Interaction of maleic acid with thiol compounds

Morgan, Edward J.; Friedmann, E.

doi:10.1042/bj0320733

Cited by 76 publications

(18 citation statements)

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“…Although sodium maleate does react with sulphydryl compounds (Morgan and Friedmann, 1938), we have observed a many times more rapid reaction with maleic anhydride added to the neutral aqueous solution.…”

Section: Resultsmentioning

confidence: 68%

Further Studies on the Carcinogenic and Growth-Inhibitory Activity of Lactones and Related Substances

Dickens¹,

Jones²

1963

Br J Cancer

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IT was shown (Dickens and Jones, 1961;Dickens, 1962) that a number of lactones and related substances were slow-acting carcinogens in the rat when administered repeatedly by subcutaneous injection. The compounds tested which produced malignant tumours at the injection site included the 4-membered lactones f8-propiolactone, a-carboxy-,8-phenyl-fl-propiolactone, aa-diphenyl-flpropiolactone; and also sodium benzyl penicillin (penicillin G), which possesses a 4-membered lactam ring. That carcinogenic activity was not limited to 4-membered lactones was shown by the carcinogenicity of the following compounds which contained a 5-membered y-lactone ring: patulin, penicillic acid, methyl protoanemonin, 2-hexenoic lactone and 4-hexenoic lactone.The arachis oil used as solvent for these lactones did not itself produce any local tumours, and the freshly prepared aqueous solutions of /J-propiolactone were also carcinogenic. Tumours were not obtained with either 3-hexenoic lactone, aangelica lactone (3-pentenoic-y-lactone), or with the saturated compound ybutyrolactone.The tumours were nearly all fibroblastic with varying amounts of collagen and were classified as spindle cell sarcomas, fibrosarcomas or myxosarcomas.Before this study only f8-propiolactone in this series of compounds had been shown by Walpole et al. (1954) to possess carcinogenic properties: this compound is also capable of inducing skin tumours, including some carcinomas, in mice (Roe and Glendenning, 1956). As a result of our experiments we concluded that the high chemical reactivity associated with the highly strained ring of fl-propiolactone, e.g. the nucleophilic type of attack resulting in the alkylation of the SH group of cysteine which we demonstrated for f8-propiolactone (Dickens and Jones, 1961), was also a marked feature of the other carcinogenic lactones, which were also found to be capable of reacting with cysteine in neutral solution causing loss of the free SH group. Penicillin, because of its 4-membered,lactam ring, was already known to react similarly on incubation with cysteine, which abolishes its antibiotic properties. In this series of 5-membered lactone rings, such reactivity and carcinogenicity appears to be associated with either acfl-unsaturation or the presence of an external double-bond at the 4-position of the y-lactone ring, or preferably with both of these. If there was no double-bond, or if it was in the 3-position, carcinogenic activity was not demonstrable.In the present paper we report the results obtained with a further series of compounds of similar chemical type. These were the 4-membered ring of f,ldimethyltrimethylene oxide (I); the 5-membered ring of maleic anhydride (II);

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Section: Resultsmentioning

confidence: 68%

Further Studies on the Carcinogenic and Growth-Inhibitory Activity of Lactones and Related Substances

Dickens¹,

Jones²

1963

Br J Cancer

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“…Substrates that are sufficiently electrophilic due to the presence of double bonds or a strained ring system can be directly conjugated to GSH in the absence of GSTs (Lehman-McKeeman 2008). The presence of the carbon double bond along with two carboxy groups in maleic acid was shown to be sufficiently electrophilic for direct nonenzymatic conjugation to the thiol group in GSH (Morgan and Friedman 1938a). Thus, it is likely that depletion of GSH stores from the vitreous humor and retina in the rabbit eyes following intravitreal injection of !1.00 mg/eye (6.15 mM vitreous) maleic acid with the formation of glutathione-maleic acid conjugates either by enzymatic or nonenzymatic reactions led to overproduction of free radicals with subsequent injury of the highly sensitive GSH deficient photoreceptors.…”

Section: Discussionmentioning

confidence: 99%

An Assessment of the Ocular Safety of Excipient Maleic Acid Following Intravitreal Injection in Rabbits

et al. 2012

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Maleic acid was formulated in 0.7% saline and injected intravitreally in rabbits in order to evaluate ocular safety and tolerability. Maleic acid was formulated within a narrow pH range (2-3), administered in a fixed volume (100 ml), and concentrations ranged from 0.00 to 2.00 mg/eye (0.00 to 12.30 mM vitreous). Ocular evaluations were conducted at 2, 4, and 8 days post injection. Ocular irritation responses were observed at doses from 0.50 mg/eye (3.07 mM vitreous) to 2.00 mg/eye (12.30 mM vitreous) and included conjunctival redness and scleral swelling. Chemosis was observed at 2.00 mg/eye (12.30 mM vitreous). Funduscopic evaluations revealed enlarged retinal blood vessels and optic disk swelling at doses !1.50 mg/eye (9.22 mM vitreous), retinal folds and retinal discoloration at 2.00 mg/eye (12.30 mM vitreous). Histopathologic evaluations on days 4 and 8 post injection revealed retinal degeneration at doses !1.0 mg/eye (6.15 mM vitreous), conjunctival inflammation at doses !1.5 mg/eye (9.22 mM vitreous), and retinal pigment epithelial hypertrophy, optic nerve demyelination, anterior chamber fluid, and conjunctival fibrosis at 2.00 mg/eye (12.30 mM vitreous) maleic acid. The data suggest that maleic acid formulations at !1.00 mg/eye (6.15 mM vitreous) were not suitable for intraocular indications.

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“…Although, by analogy with arsenite, maleate might be expected to inhibit the oc-oxoglutarate oxidase, it may also affect the level of oc-oxoglutarate by a different mechanism. Morgan & Friedemann (1938) demonstrated that when maleic acid reacts with a monothiol, such as cysteine or glutathione, some of the acid is rearranged to give fumaric acid. Moreover, Coxon, Liebecq & Peters (1949) found that the addition of fumarate to the brain-pyruvate-oxidase system increases the amount of oa-oxoglutarate in such a system metabolizing pyruvate.…”

Section: Resultsmentioning

confidence: 99%

Blood keto acid levels during intoxication with inhibitors of carbohydrate metabolism

Hawary

1955

Biochemical Journal

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Interaction of maleic acid with thiol compounds

Cited by 76 publications

References 0 publications

Further Studies on the Carcinogenic and Growth-Inhibitory Activity of Lactones and Related Substances

Further Studies on the Carcinogenic and Growth-Inhibitory Activity of Lactones and Related Substances

An Assessment of the Ocular Safety of Excipient Maleic Acid Following Intravitreal Injection in Rabbits

Blood keto acid levels during intoxication with inhibitors of carbohydrate metabolism

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