The synthesis of the glucuronide adduct of Trocade™

Mitchell, Mark B.; Whitcombe, Ian

doi:10.1016/s0040-4039(00)01556-2

Cited by 16 publications

(12 citation statements)

References 7 publications

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“…The matrix metalloproteinase inhibitor Trocade 131 metabolized mainly as an O-hydroxamoyl glucuronide in liver microsomes. 157 Mitchell and Whitcombe proved its structure by synthesis: reaction of bromosugar 9 with N-hydroxyphthalimide, followed by hydrazinolysis, afforded the versatile anomeric hydroxylamine 132. Carbodiimide coupling with acid 133 (to avoid epimerization), followed by deprotection, afforded synthetic glucuronide identical to the isolated metabolite.…”

Section: O-hydroxamoyl and O-amidoximoyl Glucuronidesmentioning

confidence: 99%

Glucuronides from metabolites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides

Stachulski

Meng

2013

Nat. Prod. Rep.

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Covering: 1998 to 2011. Previous review: Nat. Prod. Rep., 1998, 15, 173-186. The fourteen years that have passed since the previous review on this topic have seen a significant increase of interest in many aspects of glucuronide chemistry and biology. Glucuronides are the most important class of phase 2 xenobiotic metabolites and typically act in a detoxifying role. While this is generally true for O-alkyl and O-aryl glucuronides, a number of glucuronides are known to be pharmacologically active per se. Additionally the use of glucuronide prodrugs, notably to ameliorate the cytotoxicity of anticancer agents, has markedly increased. Whereas the previous review covered only the synthesis of O-glucuronides, we now include N-, S- and C-glucuronides also and discuss both synthetic and biological aspects. Synthetic methods for all classes of glucuronides are reviewed and updated, together with advances in the enzymatic synthesis of glucuronides and methods for their detection. Finally we discuss the biological reactivity of glucuronides where known, including the important morphine-6-glucuronide. A lively debate has continued for several years on whether O-acyl glucuronide metabolites of carboxylic acids are toxic, affecting both the safety assessment of well-used drugs and new drug development programmes. We summarise the current understanding, together with other known examples of interaction between glucuronides and macromolecules.

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Section: O-hydroxamoyl and O-amidoximoyl Glucuronidesmentioning

confidence: 99%

Glucuronides from metabolites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides

Stachulski

Meng

2013

Nat. Prod. Rep.

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“…29 Therefore, compound 16 , which is comprised of phenyl hydroxamic acid protected with the boronic-ester self-immolative linker, was synthesized and evaluated. In the presence of H 2 O 2 compound 16 showed no release of the desired hydroxamic acid ligand.…”

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confidence: 99%

“…Hydroxamic acid MBGs are the most prevalent metal chelators in metalloprotein inhibitors, including MMPi, yet attempts to develop proMMPi using hydroxamic acid MBGs have not generally been successful. 20 Therefore, compound 16, which is comprised of phenyl hydroxamic acid protected with the boronic-ester self-immolative linker, was synthesized and evaluated. In the presence of H 2 O 2 compound 16 showed no release of the desired hydroxamic acid ligand.…”

mentioning

confidence: 99%

Investigation of self-immolative linkers in the design of hydrogen peroxide activated metalloprotein inhibitors

2011

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“…A previous study had reported on a glycoside-protected MMP inhibitor prodrug; however, the reported system did not release the desired inhibitor upon enzymatic activation. 56 For our studies, a previously reported MMP inhibitor, 1,2-HOPO-2 was employed (Fig. 9).…”

Section: Exploiting the Metal-ligand Interaction: A Case For Metallopmentioning

confidence: 99%

Emerging trends in metalloprotein inhibition

Rouffet

Cohen

2011

Dalton Trans.

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Numerous metalloproteins are important therapeutic targets that are gaining increased attention in the medicinal and bioinorganic chemistry communities. This perspectives article describes some emerging trends and recent findings in the area of metalloprotein inhibitor discovery and development. In particular, the increasing recognition of the importance of the metal-ligand interactions in these systems calls for more input and consideration from the bioinorganic community to address questions traditionally confined to the medicinal chemistry community.

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The synthesis of the glucuronide adduct of Trocade™

Cited by 16 publications

References 7 publications

Glucuronides from metabolites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides

Glucuronides from metabolites to medicines: a survey of the in vivo generation, chemical synthesis and properties of glucuronides

Investigation of self-immolative linkers in the design of hydrogen peroxide activated metalloprotein inhibitors

Emerging trends in metalloprotein inhibition

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