The Mechanism of the Antibiotic Action of Clavacin and Penicillic Acid<sup>1,2</sup>

Geiger, Walton B.; Conn, Jean E.

doi:10.1021/ja01217a038

Cited by 136 publications

(55 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…28) The antimicrobial activity of a,b-unsaturated ketones is due to their reactions with essential thiol groups in bacteria and fungi, resulting in b-ketothioethers. 29) Electron densities on b-carbons are lower 30) than on a-carbons in various unsaturated ketones, and thus the attack of the nucleophils should occur at the b-carbon atoms. It was also shown that increased antimicrobial activity was associated with an increased breakdown of the Mannich bases.…”

mentioning

confidence: 99%

“…It was also shown that increased antimicrobial activity was associated with an increased breakdown of the Mannich bases. 29) Similarly, a number of a,b-unsaturated ketones have alkylating ability against biologically important nucleophiles to produce cytotoxicity. 21,23) The amino group in Mannich bases would increase the water solubilizing property of the molecule, which may assist in transportation of the compound to the site of action.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Gül

Vepsäläinen

et al. 2003

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Mannich bases have several biological activities such as antimicrobial, [1][2][3][4][5] cytotoxic, [6][7][8][9] anticancer, 10) analgesic, 11) anti-inflammatory, 12,13) diuretic 14,15) and anticonvulsant [16][17][18][19] activities. An amino ketone, Mannich base, containing at least one activated hydrogen atom at the b position to an amino function, can undergo deamination in vivo 20) or under simulated in vitro conditions 1,3,6) to liberate the corressponding a,b-unsaturated ketones. The a,b-unsaturated ketone is an active center for nucleophilic attack. The biological activities of Mannich bases, such as antimicrobial, [1][2][3]21,22) cytotoxic and anticancer 6,9,23) activities, have been attributed to these liberated a,b-unsaturated ketones which can alkylate nucleophiles, especially thiol groups 1,6,24,25) rather than amino and hydroxyl groups, 26) by Michael type addition reactions of nucleophiles to a,b-unsaturated ketones.27) In addition, enzyme-catalyzed alkylation of the thiol group of cystein with a,b-unsaturated carbonyl compounds has been observed. 28)The antimicrobial activity of a,b-unsaturated ketones is due to their reactions with essential thiol groups in bacteria and fungi, resulting in b-ketothioethers.29) Electron densities on b-carbons are lower 30) than on a-carbons in various unsaturated ketones, and thus the attack of the nucleophils should occur at the b-carbon atoms. It was also shown that increased antimicrobial activity was associated with an increased breakdown of the Mannich bases.29) Similarly, a number of a,b-unsaturated ketones have alkylating ability against biologically important nucleophiles to produce cytotoxicity. 21,23) The amino group in Mannich bases would increase the water solubilizing property of the molecule, which may assist in transportation of the compound to the site of action.Production of thiol adducts in the stability studies, 1,3,6) carried out under in vitro physiological conditions (in phosphate buffer with pH 7.4, at 37°C), with 2-mercaptoethanol, various unsaturated ketones or Mannich bases, suggests that a,bunsaturated ketones and Mannich bases producing unsaturated ketones by deamination to exert their antimicrobial activities by thiol alkylation of unsaturated ketones.Clark and co-workers 31) found that the thiol adduct had the greatest fungitoxicity, which was probably due to the same reaction. Dimmock et al. (1994) have shown that Mannich bases of conjugated styryl ketones inhibit one or more of the following enzymes in the glutathione metabolic pathway: namely, glutathione S-transferases, glutathione reductase, gamma-glutamyl transpeptidase and glutathione peroxidase in Candida albicans. 32) They concluded that the antifungal activity of the Mannich bases of conjugated styryl ketones may be due, at least in part, to interference with the GSH metabolic pathway. In one of our previous studies, we observed that mono-Mannich bases and bis Mannich bases decrease the total glutathione level in a dose-dependent manner when Jurkat cells are exposed to the co...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Gül

Vepsäläinen

et al. 2003

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…Moreover, under its alternative name of acrylophenone, this compound is one of several unsaturated ketones found by Geiger and Conn (1945) to share with the unsaturated lactones patulin and penicillic acid the possession of marked antibacterial activity. We have shown that, like penicillin G, both of these latter antibiotics are carcinogenically active (Dickens andJones 1961, 1963a), and these compounds all react chemically with sulphydryl groups quite readily (Cavallito and Haskell, 1945;see Dickens, 1964) whereby their antibiotic activity is lost.…”

Section: Discussionmentioning

confidence: 99%

“…In the first place, we have added further tests on coumarin (I) (since the coumarin ring is contained in the aflatoxins), and on coumalic acid (II) a near relative: unfortunately both compounds proved highly toxic. (Geiger and Conn, 1945;Cavallito and Haskell, 1945. ) Finally, 6-aminopenicillanic acid (XIV) was included because of our earlier findings (Dickens and Jones, 1961 ;1963a) that the benzyl derivative of this compound-penicillin G (sodium benzyl penicillin)-produced sarcomas after its prolonged subcutaneous injection into rats.…”

Section: Further Studies On the Carcinogenic Action Of Certain Lactonmentioning

confidence: 99%

Further Studies on the Carcinogenic Action of Certain Lactones and Related Substances in the Rat and Mouse

Dickens¹,

Jones²

1965

Br J Cancer

134

View full text Add to dashboard Cite

On the other hand, in the lactones hitherto tested, absence of xfl-unsaturation, as in the fly-unsaturated a-angelica lactone and in the fully saturated y-butyro lactone, or opening of the lactone ring by hydrolysis, resulted in loss of carcinogenicity.In the case of the remarkably highly carcinogenic unsaturated lactone represented by the mould-product aflatoxin, the chemical structure of this compound was not known at the time when groundnut meal infected with Aspergillus fiavus was first shown to constitute a hepato-carcinogenic diet for the rat (Lancaster, Jenkins and Philp, 1961 ; see also Butler and Barnes, 1963). The purified toxin (mixed aflatoxins B1 and G1), made available to us by the Tropical Products Institute, D.S.I.R., London, was shown to produce local malignant tumours at the injection site in rats in doses as low as 50 ,tg (Dickens and Jones, 1963b). Later, feeding similar purified toxin to rats was shown to lead to hepatoma formation, like the contaminated meal (Barnes and Butler, 1964). Chemical studies at the Massachusetts Institute of Technology have now revealed that both purified aflatoxins B1 and G1 contain respectively one or two 6-membered lactone rings possessing oc,-unsaturation which is conjugated directly with further double bonds in the molecule (Asao et al., 1963; see also Dickens and Jones, 1963b). Whether the remaining parts of these fairly complex molecules are involved in their carcinogenicity remains to be studied.In the present paper we have extended the above observations in various directions. In the first place, we have added further tests on coumarin (I) (since the coumarin ring is contained in the aflatoxins), and on coumalic acid (II) a near relative: unfortunately both compounds proved highly toxic. The same applied to N-ethyl maleimide (III), a nitrogen analogue of maleic anhydride and a powerful sulphydryl-reacting material.

show abstract

“…Its structure was elucidated by Birkinshaw et al (1936) and its antibacterial effect against Gram positive and Gram negative bacteria was first reported by Oxford in 1942, Oxford et al in 1942and Geiger and Conn in 1945, as reviewed by Korzybski et al (1967). Later the antibiotic effect of penicillic acid has also been reported by Ezzat et al (2007).…”

Section: Introductionmentioning

confidence: 99%

A critical review of producers of small lactone mycotoxins: patulin, penicillic acid and moniliformin

Frisvad

2018

WMJ

View full text Add to dashboard Cite

A very large number of filamentous fungi has been reported to produce the small lactone mycotoxins patulin, penicillic acid and moniliformin. Among the 167 reported fungal producers of patulin, only production by 29 species could be confirmed. Patulin is produced by 3 Aspergillus species, 3 Paecilomyces species, 22 Penicillium species from 7 sections of Penicillium, and one Xylaria species. Among 101 reported producers of penicillic acid, 48 species could produce this mycotoxin. Penicillic acid is produced by 23 species in section Aspergillus subgenus Circumdati section Circumdati, by Malbranchea aurantiaca and by 24 Penicillium species from 9 sections in Penicillium and one species that does not actually belong to Penicillium (P. megasporum). Among 40 reported producers of moniliformin, five species have been regarded as doubtful producers of this mycotoxin or are now regarded as taxonomic synonyms. Moniliformin is produced by 34 Fusarium species and one Penicillium species. All the accepted producers of patulin, penicillic acid and moniliformin were revised according to the new one fungus – one name nomenclatural system, and the most recently accepted taxonomy of the species.

show abstract

The Mechanism of the Antibiotic Action of Clavacin and Penicillic Acid^1,2

Cited by 136 publications

References 0 publications

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Further Studies on the Carcinogenic Action of Certain Lactones and Related Substances in the Rat and Mouse

A critical review of producers of small lactone mycotoxins: patulin, penicillic acid and moniliformin

Contact Info

Product

Resources

About

The Mechanism of the Antibiotic Action of Clavacin and Penicillic Acid1,2

Cited by 136 publications

References 0 publications

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Further Studies on the Carcinogenic Action of Certain Lactones and Related Substances in the Rat and Mouse

A critical review of producers of small lactone mycotoxins: patulin, penicillic acid and moniliformin

Contact Info

Product

Resources

About

The Mechanism of the Antibiotic Action of Clavacin and Penicillic Acid^1,2