A novel series of methoxy-trans-stilbenes with 3,4-dimethoxy motifs was designed and synthesized. The inhibitory potency of 3,4-dimethoxystilbene derivatives against cytochrome P450 isozymes CYP1A1, CYP1B1 and CYP1A2 was evaluated. 3,4,2 0 -Trimethoxy-trans-stilbene (3,4,2 0 -TMS) exhibited extremely potent inhibitory action against CYP1B1 activity with an IC 50 of 0.004 mM. 3,4,2 0 -TMS exhibited 90-fold selectivity for CYP1B1 over CYP1A1 and 830-fold selectivity for CYP1B1 over CYP1A2. However, 3,4,2 0 ,4 0tetramethoxy-trans-stilbene appeared to be the most selective inhibitor of both CYP1B1 and CYP1A1showing very low affinity toward CYP1A2. Complementary experimental studies and computational methods were used to explain what structural determinants decide the specific affinity of stilbene derivatives to CYP1A2 and CYP1B1 binding sites.

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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Key indicators: single-crystal X-ray study; T = 295 K; mean (C-C) = 0.005 Å; R factor = 0.038; wR factor = 0.106; data-to-parameter ratio = 13.0.The molecule of the title compound, C 16 H 13 BrO 3 , is built of two approximately planar fragments, viz. 3-bromobenzoate [maximum deviation = 0.055 (2) Å and 2-oxo-2-p-tolylethyl [maximum deviation = 0.042 (2) Å ], inclined by 46.51 (7) . In the crystal, weak C-HÁ Á ÁO hydrogen bonds and BrÁ Á ÁBr contacts [3.6491 (7) Å ] connect the molecules into infinite layers parallel to (221). Related literature ExperimentalCrystal data

The crystal structures of two compounds containing enaminone heterodiene systems and forming intermolecular hydrogen bonds N-H--O are reported: 1) 3-ethoxycarbonyl-2-methyl-4-pyridone (hereafter ETPY) and 2) 3-ethoxycarbonyl-2-phenyl-6-methoxycarbonyl-5,6-dihydro-4-pyridone (hereafter EPPY). The crystal packing is controlled by intermolecular hydro gen bonds N-H-0 = C connecting the heteroconjugated enaminone groups in infinite chains. In ETPY crystals the intermolecular hydrogen bond involves the heterodienic pathway with the highest 7r-delocalization that is effective fo ra very short N -O distance of 2.701(9) A (average from two molecules in the asymmetric unit). Probably due to the steric hindrance, the hydrogen bond in EPPY is formed following the heterodienic pathway that involves the ester C = 0 group, although 7r-delocalization along this pathway is less than that along the pyridone-part pathway resulting in a longer N -O distance of 2.886(3) A.