Zbigniew Dutkiewicz

3,4,2′-Trimethoxy-trans-stilbene – a potent CYP1B1 inhibitor

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′-Trimethoxy-trans-stilbene (3,4,2′-TMS) exhibited extremely potent inhibitory action against CYP1B1 activity with an IC50 of 0.004 μM. 3,4,2′-TMS exhibited 90-fold selectivity for CYP1B1 over CYP1A1 and 830-fold selectivity for CYP1B1 over CYP1A2. However, 3,4,2′,4′-tetramethoxy-trans-stilbene appeared to be the most selective inhibitor of both CYP1B1 and CYP1A1 showing 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.

Full characterization and cytotoxic activity of new silver(I) and copper(I) helicates with quaterpyridine

The self-assembly of 6,6′′′′-dimethyl-2,2′;6′,2′′;6′′,2′′′-quaterpyridine L with tetrahedral ions of silver(I) and copper(I) leads to the formation of dinuclear double stranded helicates 1–4. 1H NMR studies confirm the stability of each helicate both in 2% aqueous DMSO solution, which plays the role of a medium in biological studies, and in the cell extract solution. The cytotoxic properties of complexes were examined on two cancerous cell lines: HeLa and T-47D as well as on the non-neoplastic fibroblasts HaCaT by using the MTT assay method. The IC50 values of cisplatin towards cancerous cell lines are rather comparable. However, the trend of cancerous/healthy cell selectivity is not maintained. One may assume a different mechanism of action. Moreover, it is possible to distinguish the cell death pathway triggered by Ag(I) and Cu(I) helicates presented in this study. Flow cytometry, EtBr displacement titrations, CD titrations, DNA melting experiments and DFT calculations were used to characterize the type of interaction and the mechanism of cytotoxic action.

Experimental and computational study on the reactivity of 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile, a key intermediate for the synthesis of tribenzoporphyrazine bearing peripheral methyl(3-pyridylmethyl)amino substituents.

An earlier developed alkylating path leading to tetraalkylated diaminomaleonitrile derivatives was explored. Attempts to explain the reactivity of the representative dialkylated diaminomaleonitrile 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile during the alkylation reaction were performed using X-ray and density functional theory (DFT) studies. The condensed Fukui functions accompanied by softness indices were found to be useful in explaining its reactivity observed during the reaction. The values of the Fukui functions and condensed softness for electrophilic attack calculated from Mulliken, Löwdin, and natural population analyses closely corresponded to the experimental observations. When 2,3-bis[(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile disodium salt was treated with dimethyl sulfate at lower temperatures the alkylation reaction prevailed, whereas at higher temperatures the alkylating agent acted as a hydride anion acceptor, which favored the elimination reaction. The tetraalkylated dinitrile 2,3-bis[methyl(3-pyridylmethyl)amino]-2(Z)-butene-1,4-dinitrile was used in the synthesis of tribenzoporphyrazine bearing methyl(3-pyridylmethyl)amino groups, which was subsequently subjected to solvatochromic and metallation studies. The changes observed during metallation seem to result from the coordination of the 3-pyridyl group by a palladium ion. This could influence the configuration of the methyl(3-pyridylmethyl)amino moiety, causing more effective donation of a lone pair of electrons from peripheral nitrogen to the macrocyclic ring.Graphical abstract.

Synthesis, Biological Evaluation, and Docking Studies of trans-Stilbene Methylthio Derivatives as Cytochromes P450 Family 1 Inhibitors

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.

Structure-Based Drug Design for Cytochrome P450 Family 1 Inhibitors

Cytochromes P450 are a class of metalloproteins which are responsible for electron transfer in a wide spectrum of reactions including metabolic biotransformation of endogenous and exogenous substrates. The superfamily of cytochromes P450 consists of families and subfamilies which are characterized by a specific structure and substrate specificity. Cytochromes P450 family 1 (CYP1s) play a distinctive role in the metabolism of drugs and chemical procarcinogens. In recent decades, these hemoproteins have been intensively studied with the use of computational methods which have been recently developed remarkably to be used in the process of drug design by the virtual screening of compounds in order to find agents with desired properties. Moreover, the molecular modeling of proteins and ligand docking to their active sites provide an insight into the mechanism of enzyme action and enable us to predict the sites of drug metabolism. The review presents the current status of knowledge about the use of the computational approach in studies of ligand-enzyme interactions for CYP1s. Research on the metabolism of substrates and inhibitors of CYP1s and on the selectivity of their action is particularly valuable from the viewpoint of cancer chemoprevention, chemotherapy, and drug-drug interactions.

The Inhibitory Effect of Natural Stilbenes and Their Analogues on Catalytic Activity of Cytochromes P450 Family 1 in Comparison with Other Phenols - Structure and Activity Relationship

In the last decade, increasing interest in the role of nutrition in disease prevention has been observed. The World Health Organization (WHO) reported that one-third of all cancer deaths could be prevented, and that diet plays a key role in prevention (Bode & Dong, 2009). The term chemoprevention introduced and developed by Sporn (2005) and Wattenberg (1985) refers in general to multi-targeted pharmacological and nutritional intervention with the use of naturally occurring or chemically synthesized compounds. For this purpose, dietary phytochemicals believed to be safe for human use seem to be very promising. The importance of natural chemopreventive agents relies on their non-toxicity when given in small amounts for longer periods of time. Moreover, using a combination of phytochemicals provides synergistic or additive preventive effects.