Synthesis of aromatase inhibitors and dual aromatase-sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities

C. Bubert, L.W.L. Woo, O.B. Sutcliffe, M.F. Mahon, S.K. Chander, A. Purohit, M.J. Reed, B.V.L. Potter

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC50=0.26 nM) and the best DASI is 43 e (IC50 aromatase=0.45 nM, IC50 STS=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg-1, single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.
LanguageEnglish
Pages1708-1730
Number of pages22
JournalChemMedChem
Volume3
Issue number11
DOIs
Publication statusPublished - Sep 2008

Fingerprint

Sulfatases
Aromatase Inhibitors
Aromatase
Steryl-Sulfatase
Crystal structure
Inhibitory Concentration 50
Sulfones
Second Primary Neoplasms
Sulfonamides
Sulfides
In Vitro Techniques
4-(4H-1,2,4-triazol-4-ylamino)benzonitrile
Ether
Derivatives
Estradiol
X-Rays
Hormones
Liver

Keywords

  • aromatase inhibitors
  • breast cancer
  • dual aromatase-sulfatase inhibitors
  • endocrine therapy
  • sulfatase inhibitors
  • pharmacology

Cite this

Bubert, C. ; Woo, L.W.L. ; Sutcliffe, O.B. ; Mahon, M.F. ; Chander, S.K. ; Purohit, A. ; Reed, M.J. ; Potter, B.V.L. / Synthesis of aromatase inhibitors and dual aromatase-sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities. In: ChemMedChem. 2008 ; Vol. 3, No. 11. pp. 1708-1730.
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Synthesis of aromatase inhibitors and dual aromatase-sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities. / Bubert, C.; Woo, L.W.L.; Sutcliffe, O.B.; Mahon, M.F.; Chander, S.K.; Purohit, A.; Reed, M.J.; Potter, B.V.L.

In: ChemMedChem, Vol. 3, No. 11, 09.2008, p. 1708-1730.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis of aromatase inhibitors and dual aromatase-sulfatase inhibitors by linking an arylsulfamate motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, crystal structures, in vitro and in vivo activities

AU - Bubert, C.

AU - Woo, L.W.L.

AU - Sutcliffe, O.B.

AU - Mahon, M.F.

AU - Chander, S.K.

AU - Purohit, A.

AU - Reed, M.J.

AU - Potter, B.V.L.

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Y1 - 2008/9

N2 - 4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC50=0.26 nM) and the best DASI is 43 e (IC50 aromatase=0.45 nM, IC50 STS=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg-1, single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.

AB - 4-(((4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)phenyl sulfamate (6 a) was the first dual aromatase-sulfatase inhibitor (DASI) reported. Several series of its derivatives with various linker systems between the steroid sulfatase (STS) and the aromatase inhibitory pharmacophores were synthesised and evaluated in JEG-3 cells. The X-ray crystal structures of the aromatase inhibitors, DASI precursors 42 d and 60, and DASI 43 h were determined. Nearly all derivatives show improved in vitro aromatase inhibition over 6 a but decreased STS inhibition. The best aromatase inhibitor is 42 e (IC50=0.26 nM) and the best DASI is 43 e (IC50 aromatase=0.45 nM, IC50 STS=1200 nM). SAR for aromatase inhibition shows that compounds containing an alkylene- and thioether-based linker system are more potent than those that are ether-, sulfone-, or sulfonamide-based, and that the length of the linker has a limited effect on aromatase inhibition beyond two methylene units. Compounds 43 d-f were studied in vivo (10 mg kg-1, single, p.o.). The most potent DASI is 43 e, which inhibited PMSG-induced plasma estradiol levels by 92 % and liver STS activity by 98 % 3 h after dosing. These results further strengthen the concept of designing and developing DASIs for potential treatment of hormone-related cancers.

KW - aromatase inhibitors

KW - breast cancer

KW - dual aromatase-sulfatase inhibitors

KW - endocrine therapy

KW - sulfatase inhibitors

KW - pharmacology

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