Oxidative Dearomatization of Pyridines.

Dearomatization of pyridines is a well-established synthetic approach to access piperidines. Although remarkably powerful, existing dearomatization processes have been limited to the hydrogenation or addition of carbon-based nucleophiles to activated pyridiniums. Here, we show that arenophile-mediated dearomatizations can be applied to pyridines to directly introduce heteroatom functionalities without prior substrate activation. The arenophile platform in combination with olefin oxidation chemistry provides access to dihydropyridine cis-diols and epoxides. These previously elusive compounds are now readily accessible and can be used for the downstream preparation of diversely functionalized piperidines.

Role of omega-3 endocannabinoids in the modulation of T-cell activity in a multiple sclerosis experimental autoimmune encephalomyelitis (EAE) model.

Epidemiological studies show that omega-3 fatty acid consumption is associated with improved conditions in neurodegenerative diseases such as multiple sclerosis (MS). However, the mechanism of this association is not well understood. Emerging evidence suggests that parent molecules such as docosahexaenoic acid are converted into downstream metabolites that are capable of directly modulating immune responses. In vitro, we found that docosahexaenoyl ethanolamide (DHEA), another dietary component and its epoxide metabolite, reduced the polarization of naïve T-cells toward proinflammatory Th1 and Th17 phenotypes. Furthermore, we identified that DHEA and related endocannabinoids are changing during the disease progression in mice undergoing relapse-remitting experimental autoimmune encephalomyelitis (RR-EAE). In addition, daily administration of DHEA to mice delayed the onset of disease, the rate of relapse, and the severity of clinical scores at relapse in RR-EAE, an animal model of MS. Collectively, these data indicate that DHEA and their downstream metabolites reduce the disease severity in the RR-EAE model of MS and can be potential dietary adjuvants to existing MS therapeutics.

Amaryllidaceae Alkaloids Decrease the Proliferation, Invasion, and Secretion of Clinically Relevant Cytokines by Cultured Human Colon Cancer Cells.

Alkaloids isolated from members of the Amaryllidaceae plant family are promising anticancer agents. The purpose of the current study was to determine if the isocarbostyrils narciclasine, pancratistatin, lycorane, lycorine, crinane, and haemanthamine inhibit phenomena related to cancer progression in vitro. To achieve this, we examined the proliferation, adhesion, and invasion of cultured human colon cancer cells via MTT assay and Matrigel-coated Boyden chambers. In addition, Luminex assays were used to quantify the secretion of matrix metalloproteinases (MMP) and cytokines associated with poor clinical outcomes. We found that all alkaloids decreased cell proliferation regardless of TP53 status, with narciclasine exhibiting the greatest potency. The effects on cell proliferation also appear to be specific to cancer cells. Narciclasine, lycorine, and haemanthamine decrease both adhesion and invasion but with various potencies depending on the cell line. In addition, narciclasine, lycorine, and haemanthamine decreased the secretion of MMP-1, -2, and -7, as well as the secretion of the cytokines pentraxin 3 and vascular endothelial growth factor. In conclusion, the present study shows that Amaryllidaceae alkaloids decrease phenomena and cytokines associated with colorectal cancer progression, supporting future investigations regarding their potential as multifaceted drug candidates.

Dearomative Ring Expansion of Polycyclic Arenes.

Benzocycloheptenes constitute a common structural motif embedded in many natural products and biologically active compounds. Herein, we report their concise preparation from non-activated polycyclic arenes using a two-step sequence involving dearomative [4+2]-cycloaddition with arenophile in combination with palladium-catalyzed cyclopropanation, followed by cycloreversion-initiated ring expansion. The described strategy provides a working alternative to the Buchner reaction, which is limited to monocyclic arenes. Overall, this methylene-insertion molecular editing approach enables rapid and direct conversion of simple (hetero)arenes into a range of substituted (aza)benzocycloheptatrienes, which can undergo a myriad of downstream functionalizations.

Nutritional and physico-chemical implications of avocado meal as a novel dietary fiber source in an extruded canine diet.

This study assessed the effects of a diet containing avocado meal (AMD), an underutilized by-product avocado oil processing, on apparent total tract digestibility (ATTD) and fecal fermentative end-products when compared with beet pulp (BPD) and cellulose (CD) diets targeting 15% total dietary fiber (TDF). The concentration of persin, a natural fungicidal toxin present in avocado, was also determined on several parts of the fruit and avocado meal. Nine intact female beagles (4.9 ± 0.6 yr and 11.98 ± 1.76 kg) were randomly grouped in a 3 × 3 replicated Latin square design. Periods were 14 d long, with 10 d of adaptation followed by 4 d of total fecal and urine collection for apparent total tract digestibility (ATTD) calculations. Fresh fecals were analyzed for fermentative end-products. The BPD (87.0 g/d) caused higher (P < 0.05) fecal output (as-is basis) than AMD (62.3 g/d) and CD (58.0 g/d). Fecal score for the BPD (3.1) was greater (P < 0.05) than for AMD (2.8) or CD (2.6). Acid-hydrolyzed fat ATTD was lower (P < 0.05) for the BPD (94.1%) than for the AMD (95.5%) and CD (95.7%). Crude protein ATTD was greater (P < 0.05) for the CD (88.5%) than the AMD (82.2%) or BPD (83.7%). Dogs fed AMD (49.9%) or BPD (51.0%) exhibited greater (P < 0.05) TDF ATTD than CD. The fermentative profile for the AMD (233.4, 70.9, 8.8, and 12.0 µmole/g DM, respectively) was similar (P > 0.05) to the CD (132.9, 61.7, 7.5, and 9.5 µmole/g DM, respectively) profile, with lower (P < 0.05) concentrations of acetate and propionate and higher (P < 0.05) concentrations of isovalerate and indoles compared to the BPD. Dogs fed AMD (47.0 µmole/g DM) or BPD (54.2 µmole/g DM) exhibited similar (P > 0.05) fecal butyrate concentrations greater (P < 0.05) than for CD (24.7 µmole/g DM). Given these results, avocado meal appears to be an adequate dietary fiber source when compared with traditional fiber sources used in canine diets. No health adverse effects were observed in dogs fed extruded diet containing as much as 18% of avocado meal (as-is basis).

Development of a Scalable and Sublimation-Free Route to MTAD.

The cyclic azodicarbonyl 4-methyl-1,2,4-triazoline-3,5-dione (MTAD) is a versatile and powerful reagent used mainly in cycloaddition chemistry. Though known for more than 50 years, its unsafe preparation, as well as purification by sublimation, hampered its widespread applicability on a larger scale. Herein we report a scalable and safe route to MTAD, which avoids the generation of methyl isocyanate. Moreover, we demonstrate that sublimation can be circumvented by the application of judicious oxidation conditions, followed by simple filtration. Overall, up to 25 g of MTAD was prepared in a single batch from commercial starting materials in three steps, with recrystallization serving as the only purification in the sequence. When employed in dearomative methodologies, the MTAD obtained by this protocol displayed synthetic efficiency equivalent to that of MTAD purified by sublimation.

Enantioselective Synthesis of Isocarbostyril Alkaloids and Analogs Using Catalytic Dearomative Functionalization of Benzene.

Enantioselective total syntheses of the anticancer isocarbostyril alkaloids (+)-7-deoxypancratistatin, (+)-pancratistatin, (+)-lycoricidine, and (+)-narciclasine are described. Our strategy for accessing this unique class of natural products is based on the development of a Ni-catalyzed dearomative trans-1,2-carboamination of benzene. The effectiveness of this dearomatization approach is notable, as only two additional olefin functionalizations are needed to construct the fully decorated aminocyclitol cores of these alkaloids. Installation of the lactam ring has been achieved through several pathways and a direct interconversion between natural products was established via a late-stage C-7 cupration. Using this synthetic blueprint, we were able to produce natural products on a gram scale and provide tailored analogs with improved activity, solubility, and metabolic stability.

Synthesis of (+)-Pancratistatins via Catalytic Desymmetrization of Benzene.

A concise synthesis of (+)-pancratistatin and (+)-7-deoxypancratistatin from benzene using an enantioselective, dearomative carboamination strategy has been achieved. This approach, in combination with the judicious choice of subsequent olefin-type difunctionalization reactions, permits rapid and controlled access to a hexasubstituted core. Finally, minimal use of intermediary steps as well as direct, late stage C-7 hydroxylation provides both natural products in six and seven operations.