Mutual pro-drugs of .BETA.-lactam antibiotics and .BETA.-lactamase inhibitors.

Baltzer, B.; Binderup, Ernst; Daehne, W. von; Godtfredsen, W. O.; Hansen, K.; Nielsen, B; Sørensen, H.; Vangedal, S.

doi:10.7164/antibiotics.33.1183

Cited by 52 publications

(15 citation statements)

References 9 publications

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“…40%) absorbed with oral administration, and oral absorption of SBT is very poor [18]. This problem was overcome with the combination of AMP and SBT in one oral prodrug, sultamicillin [26]. This doublebound ester is readily absorbed (>80% bioavailability) and rapidly hydrolysed during absorption from the gastrointestinal tract to provide high levels (in equimolar quantities) of AMP and SBT [16,18].…”

Section: Adultsmentioning

confidence: 99%

Rational antibiotic therapy and the position of ampicillin/sulbactam

Lode

2008

International Journal of Antimicrobial Agents

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Section: Adultsmentioning

confidence: 99%

Rational antibiotic therapy and the position of ampicillin/sulbactam

Lode

2008

International Journal of Antimicrobial Agents

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“…The extracts were washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure to give the title compound which crystallized from ethanol-water, mp 71-72°C. The N.Ndiethylglycolamide ester (IV) was prepared in a similar way using 2-chloro-N.N-diethylacetamide, mp 60-61 "C. Ampicillin N.N-diethylglycolamide ester (VII) was prepared by reacting potassium N-( 1 -methoxycarbonylpropen-2-yl)-~-a-aminobenzylpenicillinate (Baltzer et al 1980) with 2-chloro-N,N-diethylacetamide in a similar way. The enamine-protecting group was removed as described by Clayton et al (1976), yielding VII as a fine white amorphous solid.…”

Section: Synthesis Of Penicillin Estersmentioning

confidence: 99%

Facile plasma-catalysed degradation of penicillin alkyl esters but with no liberation of the parent penicillin

Nielsen

Bundgaard

1988

Journal of Pharmacy and Pharmacology

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The methyl ester and some glycolamide esters of benzylpenicillin and ampicillin were shown to be rapidly degraded by human plasma at 37 degrees C with no parent penicillin being produced. The plasma-catalysed degradation which was also observed in rat plasma proceeds most likely through hydrolytic cleavage of the beta-lactam bonds of the penicillin esters and is suggested to be due to the presence of an ester-specific beta-lactamase in plasma. The results show that the failure of simple alkyl esters of penicillins to function as prodrugs is not due to a high enzymatic stability of the esters, as widely believed, but rather to a pronounced susceptibility to undergo hydrolytic cleavage of their beta-lactam ring in-vivo. Since double ester prodrugs of penicillins, such as the pivaloyloxymethyl ester of ampicillin, are readily hydrolysed in plasma to yield the parent penicillin although at a rate lower than e.g. that of inactivation of a simple methyl ester, the plasma enzyme apparently attacking the beta-lactam bond of penicillin esters appears to have a high degree of specificity for the ester structure.

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“…We have recently implemented a similar strategy to prepare penicillin‐G–squalene conjugates 15. As previously reported, chloromethyl ester 6 was straightforwardly obtained by treatment of squalenic acid 5 with chloromethyl chlorosulfate (Scheme ) 15,26…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Cytotoxic Activity of Self‐Assembling Squalene Conjugates of 3‐[(Pyrrol‐2‐yl)methylidene]‐2,3‐dihydro‐1H‐indol‐2‐one Anticancer Agents

et al. 2014

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Squalenoyl conjugates of semaxanib and sunitinib, two potent antiangiogenic (pyrrolyl)methylidenyl‐substituted oxindole multitarget tyrosine kinase inhibitors, were synthesized with a hemiaminal‐based pH‐sensitive linker. The prodrugs were prepared according to a three‐step sequence involving (i) N‐alkylation with chloromethoxy‐triisopropylsilane; (ii) desilylation; and (iii) acylation with trisnorsqualenic acid. These squalenoyl prodrugs were found to self‐assemble into nanoassemblies in aqueous media without the need for any surfactant. The nanosized aggregates were characterized by dynamic light scattering and transmission electron microscopy, and appeared to be stable in water for several days, as determined by particle‐size measurement. In vitro biological studies showed that squalenoyl sunitinib nanoassemblies are notably cytotoxic against the human umbilical vein endothelial cell line (HUVEC), which is involved in the tumor vessel formation.

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Mutual pro-drugs of .BETA.-lactam antibiotics and .BETA.-lactamase inhibitors.

Cited by 52 publications

References 9 publications

Rational antibiotic therapy and the position of ampicillin/sulbactam

Rational antibiotic therapy and the position of ampicillin/sulbactam

Facile plasma-catalysed degradation of penicillin alkyl esters but with no liberation of the parent penicillin

Synthesis and Cytotoxic Activity of Self‐Assembling Squalene Conjugates of 3‐[(Pyrrol‐2‐yl)methylidene]‐2,3‐dihydro‐1H‐indol‐2‐one Anticancer Agents

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