Novel imidazolyl and triazolyl substituted biphenyl compounds: synthesis and evaluation as nonsteroidal inhibitors of human 17α-hydroxylase-C17, 20-Lyase (P450 17)

Zhuang, Yan; Wachall, Bertil G.; Hartmann, Rolf W.

doi:10.1016/s0968-0896(00)00076-6

Cited by 52 publications

(26 citation statements)

References 20 publications

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“…[14][15][16] However, to the best of our knowledge, the exploitation of the biphenyl system, a putative steroidal A/C ring mimic, as a scaffold in the design of NSAIs has yet to be realised, although Hartmann et al have previously reported several imidazole-and triazole-substituted biphenyls as highly potent 17a-hydroxylase-C17,20-lyase (Cyp17) inhibitors for the potential treatment of prostate cancer. [17,18] Given that Cyp17 is a member of the cytochrome P450 family of enzymes that includes aromatase, it is reasonable to explore the possibility of adopting the biphenyl scaffold as a template for designing a new structural class of AIs. Herein we report a series of novel AIs by incorporating the triazolylmethyl moiety into a biphenyl framework.…”

Section: Introductionmentioning

confidence: 99%

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

et al. 2008

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The synthesis and in vitro biological evaluation (JEG-3 cells) of a series of novel and potent aromatase inhibitors, prepared by microwave-enhanced Suzuki cross-coupling methodology, are reported. These compounds possess a biphenyl template incorporated with the haem-ligating triazolylmethyl moiety, either on its own or in combination with other substituent(s) at various positions on the phenyl rings. The most potent aromatase inhibitor reported herein has an IC(50) value of 0.12 nM, although seven of its congeners are also highly potent (IC(50)

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Section: Introductionmentioning

confidence: 99%

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

et al. 2008

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“…Bearing this in mind, above studies seem to conform to our QSAR findings rather well. The second example deals with the inhibitory activity against CYP17 of N-biphenylmethylimidazoles with various substituents [22]. Perhaps because structural variations are occurring only at the most distant positions from the azole N-heme coordination site in this "linearly" ring-connected system, the QSAR characteristics are believed to be different and not comparable with ours.…”

Section: Discussionmentioning

confidence: 77%

Quantitative Structure–Activity Relationship for Inhibition of CYP2B6 and CYP3A4 by Azole Compounds – Comparison with Their Binding Affinity

2009

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Azole compounds are widely used as antifungal agents. They interact with cytochrome P450 14DM (CYP51) via coordination of the nucleophilic nitrogen of their heterocyclic ring to the heme iron in CYP51. In our previous study, we showed that the binding affinity of eighteen azole compounds for rat CYP2B and CYP3A was nicely expressed by the bilinear model of log P. In this study, the same azole compounds were examined as to their inhibitory effect on the substrates for human CYP2B6 and CYP3A4. The inhibitory activity determined was analyzed as to the molecular properties of the azole compounds. A nice correlation was found with the bilinear model of log P. These results suggested that the molecular hydrophobicity of the azole compounds plays a major role in the inhibition as well as in the binding. For the binding, HOMO was significant as an additional descriptor in the correlation equations, whereas the existence of a hydroxyl group was significant for the inhibition.

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“…When comparing the activities of the compounds of this study to the ones of the parent compounds [11], it must be mentioned that the structural modifications did not increase activities.…”

Section: Biological Resultsmentioning

confidence: 91%

“…Some of these compounds had been designed as mimetics of the steroidal AC-rings ( Fig. 1) [10,11]. Since they had shown a high activity and a good selectivity, we chose them for further optimizations.…”

Section: Introductionmentioning

confidence: 99%

CYP17 Inhibitors. Annulations of Additional Rings in Methylene Imidazole Substituted Biphenyls: Synthesis, Biological Evaluation and Molecular Modelling

Mendieta

Negri

et al. 2008

Archiv der Pharmazie

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Twenty-one novel compounds originating from two classes of annulated biphenyls were synthesized as mimetics of the steroidal A- and C-rings and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of the hepatic CYP enzyme 3A4. Potent CYP17 inhibitors were found for each class, compound 9 (17 and 71% at 0.2 and 2 microM, respectively) and 21 (591 nM). Compound 21 showed only weak inhibition of CYP3A4 (32 and 64% at 2 and 10 microM, respectively). Both compounds, however, exhibited moderate to strong inhibition of the glucocorticoid-forming enzyme CYP11B1. The most interesting compounds were docked into our protein model. They bound into one of the modes which we have previously published. New interaction regions were identified.

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Novel imidazolyl and triazolyl substituted biphenyl compounds: synthesis and evaluation as nonsteroidal inhibitors of human 17α-hydroxylase-C17, 20-Lyase (P450 17)

Cited by 52 publications

References 20 publications

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

Non‐Steroidal Aromatase Inhibitors Based on a Biphenyl Scaffold: Synthesis, in vitro SAR, and Molecular Modelling

Quantitative Structure–Activity Relationship for Inhibition of CYP2B6 and CYP3A4 by Azole Compounds – Comparison with Their Binding Affinity

CYP17 Inhibitors. Annulations of Additional Rings in Methylene Imidazole Substituted Biphenyls: Synthesis, Biological Evaluation and Molecular Modelling

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