Hydrolysis of 3-cloro-3-cephems. Intramolecular nucleophilic attack in cefaclor

Indelicato, Joseph M.; Dinner, A.; Peters, Lynn R.; Wilham, William L.

doi:10.1021/jm00217a021

Cited by 42 publications

(7 citation statements)

References 4 publications

(4 reference statements)

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“…However, in neutral medium, we found H-C(6) and H-C(7) not to be eliminated; therefore, the mechanism given in [13] can just take place in an alkaline medium or in the presence of a base abstracting such protons. To check the mechanism proposed in [13], we carried out the hydrolysis of 1 in an alkaline medium (PD 10.5, 37", Z = 0.5111) and found that the C1-atom was released (35C1-NMR: s at 0 ppm that appeared gradually as the reaction developed) and that the signals of H-C(6) and H-C(7) disappeared as the reaction progressed.…”

Section: Co2-mentioning

confidence: 59%

“…These products were identified as the isomers 11. Indelicato et al [13] found that, during the formation of the diketopiperazine from cefaclor (l), a C1-atom was released. They suggested that this took place in a reaction subsequent to the cleavage of thep-lactam ring.…”

Section: Coo-c(7)a) C(l0)a) Cips H-cp H-c H-c H-c(5) H-c(2) Ch-cmentioning

confidence: 99%

“…For the elimination of the C1-atom in the hydrolysis of 1 in benzene, Zndelicato et al [13] proposed the opening of the four-membered ring -by attack of a nucleophile on the p-lactam carbonyl group -, followed by elimination of H-C(6) and release of the C1-atom; subsequently, H-C(7) would be removed. However, in neutral medium, we found H-C(6) and H-C(7) not to be eliminated; therefore, the mechanism given in [13] can just take place in an alkaline medium or in the presence of a base abstracting such protons.…”

Section: Co2-mentioning

confidence: 99%

“…fndelicato et al [13] isolated and identified a diketopiperazine compound 3 in the degradation of the 4-nitrobenzyl (pNB) ester of cefaclor (1) in nonaqueous medium (refluxing benzene). The elemental analysis of the degradation product revealed the absence of C1 from its formula, thereby suggesting that the loss of the C1-atom was subsequent to the opening of the p-lactam ring.…”

mentioning

confidence: 99%

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The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Vilanova

Donoso

Muñoz

et al. 1996

Helvetica Chimica Acta

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The degradation of cefaclor (l), an oral cephalosporin antibiotic, was studied at 37O in a neutral aqueous medium by HPLC and 'H-NMR. Under these conditions, 1 underwent intramolecular aminolysis by the 7-sidechain NH, group on the 8-lactam moiety to give a piperazine-2,s-dione. The most prominent peak in the HPLC profile of a degradation solution from 1 was isolated by prep. HPLC. Mechanistically, the formation of this degradation product cis-11 from 1 involves the contraction from a six-membered cephem ring to a live-membered ring, which presumably takes place via a common episulfonium ion intermediate 9 (see Scheme). Loss of the C1-atom from 3-chloro-3-cephem is a general reaction subsequent to b-lactam ring opening.

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Section: Co2-mentioning

confidence: 59%

Section: Coo-c(7)a) C(l0)a) Cips H-cp H-c H-c H-c(5) H-c(2) Ch-cmentioning

confidence: 99%

Section: Co2-mentioning

confidence: 99%

mentioning

confidence: 99%

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The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Vilanova

Donoso

Muñoz

et al. 1996

Helvetica Chimica Acta

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“…The mechanism(s) underlying tubular injury include the ability of beta-lactams to actively accumulate in renal proximal tubular cells, acylate proteins [238], and/or induce lipid peroxidation (for cephaloridine) [239–241]. The side group substitutions of beta-lactams greatly affect transport rates and protein reactivity and hence contribute to the varying degrees of nephrotoxicity [242, 243]. Very few cephalosporins cause tubular damage at therapeutic doses.…”

Section: Prototypical Nephrotoxicantsmentioning

confidence: 99%

Xenobiotic transporters and kidney injury

George

You

Joy

et al. 2017

Advanced Drug Delivery Reviews

101

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Renal proximal tubules are targets for toxicity due in part to the expression of transporters that mediate the secretion and reabsorption of xenobiotics. Alterations in transporter expression and/or function can enhance the accumulation of toxicants and sensitize the kidneys to injury. This can be observed when xenobiotic uptake by carrier proteins is increased or efflux of toxicants and their metabolites is reduced. Nephrotoxic chemicals include environmental contaminants (halogenated hydrocarbon solvents, the herbicide paraquat, the fungal toxin ochratoxin, and heavy metals) as well as pharmaceuticals (certain beta-lactam antibiotics, antiviral drugs, and chemotherapeutic drugs). This review explores the mechanisms by which transporters mediate the entry and exit of toxicants from renal tubule cells and influence the degree of kidney injury. Delineating how transport proteins regulate the renal accumulation of toxicants is critical for understanding the likelihood of nephrotoxicity resulting from competition for excretion or genetic polymorphisms that affect transporter function.

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Covalent Inhibition of New Delhi Metallo‐β‐Lactamase‐1 (NDM‐1) by Cefaclor

et al. 2014

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Covalent irreversible inhibitors can successfully treat antibiotic-resistant infections by targeting serine β-lactamases. However, this strategy is useless for New Delhi metallo-β-lactamase (NDM), which uses a non-covalent catalytic mechanism and lacks an active-site serine. Here, NDM-1 was irreversibly inactivated by three β-lactam substrates: cephalothin, moxalactam, and cefaclor, albeit at supratherapeutic doses (e.g., cefaclor KI =2.3 ± 0.1 mM; k(inact) =0.024 ± 0.001 min(-1)). Inactivation by cephalothin and moxalactam was mediated through Cys208. Inactivation by cefaclor proceeded through multiple pathways, in part mediated by Lys211. Use of a cefaclor metabolite enabled mass spectrometric identification of a +346.0735 Da covalent adduct on Lys211, and an inactivation mechanism is proposed. Lys211 was identified as a promising "handhold" for developing covalent NDM-1 inhibitors and serves as a conceptual example for creating covalent inhibitors for enzymes with non-covalent mechanisms.

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Hydrolysis of 3-cloro-3-cephems. Intramolecular nucleophilic attack in cefaclor

Cited by 42 publications

References 4 publications

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

The Degradation Mechanism of an Oral Cephalosporin: Cefaclor

Xenobiotic transporters and kidney injury

Covalent Inhibition of New Delhi Metallo‐β‐Lactamase‐1 (NDM‐1) by Cefaclor

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