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A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.

ABSTRACT: A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.

SUBMITTER: Wolfe AL

PROVIDER: S-EPMC3386426 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.

Wolfe Amanda L AL Duncan Katharine K KK Parelkar Nikhil K NK Weir Scott J SJ Vielhauer George A GA Boger Dale L DL

Journal of medicinal chemistry 20120612 12

A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptional ...[more]

PMID: 22650244

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Project description:BackgroundIndoor residual spraying is one of the key vector control interventions for malaria control in Ethiopia. As malaria transmission is seasonal in most parts of Ethiopia, a single round of spraying can usually provide effective protection against malaria, provided the insecticide remains effective over the entire malaria transmission season. This experiment was designed to evaluate the residual efficacy of bendiocarb, pirimiphos-methyl, and two doses of propoxur on four different wall surfaces (rough mud, smooth mud, dung, and paint). Filter papers affixed to wall surfaces prior to spraying were analyzed to determine the actual concentration applied. Cone bioassays using a susceptible Anopheles arabiensis strain were done monthly to determine the time for which insecticides were effective in killing mosquitoes.ResultsThe mean insecticide dosage of bendiocarb applied to walls was 486 mg/m2 (target 400/mg). This treatment lasted 1 month or less on rough mud, smooth mud, and dung, but 4 months on painted surfaces. Pirimiphos-methyl was applied at 1854 mg/m2 (target 1000 mg/m2), and lasted between 4 and 6 months on all wall surfaces. Propoxur with a target dose of 1000 mg/m2 was applied at 320 mg/m2, and lasted 2 months or less on all surfaces, except painted surfaces (4 months). Propoxur with a target dose of 2000 mg/m2, was applied at 638 mg/m2, and lasted 3 months on rough mud, but considerably longer (5-7 months) on the other substrates.ConclusionsIt would appear that the higher dose of propoxur and pirimiphos-methyl correspond best to the Ethiopian transmission season, although interactions between insecticide and the substrate should be taken into account as well. However, the insecticide quantification revealed that the dosages actually applied differed considerably from the target dosages, even though care was taken in the mixing of insecticide formulations and spraying of the walls. It is unclear whether this variability is due to initial concentrations of insecticides, poor application, or other factors. Further work is needed to ensure that target doses are correctly applied, both operationally and in insecticide evaluations.

Dataset Information

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.

Publications

A novel, unusually efficacious duocarmycin carbamate prodrug that releases no residual byproduct.

Similar Datasets

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