Biochemical properties of anti-inflammatory drugs—IX: Uncoupling of oxidative phosporylation and inhibition of a thiol enzyme (papain) by some cyclic β-diones and ninhydrin

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Abstract

Some novel 2-acyl-indan-1,3-diones were synthesized and characterized. These and other acyl-indandiones were tested for uncoupling activity using rat liver mitochondria (oxidizing succinate). o.Hydroxybenzoyl-indandiones, which readily cyclized to yield chromones during their preparation, also uncoupled oxidative phosphorylation.

The uncoupling potency of acyl-indandiones, pyrazolidinediones and certain acidic pyrazolones generally paralleled (a) their lipophilic character and (b) their avidity for protein ϵ-lysyl amino groups (as indicated by the compound's ability to inhibit the 2,4,6-trinitrobenzaldehyde-albumin reaction). p.p′-Dichlorophenylbutazone, the 4-butyryl analogue of phenylbutazone and the following indandiones = 2-isoheptanoyl-2-p. chlorphenyl-, 2-(3′, 4′) dichlorobenzoyl-, were the most active uncoupling agents found in this limited survey. The anomalous (low) uncoupling activity and lysyl-binding activity of certain ortho substituted benzoyl-indandiones could be attributed to steric hindrance.

Some limitations of the trinitrobenzaldehyde-albumin reaction for screening compounds for potential drug activity are disclosed, notably (i) reaction of the aldehyde with compounds containing an active methylene group (e.g. unsubstituted β-diones like indan-1,3-dione itself), and (ii) where the drug under investigation may bind to plasma albumin at sites other thsn lysine amino groups (e.g. sulphinpyrazone). Sulphamethazine potentiates the reaction between trinitrobenzaldehyde and bovine plasma albumin.

Ninhydrin, hydrindantin and some related non-acidic aromatic 1,2 and 1,4-diones also uncoupled oxidative phosphorylation, but only in the absence of added thiols, and did not inhibit the trinitrobenzaldehyde-albumin reaction (in those instances where these diones did not react with either the albumin or the trinitrobenzaldehyde). These compounds, and also phenylbutazone and some of its analogues, were potent inhibitors of the esterase activity of crystalline papain in the presence of excess thiol.

It is postulated that non-acidic diones may uncouple oxidative phosphorylation by reacting with essential thiol groups involved in mitochondrial energy conservation, whereas acidic uncoupling drugs primarily inhibit mitochondrial phosphorylation by “neutralizing” essential amino groups.

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    Present address: Department of Experimental Pathology, John Curtin School of Medical Research, The Australian National University, Canberra, A.C.T. Australia.

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