Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity.

Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Research Abstract Details 

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Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Abstract Text:

Toby Jackson,L W Lawrence Woo,Melanie N Trusselle,Surinder K Chander,Atul Purohit,Michael J Reed,Barry V L Potter,Toby Jackson,L W Lawrence Woo,Melanie N Trusselle,Surinder K Chander,Atul Purohit,Michael J Reed,Barry V L Potter,

The synthesis and biological evaluation of a series of novel Dual Aromatase-Sulfatase Inhibitors (DASIs) are described. It is postulated that dual inhibition of the aromatase and steroid sulfatase enzymes, both responsible for the biosynthesis of oestrogens, will be beneficial in the treatment of hormone-dependent breast cancer. The compounds are based upon the Anastrozole aromatase inhibitor template which, while maintaining the haem ligating triazole moiety crucial for enzyme inhibition, was modified to include a phenol sulfamate ester motif, the pharmacophore for potent irreversible steroid sulfatase inhibition. Adaption of a synthetic route to Anastrozole was accomplished via selective radical bromination and substitution reactions to furnish a series of inhibitory aromatase pharmacophores. Linking these fragments to the phenol sulfamate ester moiety employed S(N)2, Heck and Mitsunobu reactions with phenolic precursors, from where the completed DASIs were achieved via sulfamoylation. In vitro, the lead compound, 11, had a high degree of potency against aromatase (IC(50) 3.5 nM), comparable with that of Anastrozole (IC(50) 1.5 nM) whereas, only moderate activity against steroid sulfatase was found. However, in vivo, 11 surprisingly exhibited potent dual inhibition. Compound 11 was modelled into the active site of a homology model of human aromatase and the X-ray crystal structure of steroid sulfatase.

Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Publishing Authors By Initials

T Jackson,LW Woo,MN Trusselle,SK Chander,A Purohit,MJ Reed,BV Potter,T Jackson,LW Woo,MN Trusselle,SK Chander,A Purohit,MJ Reed,BV Potter,

For similar heterocyclic compounds: heterocyclic compounds, 1-ring: azoles: triazoles research abstracts see: heterocyclic compounds: heterocyclic compounds, 1-ring: azoles: triazoles research

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Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Organic & biomolecular chemistry

VOLUME: 5

Page Numbers: 2940-52

Journal Abbreviation: Org. Biomol. Chem.

ISSN: 1477-0520

DAY: 7

MONTH: 08

YEAR: 2007

Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Information

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LANGUAGE: eng

NlmUniqueID: 101154995

Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Keywords Mesh Terms:

KEYWORDS: Triazoles

MESH TERMS: chemistry

Chemical & Substance for Abstract: Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity. Information

Substance Name: Sulfatases

Registry Number: EC 3.1.6.-

Grant and Affiliation Information for Dual aromatase-sulfatase inhibitors based on the anastrozole template: synthesis, in vitro SAR, molecular modelling and in vivo activity.

AFFILIATION: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

Country: England

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MEDLINETA: Org Biomol Chem

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