1-[(Benzofuran-2-yl)phenylmethyl]-triazoles and -tetrazoles - potent competitive inhibitors of aromatase

Vinh, Tai Ky; Ahmadi, M.; Delgado, Paula; Pérez, S.; Walters, H. M.; Smith, H. J.; Nicholls, P. J.; Simons, Claire

doi:10.1016/s0960-894x(99)00328-5

Cited by 39 publications

(28 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These inhibitors bind to the active site of P450 AROM through coordination of a heterocyclic nitrogen lone pair of electrons with the Fe 3þ of the haem in the active site of the enzyme, therefore the coordination potential of the heterocyclic nitrogen is of importance. We have previously shown that, with respect to coordination potential/inhibitory activity, an imidazole is more efficient than a triazole, which is more efficient than a tetrazole heterocyclic moiety [12]. However, imidazole derivatives may also be less selective compared with triazole derivatives, which are also more stable metabolically.…”

Section: Introductionmentioning

confidence: 99%

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

Saberi

Shah

Simons

2005

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A series of benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives were prepared using an efficient 1-step procedure in good yields. In addition furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were also prepared to determine the effect of the benzene ring in benzofuran with respect to inhibitory activity. The pyridylmethanol derivatives were all evaluated in vitro for inhibitory activity against aromatase (P450 AROM , CYP19), using human placental microsomes. The benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives showed good to moderate activity ðIC 50 ¼ 1:3 -25:1 mMÞ; which was either better than or comparable with aminoglutethimide ðIC 50 ¼ 18:5 mMÞ but lower than arimidex ðIC 50 ¼ 0:6 mMÞ; with the 4-methoxyphenyl substituted derivative displaying optimum activity. Molecular modelling of the benzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol derivative suggested activity to reside with the (S)-enantiomer. The furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were devoid of activity indicating the essential role of the benzene ring of the benzofuran component for enzyme binding.

show abstract

Section: Introductionmentioning

confidence: 99%

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

Saberi

Shah

Simons

2005

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…65 On the other side, replacing the imidazole ring of 12 with a triazole led to a series of compounds, of which 13 was the most potent AI (IC 50 ¼ 0.19 mM) even if weaker than the corresponding lead. 66 In the second half of the nineties, a number of articles appeared, where the development of earlier patented compounds was reported. In almost no case, the aromatase inhibitory potency was high, but it might be interesting to look at the different structures taken into consideration.…”

mentioning

confidence: 99%

Nonsteroidal aromatase inhibitors: Recent advances

Recanatini

Cavalli

Valenti

2002

Medicinal Research Reviews

106

102

View full text Add to dashboard Cite

Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure-activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly.

show abstract

“…Reaction of (4-(benzo[d ]oxazol-2-ylamino)phenyl)(phenyl)-methanol [14] (10) with either 1,1'-sulfinylbis(1H-1,2,4-triazole) or 1,1'-sulfinylbis(1H-tetrazole), generated in situ from thionyl chloride and traizole or tetrazole, as previously described [24], gave the corresponding 1H-1,2,4-triazole (11), 1H-1,2,4-triazole (12) and 1H-tetrazole (13) (Scheme 3),…”

Section: Chemistrymentioning

confidence: 99%

Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Pautus

Aboraia

Bassett

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

1-[(Benzofuran-2-yl)phenylmethyl]-triazoles and -tetrazoles - potent competitive inhibitors of aromatase

Cited by 39 publications

References 5 publications

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

Nonsteroidal aromatase inhibitors: Recent advances

Design and synthesis of substituted imidazole and triazole N-phenylbenzo[d]oxazolamine inhibitors of retinoic acid metabolizing enzyme CYP26

Contact Info

Product

Resources

About