120511-88-8Relevant articles and documents
Dual aromatase-sulfatase inhibitors based on the anastrozole template: Synthesis, in vitro SAR, molecular modelling and in vivo activity
Jackson, Toby,Woo, L. W. Lawrence,Trusselle, Melanie N.,Chander, Surinder K.,Purohit, Atul,Reed, Michael J.,Potter, Barry V. L.
, p. 2940 - 2952 (2008/04/02)
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 SN2, 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 (IC50 3.5 nM), comparable with that of Anastrozole (IC50 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. This journal is The Royal Society of Chemistry.
(SUBSTITUTED ARALKYL) HETEROCYCLIC COMPOUNDS
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, (2008/06/13)
A (substituted-aralkyl)heterocyclic compound of the formula I wherein R1 is an azido, carbamoyl, cyano, formyl, hy-droxy or nitro radical, a 1-6C 1-hydroxyalkyl, alkoxy, alkylcarbamoyl, alkylthio, alkylsulphinyl or alkylsulphonyl radical, a 2-cyanoethyl radical, optionally bearing one to four 1-6C alkyl substituents, or a 2-6C alkanoyl, halogenoalkanoyl, alkanoyloxy, alkanoylamino, dialkylcarbamoyl or alkoxycarbonyl radical; R2 and R3, which may be the same or different, are each a hydrogen atom, a 1-6C alkyl, dueterioalkyl or halogenoalkyl radical, or a phenyl or phenyl(l-6C alkyl) radical, in each of which the phenyl may optionally bear one or more substituents; or R2 and R3, together with the carbon atom to which they are attached, may form a 3- to 6-membered ring; or R1R2R3C- is a 1,1-dicyanoethyl or trifluoromethylsulphonyl radical; R4 is a hydrogen or halogen atom, a cyano or nitro radical or a 1-6C alkyl or halogenoalkyl radical; R5 has any of the values de-fined above for the group RIR2R3C but is not necessarily the same as R1R2R3C, or has any of the values de-fined above for R4 but is not necessarily the same as R4, or is a carbamoyl, 1-pyrrolidinyl-carbonyl, piperidino-carbonyl, morpholinocarbonyl or nitro radical, a 1-6C alkoxy or halogenoalkoxy radical or a 2-6C alkanoyl or alkoxy-carbonyl radical; A is a methylene or ethylene radical optionally bearing one or more substituents selected from deuterium and halogen atoms, carbamoyl, cyano and hydroxy radicals, 1-6C alkyl and alkoxy radicals, and 2-6C alkanoyloxy radicals provided that when A is linked to R through a nitrogen atom thereof, it may not bear a hydroxy, alkoxy or alkanoyloxy sub-stituent on the carbon atom adjacent to such nitrogen atoms; and R6is a lH-l,2,4-triazol-l-yl, 4H-l,2,4-triazol-4-yl, IH-imidazol-1-yl, 5-cyano-lH-imidazol-l-yl, 3-pyridyl or 5-pyrimidinyl radical, or a IH-imidazol-1-yl radical, bearing at the 5-position thereof a 1-6C alkyl substituent which is itself optionally substituted by one or more carbamoyl, cyano, hydroxy or 2-6C alkoxycar-bonyl radicals; and provided that when R2, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is a 3-pyridyl radical, R1 is not a cyano, hydroxy or hydroxymethyl radical, and when R1 is a hydroxy radical, R3, R4 and R5 are hydrogen, A is a methylene radical and R6 is 3-pyridyl, R2 is not a methyl or a 2-chloro-1-methylethyl radical, and provided that when R1 is a methoxycarbonyl radical, R2, R3, R4 and R5 are hydrogen and A is a methylene radical, Ri is not a IH-imidazol-a1-yl radical; and the pharmaceutically acceptable acid addition salts thereof
