Design, Synthesis, and Biological Studies of Flavone-Based Esters and Acids as Potential P450 2A6 Inhibitors.

As a potential means for smoking cessation and consequently prevention of smoking-related diseases and mortality, in this study, our goal was to investigate the inhibition of nicotine metabolism by P450 2A6. Smoking is the main cause of many diseases and disabilities and harms nearly every organ of the body. As reported by the Centers for Disease Control and Prevention (CDC), more than 16 million Americans are living with diseases caused by smoking. On average, the life expectancy of a smoker is about 10 years less than a nonsmoker. Smoking cessation can substantially reduce the incidence of smoking-related diseases, including cancer. At least, 70 of the more than 7000 cigarette smoke components, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are known carcinogens. Nicotine is the compound responsible for the addictive and psychopharmacological effects of tobacco. Cytochrome P450 enzymes are responsible for the phase I metabolism of many tobacco components, including nicotine. Nicotine is mainly metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism decreases the amount of available nicotine in the bloodstream, leading to increased smoking behavior and thus exposure to tobacco toxicants and carcinogens. Here, we report the syntheses and P450 2A6 inhibitory activities of a number of new flavone-based esters and acids. Three of the flavone derivatives studied were found to be potent competitive inhibitors of the enzyme. Docking studies were used to determine the possible mechanisms of the activity of these inhibitors.

Study of Ceramide-Flavone Analogs Showing Self-Fluorescence and Anti-Proliferation Activities.

Background: Many current anti-cancer drugs used to treat breast cancer mediate tumor cell death through the induction of apoptosis. Cancer cells, however, often acquire multidrug-resistance following prolonged exposure to chemotherapeutics. Consequently, molecular pathways involved in tumor cell proliferation have become potential targets for pharmacological intervention. Ceramides are tumor suppressor lipids naturally found in the cell membrane, and are central molecules in the sphingolipid signalling pathway. Methods: Our lab has targeted the ceramide signaling pathway for potential pharmacological intervention in the treatment of breast cancer. Previously, we have shown that certain ceramide analogs have therapeutic potential in the treatment of chemo-sensitive and multidrug-resistant breast cancers. Using the most active analog from our previous studies as the lead compound, new analogs containing a flavone moiety were designed and synthesized. In general, flavone derivatives often show interesting pharmacological properties, and compounds based on these molecules have been found useful in many different therapeutic areas including anti-tumor, anti-coagulants, and anti-HIV therapy. Results: Synthesis and biological evaluation of five new flavonoid ceramide analogs are reported here. These compounds were also shown to be self-fluorescent, which can be useful when investigating their distribution and action in cancer cells. Conclusion: Four out of the five flavone ceramide analogs in this study showed significant anti-proliferation activities in the three cell lines studied, MDA-MB-232, MCF-7, and MCF-7TN-R; some showing varying degrees of selectivity. The mechanisms involved in cell proliferation inhibition are complicated and further studies are needed.

Identification of CYP 2A6 inhibitors in an effort to mitigate the harmful effects of the phytochemical nicotine.

AIM: In this study, our goal was to study the inhibition of nicotine metabolism by P450 2A6, as a means for reduction in tobacco use and consequently the prevention of smoking-related cancers. Nicotine, a phytochemical, is an addictive stimulant, responsible for the tobacco-dependence in smokers. Many of the other phytochemicals in tobacco, including polycyclic aromatic hydrocarbons, N-nitrosamines, and aromatic amines, are potent systemic carcinogens. Tobacco smoking causes about one of every five deaths in the United States annually. Nicotine plasma concentration is maintained by the smokers' smoking behavior within a small range. Nicotine is metabolized by cytochrome P450s 2A6 and 2A13 to cotinine. This metabolism causes a decrease in nicotine plasma levels, which in turn leads to increased tobacco smoking, and increased exposure to the tobacco carcinogens. METHODS: Using the phytochemical nicotine as a lead structure, and taking its interactions with the P450 2A6 binding pocket into consideration, new pyridine derivatives were designed and synthesized as potential selective mechanism-based inhibitors for this enzyme. RESULTS: The design and synthesis of two series of novel pyridine-based compounds, with varying substituents and substitution locations on the pyridine ring, as well as their inhibitory activities on cytochrome P450 2A6 and their interactions with its active site are discussed here. Substitutions at position 3 of the pyridine ring with an imidazole or propargyl ether containing group showed the most optimal interactions with the P4502A6 active site. CONCLUSION: The pyridine compounds with an imidazole or propargyl ether containing substituent on position 3 were found to be promising lead compounds for further development. Hydrogen-bonding interactions were determined to be crucial for effective binding of these molecules within the P450 2A6 active site.

DESIGN AND SYNTHESIS OF DIBENZYLFURAN BASED ETHER AND ESTER DERIVATIVES AS POTENTIAL P450 INHIBITORS.

Cytochrome P450 enzymes are a superfamily of hemoproteins involved in the metabolism and detoxification of endogenous and exogenous compounds. P450s are involved in the bioactivation of certain procarcinogens leading to the production of carcinogenic species. This has resulted in P450s' popularity as targets in cancer research. Developing selective and potent mechanism-based inhibitors for these enzymes is expected to be the key to understanding their mechanisms of action, as well as, developing potential anticancer agents. Our group has shown that certain aryl and aryl-alkyl acetylenes act as inhibitors of these enzymes. In an attempt to increase the number of selective P450 inhibitors available for enzymatic studies, five novel dibenzofuran ethers and esters have been designed and synthesized successfully.

A dibenzofuran derivative: 2-(pentyloxy)dibenzo[b,d]furan.

The title compound, C17H18O2, crystallizes in two-dimensional sheets, in which the 2-(pentyloxy)dibenzo[b,d]furan molecules are arranged in a head-to-head and tail-to-tail fashion that enables hydrophobic interactions between fully extended 2-pentoxy chains and π-π stacking between dibenzofuran rings in adjacent rings. Nearest intermolecular π-π stacking contacts are 3.3731 (12) Å. The molecule is nearly planar with an r.m.s. deviation of 0.0803 Å from the mean plane defined by the nineteen non-hydrogen atoms.

Ethyl 2-[2-(4-oxo-4H-chromen-2-yl)phenoxy]acetate.

In the title flavonoid derivative, C19H16O5, the chromene portion is planar (r.m.s. deviation = 0.022 Å) with the substituents lying closely to the same plane. The dihedral angle between its mean plane and that of the benzene ring is 4.9 (1)°. This planarity is due, in part, to the presence of a strong intramolecular C-H⋯O hydrogen bond and to two weak C-H⋯O contacts. In the crystal, neighboring molecules are linked by a C-H⋯O hydrogen bond and a C-H⋯π interaction, forming chains along the a-axis direction.

Complete Genome Sequences of Mycobacteriophages Clautastrophe, Kingsolomon, Krypton555, and Nicholas.

We report here the complete genome sequences of four subcluster L3 mycobacteriophages newly isolated from soil samples, using Mycobacterium smegmatis mc2155 as the host. Comparative genomic analyses with four previously described subcluster L3 phages reveal strong nucleotide similarity and gene conservation, with several large insertions/deletions near their right genome ends.

OPTIMIZATION OF SCALE-UP SYNTHESIS OF ANTI-CANCER CERAMIDE ANALOG 315.

Ceramides, serve as central mediators in sphingolipid metabolism and signaling pathways. They function in signaling events which induce apoptosis, cell cycle arrest, and autophagic responses. In cancer cells, ceramide levels are often suppressed by the up-regulation of ceramide-metabolizing enzymes or the down-regulation of ceramide-generating enzymes, resulting in increased cancer cell survival. Chemotherapeutic drugs and radiation therapy have been shown to increase intracellular ceramide levels leading to anti-cancer effects. Anti-cancer effects have also been seen in cancer cells with the use of exogenous short-chain ceramides. Our laboratory has synthesized a library of ceramide analogs and tested their effects on breast cancer cell lines. Analog 315 has been shown to be the most effective ceramide analog in our library. Here, we are reporting a large-scale synthesis of that analog is reported.