Hill inhibitors

Artificial electron acceptors, such as ferricyanide, can be substituted for NADP these give rise to oxygen evolution but involve only a short segment of the oxidation chain. This partial reaction is known as the Hill reaction and compounds that disrupt it are known as Hill inhibitors. Herbicides that inhibit the Hill reaction, by blocking electron transport, prevent the production of ATP and NADPH required for carbon dioxide fixation. 

Heterocyclic Inhibitors. Around 1968, results obtained with a new generation of Hill inhibitors, which lacked a free amide hydrogen, began to appear in the literature. A very complete structure-activity study was conducted by Draber et at. 

Starvation. The early reports that Hill inhibitors limited photosynthesis and that starch disappeared from treated plants, prompted some investigators to refer to these compounds as photosynthesis inhibitors. Photosynthesis is inhibited because ATP and NADFH are not available for carbon dioxide fixation. However, there is little evidence that the plants starve to death. If this were the only process affected, phytotoxic symptoms should resemble those that appear on plants kept in total darkness. Deficiency of photosynthate does limit new growth, but does not account for the morphological alterations that occur within a few hours after treatment. The mechanisms that lead to phytotoxicity appear to be considerably more complex than would result from limiting carbohydrate synthesis by suppression of carbon dioxide fixation (2). ... 

Free Radical Mechanisms. The appearance of phytotoxic symptoms only in the light after treatment of plants with herbicides such as diuron and atrazine prompted some investigators to propose "light-activation1 hypotheses, the formation of toxic substances, or the formation of reactive free radicals. However, except for the strong documentation on the formation of free radicals by bipyridiliums, there is no direct evidence that toxic components are formed from an interaction between a herbicidal Hill inhibitor and light (2). ... 

Many, if not all, of the biochemical, physiological, and morphological alterations observed following application of the Hill inhibitors to plants can be accounted for on the basis of interference with ATP production. Without the needed ATP, growth stops, cellular functions are arrested, the integrity of the... 

Rozenfeld I L 1981 Corrosion inhibitors (New York McGraw-Hill)... 

Rozenfeld, 1. L., Corrosion Inhibitors, McGraw-Hill, New York (1981)... 

Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR (1996) Identification of a major co-receptor for primary isolates of HIV-1. Nature 381 661-666 Derdeyn CA, Decker JM, Sfakianos JN, Wu X, O Brien WA, Ratner L, Kappes JC, Shaw GM, Hunter E (2000) Sensitivity of human immunodeficiency virus type 1 to the fusion inhibitor T-20 is modulated by coreceptor specificity defined by the V3 loop of gpl20. J Virol 74 8358-8367... 

Tartrate is a most widely used inhibitor of prostatic acid phenylphosphatase activity. With this inhibitor Bonner and associates detected five cases of unsuspected carcinoma of the prostate in 221 hospital patients and clarified the diagnoses in another four patients (98). Nonetheless, the diagnostic specificity of an elevated 1-tartrate inhibited activity is not absolute, as Fishman et. al found it elevated in 48 of 1,190 males without cancer. Whitmore and associates also observed this activity to be elevated in 3 of 20 patients with uncomplicated nodular hyperplasia (102). Hill compared the total versus the "prostatic" serum activities in 20 patients with localized untreated carcinoma of the prostate and observed... 

To account for differences in the Hill coefficient, enzyme inhibition data are best ht to Equation (5.4) or (5.5). In measuring the concentration-response function for small molecule inhibitors of most target enzymes, one will hnd that the majority of compounds display Hill coefficient close to unity. However, it is not uncommon to hnd examples of individual compounds for which the Hill coefficient is signihcandy greater than or less than unity. When this occurs, the cause of the deviation from expected behavior is often reflective of non-ideal behavior of the compound, rather than a true reflection of some fundamental mechanism of enzyme-inhibitor interactions. Some common causes for such behavior are presented below. 

Figure 5.6 Biphasic concentration-response plot for an enzyme displaying a high- and low-affinity binding interaction with an inhibitor. In panel A, the data are fit to Equation (5.4) and the best fit suggests a Hill coefficient of about 0.46. In panel B, the data are fitted to an equation that accounts for two, nonidentical binding interactions Vj/v0 = (a/(l + ([/]/ICs0))) + ((1 - a)/(l+([t]/IC(o)))> where a is an amplitude term for the population with high binding affinity, reflected by IC , and IC 0 is the IC50 for the lower affinity interaction. (See Copeland, 2000, for further details.)...

The second common cause of a low Hill coefficient is a partitioning of the inhibitor into an inactive, less potent, or inaccessible form at higher concentrations. This can result from compound aggregation or insolubility. As the concentration of compound increases, the equilibrium between the accessible and inaccessible forms may increase, leading to a less than expected % inhibition at the higher concentrations. This will tend to skew the concentration-response data, resulting in a poorer... 

For example, if the Hill coefficient (h) is unity, and we wish to achieve 25% inhibition, the fraction velocity would be 0.75, and its reciprocal (voM) would be 1.33. Plugging this into Equation (5.9), we find that 25% inhibition is obtained at a concentration of inhibitor equal to 1/3 IC50. Table 5.3 summarizes the four inhibitor concentrations needed to achieve the desired inhibition levels (again, at [5] = KM) when the Hill coefficient is unity and 3.0. 

Table 5.3 Concentrations of inhibitor, relative to the IC50, required for different levels of inhibition for concentration-response plots displaying Hill coefficients (h) of 1.0 and 3.0...

Figure 7.1 Concentration-response plots for a series of compounds displaying Kf9p values ranging from 100 to 0.01 nM, when studied in an enzyme assay for which the enzyme concentration is 50nM. The lines through the data sets represent the best fits to the standard isotherm equation that includes a non-unity Hill coefficient (Equation 5.4). Note that for the more potent inhibitors (where Kf" < [E]T), the data are not well fit by the isotherm equation.

Provided that a value for KL is available, it is possible to use this equation to obtain a value for Kh the dissociation equilibrium constant for the inhibitor, by nonlinear least-squares analysis of the displacement curve. Alternatively, K can be calculated from the IC50, which may be obtained by simple interpolation by eye from a Hill plot or by fitting a curve to an equation of the type ... 

Schimmer, B.P. and Parker, K.L., Adrenocorticotropic hormone adrenocortical steroids and their synthetic analogs inhibitors of the synthesis and actions of adrenocortical hormones, in Goodman and Gilman s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J.G. and Limbird, L.E., Eds., McGraw-Hill, New York, 1996, chap. 59. 

The overall influence of ATP on the rate V (ATP) is measured by a saturation parameter C (—oo, 1]. Note that, when using Eq. (139) as an explicit rate equation, the saturation parameter implicitly specifies a minimal Hill coefficient min > C necessary to allow for the reverse transformation of the parameters. The interval 6 [0,1] corresponds to conventional Michaelis Menten kinetics. For = 0, ATP has no net influence on the reactions, either due to complete saturation of a Michaelis Menten term or, equivalently, due to an exact compensation of the activation by ATP as a substrate by its simultaneous effect as an inhibitor. For < 0, the inhibition by ATP supersedes the activation of the reaction by its substrate ATP. 

Barret JM, Kmczynski A, Etievant C, Hill BT. (2002) Synergistic effects of F 11782, a novel dual inhibitor of topoisomerases I and II, in combination with other anticancer agents. Cancer Chemother Pharmacol 49 479 86. 

Sargent JM, Elgie AW, Williamson CJ, Hill BT. (2003) Ex vivo effects of the dual topoisomerase inhibitor tafluposide (FI 1782) on cells isolated from fresh tumor samples taken from patients with cancer. Anti-Cancer Drugs 14 467-473. 

The eleven equations shown in Table VI express the activity of a group of Hill Reaction inhibitors (4-11). A common structural feature, in all the sets except Number 5, seems to be a nitrogen atom having considerable double bond character. Activity is... 

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