Synthesis,biological evaluation and docking studies of trans‐stilbene methylthio derivatives as cytochromes P450 family 1 inhibitors |
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Authors: | Zbigniew Dutkiewicz Agnieszka Gielara‐Korzańska Artur Korzański Anna Teubert Artur Teżyk Tomasz Stefański Wanda Baer‐Dubowska Renata Mikstacka |
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Affiliation: | 1. Department of Chemical Technology of Drugs, Faculty of Pharmacy, Poznan University of Medical Sciences, Poznań, PolandThese authors contributed equally to the work presented here and should therefore be regarded as equivalent authors.;2. Department of Chemical Technology of Drugs, Faculty of Pharmacy, Poznan University of Medical Sciences, Poznań, Poland;3. Department of Crystallography, Adam Mickiewicz University, Poznań, Poland;4. Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznań, Poland;5. Department of Forensic Medicine, Poznan University of Medical Sciences, Poznań, Poland;6. Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland;7. Department of Inorganic and Analytical Chemistry, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University in Toruń, Bydgoszcz, Poland |
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Abstract: | Cytochromes P450 family 1 (CYP1) are responsible for the metabolism of procarcinogens, for example polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines. The inhibition of CYP1 activity is examined in terms of chemoprevention and cancer chemotherapy. We designed and synthesized a series of trans‐stilbene derivatives possessing a combination of methoxy and methylthio functional groups attached in different positions to the trans‐stilbene skeleton. We determined the effects of synthesized compounds on the activities of human recombinant CYP1A1, CYP1A2 and CYP1B1 and, to explain the variation of inhibitory potency of methoxystilbene derivatives and their methylthio analogues, we employed computational analysis. The compounds were docked to CYP1A1, CYP1A2 and CYP1B1 binding sites with the use of Accelrys Discovery Studio 4.0 by the CDOCKER procedure. For CYP1A2 and CYP1B1, values of scoring functions correlated well with inhibitory potency of stilbene derivatives. All compounds were relatively poor inhibitors of CYP1A2 that possess the most narrow and flat enzyme cavity among CYP1s. For the most active CYP1A1 inhibitor, 2‐methoxy‐4′‐methylthio‐trans‐stilbene, a high number of molecular interactions was observed, although the interaction energies were not distinctive. |
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Keywords: | cytochromes P450 family 1 molecular docking trans‐resveratrol analogues |
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