (see figure). 

Apply appropriate film-forming inhibitors to reduce atmospheric corrosion during storage and transit. 

Vapor phase inhibitors These are used for the temporary protection of new plant in transit or prior to commissioning. Volatile corrosion inhibitors such as cyclohexylamine derivatives are used. The plant must be sealed or contained to prevent rapid loss of the inhibitor. Sachets of these materials are placed in packing cases. Papers impregnated with them are available for wrapping steel items. These inhibitors are used primarily to protect steel. 

The main function of most lubricants is to reduce friction and wear between moving surfaces and to abstract heat. They also have to remove debris from the contact area, e.g. combustion products in an engine cylinder, swarf in metal-cutting operations. Sometimes they have to protect the lubricated or adjacent parts against corrosion, but this is not a prime function of most lubricants. On the other hand, many lubricants do contain corrosion inhibitors and some lubricating oils, greases, mineral fluids and compounds are specially formulated to prevent the corrosion of machinery or machine parts, particularly when these components are in storage or transit. These temporary protectives are described in Section 17.3. 

S,3S)-Dicarboxyaziridine (112) was isolated from a Streptomyces strain in 1975 and found to have moderate antibacterial activity against Aeromonas salmonecida [176]. Subsequent studies showed that 112 acts as a competitive inhibitor of fumar-ase, through mimicry of a carbanionic transition state [177]. No biosynthetic studies have been reported for 112, but it is conceivable that it may arise from cydiza-tion of (3R)-hydroxyaspartic acid (Figure 11.18). 

The experimental evidence for the availability of the coordinative insufficiency of the transition metal ion in the propagation centers was obtained (175) in the study of the deactivation of the propagation centers by coordination inhibitors. On the introduction of such inhibitors as phosphine and carbon monoxide into the polymerization medium, the reaction stops, but the metal-polymer bond is retained. It shows that in this case the interaction of the inhibitor with the propagation center follows the scheme ... 

The propagation centers also react with the inhibitors inevitably present in the reaction medium. The interaction with coordination inhibitors may stabilize the transition metal-carbon bond, as the elimination of the coordinative insufficiency of the transition metal ion makes it impossible for the metal-carbon bond to rupture through the mechanism of the /3-hydride shift. 

The processes of reversible adsorption of the coordination" inhibitors (including the adsorption of organometallic compounds) result in an increase in the lifetime of the transition metal-carbon bond. It is possible that due to this, in the case of propylene polymerization by two-component catalysts based on TiCU, at low temperatures a long-term increase of molecular weight with time was observed (192,193). 

Olefin polymerization by catalysts based on transition metal halogenides is usually designated as coordinated anionic, after Natta (194). It is believed that the active metal-carbon bond in Ziegler-Natta catalysts is polarized following the type M+ - C. The polarization of the active metal-carbon bond should influence the route of its decomposition by some compounds ( polar-type inhibitors), e.g. by alcohols. When studying polymerization by Ziegler-Natta catalysts tritiated alcohols were used in many works to determine the number of metal-polymer bonds. However, as it was noted above (see Section IV), in two-component systems the polarization of the active bond cannot be judged by the results of the treatment of the system by alcohol, as the radioactivity of the polymer thus obtained results mainly from the decomposition of the aluminum-polymer bonds. 

Although the 3 - and 5 -polyphosphate derivatives mentioned above exhibit exquisite inhibitory potency these compounds are not cell permeable. To take advantage ofthepotency of such derivatives for studies with intact cells and tissues, there are two possibilities. One is chemically to protect the phosphate groups from exonucleotidases that also allows the compound to transit the membrane intact. The other is to provide a precursor molecule that is cell permeable and is then metabolized into an inhibitor by intracellular enzymes. The general term for such a compound is prodrug nucleotide precursors are also referred to as pronucleotides. Families of protected monophosphate derivatives were synthesized, based on (3-L- and 3-D-2, 5 -dd-3 -AMP, 3-L-2, 3 -dd-5 -AMP, and the acyclic 9-substituted adenines, PMEA and PMPA. Protective substituents were (i) -( -pivaloyl-2-thioethyl) ... 

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