Identification of New Mono/Dihydroxynaphthoquinone as Lead Agents That Inhibit the Growth of Refractive and Triple-Negative Breast Cancer Cell Lines.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in nearly 20-30% of breast cancers and is associated with metastasis resulting in poor patient survival and high recurrence. The dual EGFR/HER2 kinase inhibitor lapatinib has shown promising clinical results, but its limitations have also led to the resistance and activation of tumor survival pathways. Following our previous investigation of quinones as HER2 kinase inhibitors, we synthesized several naphthoquinone derivatives that significantly inhibited breast tumor cells expressing HER2 and trastuzumab-resistant HER2 oncogenic isoform, HER2Δ16.

Synthetic Method to Form 2,2'-Bis(naphthoquinone) Compounds.

We have discovered a transition-metal-free approach to the synthesis of 2,2'-bis(naphthoquinones) using a Diels-Alder reaction of conjugated ketene silyl acetals with benzoquinone. Its monomer analogue can also be synthesized by simply increasing the equivalents of benzoquinone.

Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer.

The human epidermal growth factor receptor 2 (HER2) is a member of the erbB class of tyrosine kinase receptors. These proteins are normally expressed at the surface of healthy cells and play critical roles in the signal transduction cascade in a myriad of biochemical pathways responsible for cell growth and differentiation. However, it is widely known that amplification and subsequent overexpression of the HER2 encoding oncogene results in unregulated cell proliferation in an aggressive form of breast cancer known as HER2-positive breast cancer.

Development of flavone propargyl ethers as potent and selective inhibitors of cytochrome P450 enzymes 1A1 and 1A2.

Naturally occurring flavonoids are known to be metabolized by several cytochrome P450 enzymes including P450s 1A1, 1A2, 1B1, 2C9, 3A4, and 3A5. In general flavonoids can act as substrates, inducers, and/or inhibitors of P450 enzymes. The position of the substituents on the flavone backbone has been shown to impact the biological activity against P450 enzymes.

Insights on cytochrome p450 enzymes and inhibitors obtained through QSAR studies.

The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes.

7-Ethynylcoumarins: selective inhibitors of human cytochrome P450s 1A1 and 1A2.

To discover new selective mechanism-based P450 inhibitors, eight 7-ethynylcoumarin derivatives were prepared through a facile two-step synthetic route. Cytochrome P450 activity assays indicated that introduction of functional groups in the backbone of coumarin could enhance the inhibition activities toward P450s 1A1 and 1A2, providing good selectivity against P450s 2A6 and 2B1. The most potent product 7-ethynyl-3,4,8-trimethylcoumarin (7ETMC) showed IC(50) values of 0.

Sulfapyridine (polymorph III), sulfapyridine dioxane solvate, sulfapyridine tetrahydrofuran solvate and sulfapyridine piperidine solvate, all at 173 K.

The X-ray crystal structures of solvates of sulfapyridine have been determined to be conformational polymorphs. 4-Amino-N-(1,2-dihydropyridin-2-ylidene)benzenesulfonamide (polymorph III), C(11)H(11)N(3)O(2)S, (1), 4-amino-N-(1,2-dihydropyridin-2-ylidene)benzenesulfonamide 1,3-dioxane monosolvate, C(11)H(11)N(3)O(2)S·C(4)H(8)O(2), (2), and 4-amino-N-(1,2-dihydropyridin-2-ylidene)benzenesulfonamide tetrahydrofuran monosolvate, C(11)H(11)N(3)O(2)S·C(4)H(8)O, (3), crystallized as the imide form, while piperidin-1-ium 4-amino-N-(pyridin-2-yl)benzenesulfonamidate, C(5)H(12)N(+)·C(11)H(10)N(3)O(2)S(-), (4), crystallized as the piperidinium salt. The tetrahydrofuran and dioxane solvent molecules in their respective structures were disordered and were refined using a disorder model.

Diet-induced effects on neuronal and glial elements in the middle-aged rat hippocampus.

Consumption of a high-fat and/or high-cholesterol diet can have detrimental effects on the brain. In the present study, dietary treatment with saturated fats, trans fats, or cholesterol to middle-aged Fischer 344 rats resulted in alterations to serum triglyceride and cholesterol levels, organ weights, and hippocampal morphology. Previously, we demonstrated that a 10% hydrogenated coconut oil and 2% cholesterol diet resulted in worse performance on the 12-day water radial arm maze, increased cholesterol and triglyceride levels, and decreased dendritic microtubule associated protein 2 (MAP2) staining in the hippocampus.

Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells.

Daidzein (1) is a natural estrogenic isoflavone. We report here that 1 can be transformed into anti-estrogenic ligands by simple alkyl substitutions of the 7-hydroxyl hydrogen. To test the effect of such structural modifications on the hormonal activities of the resulting compounds, a series of daidzein analogues have been designed and synthesized.

In silico studies of polyaromatic hydrocarbon inhibitors of cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1.

A computational study was undertaken to understand the nature of binding and the structural features that play a significant role in the binding of arylacetylene molecules to cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1. Nine polycyclic arylacetylenes determined to be mechanism-based P450 enzyme inhibitors were studied. The lack of polar substituents in these compounds causes them to be incapable of hydrogen bonding to the polar protein residues.