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Synthesis, biological evaluation and docking studies of trans ‐stilbene methylthio derivatives as cytochromes P450 family 1 inhibitors
Author(s) -
Wierzchowski Marcin,
Dutkiewicz Zbigniew,
GielaraKorzańska Agnieszka,
Korzański Artur,
Teubert Anna,
Teżyk Artur,
Stefański Tomasz,
BaerDubowska Wanda,
Mikstacka Renata
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13042
Subject(s) - chemistry , stereochemistry , enzyme , docking (animal) , cytochrome p450 , molecular model , active site , potency , biochemistry , in vitro , medicine , nursing
Cytochromes P450 family 1 ( CYP 1) are responsible for the metabolism of procarcinogens, for example polycyclic aromatic hydrocarbons and aromatic and heterocyclic amines. The inhibition of CYP 1 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 CYP 1A1, CYP 1A2 and CYP 1B1 and, to explain the variation of inhibitory potency of methoxystilbene derivatives and their methylthio analogues, we employed computational analysis. The compounds were docked to CYP 1A1, CYP 1A2 and CYP 1B1 binding sites with the use of Accelrys Discovery Studio 4.0 by the CDOCKER procedure. For CYP 1A2 and CYP 1B1, values of scoring functions correlated well with inhibitory potency of stilbene derivatives. All compounds were relatively poor inhibitors of CYP 1A2 that possess the most narrow and flat enzyme cavity among CYP 1s. For the most active CYP 1A1 inhibitor, 2‐methoxy‐4′‐methylthio‐ trans ‐stilbene, a high number of molecular interactions was observed, although the interaction energies were not distinctive.