Computer-guided total synthesis of natural products: recent examples and future perspectives

FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOQuantum chemical calculations of nuclear magnetic resonance (NMR) shifts and coupling constants have been extensively employed in recent years mainly to facilitate structural elucidation of organic molecules. When the results of such calculations are used29510411075FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOFAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO2013/07607-82014/25474-82016/12541-4The authors are grateful to FAPESP (grants 2013/07607-8, 2014/25474-8 and 2016/12541-4) and CONICET, ANPCyT and UNR for financial suppor

One-pot synthesis of organophosphate monoesters from alcohols

AbstractA one-pot procedure for the phosphorylation of alcohols provides the corresponding phosphate monoesters in improved yields. The protocol features the use of tetrabutylammonium hydrogen phosphate and trichloroacetonitrile, followed by purification of the crude product by flash chromatography on silica gel. The final step, cation exchange chromatography, affords the organophosphates as ammonium salts that are usually required for biochemical applications. The mechanism appears to be phosphate rather than alcohol activation by trichloroacetonitrile

(-)-tarchonanthuslactone exerts a blood glucose-increasing effect in experimental type 2 diabetes mellitus

A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant.A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant2035038504

Business Case for a Micro-Combined Heat and Power Fuel Cell System in Commercial Applications

Combined heat and power fuel cell systems (CHP-FCSs) provide consistent electrical power and hot water with greater efficiency and lower emissions than alternative sources. These systems can be used either as baseload, grid-connected, or as off-the-grid power sources. This report presents a business case for CHP-FCSs in the range of 5 to 50 kWe. Systems in this power range are considered micro-CHP-FCS. For this particular business case, commercial applications rather than residential or industrial are targeted. To understand the benefits of implementing a micro-CHP-FCS, the characteristics that determine their competitive advantage must first be identified. Locations with high electricity prices and low natural gas prices are ideal locations for micro-CHP-FCSs. Fortunately, these high spark spread locations are generally in the northeastern area of the United States and California where government incentives are already in place to offset the current high cost of the micro-CHP-FCSs. As a result of the inherently high efficiency of a fuel cell and their ability to use the waste heat that is generated as a CHP, they have higher efficiency. This results in lower fuel costs than comparable alternative small-scale power systems (e.g., microturbines and reciprocating engines). A variety of markets should consider micro-CHP-FCSs including those that require both heat and baseload electricity throughout the year. In addition, the reliable power of micro-CHP-FCSs could be beneficial to markets where electrical outages are especially frequent or costly. Greenhouse gas emission levels from micro-CHP-FCSs are 69 percent lower, and the human health costs are 99.9 percent lower, than those attributed to conventional coal-fired power plants. As a result, FCSs can allow a company to advertise as environmentally conscious and provide a bottom-line sales advantage. As a new technology in the early stages of adoption, micro-CHP-FCSs are currently more expensive than alternative technologies. As the technology gains a foothold in its target markets and demand increases, the costs will decline in response to improved manufacturing efficiencies, similar to trends seen with other technologies. Transparency Market Research forecasts suggest that the CHP-FCS market will grow at a compound annual growth rate of greater than 27 percent over the next 5 years. These production level increases, coupled with the expected low price of natural gas, indicate the economic payback period will move to less than 5 years over the course of the next 5 years. To better understand the benefits of micro-CHP-FCSs, The U.S. Department of Energy worked with ClearEdge Power to install fifteen 5-kWe fuel cells in the commercial markets of California and Oregon. Pacific Northwest National Laboratory is evaluating these systems in terms of economics, operations, and their environmental impact in real-world applications. As expected, the economic analysis has indicated that the high capital cost of the micro-CHP-FCSs results in a longer payback period than typically is acceptable for all but early-adopter market segments. However, a payback period of less than 3 years may be expected as increased production brings system cost down, and CHP incentives are maintained or improved

Predominant T-helper 1 cytokine profile of hepatitits B virus nucleocapsid-specific T cells in acute self-limited hepatitis B

The cytokine pattern secreted by T cells on viral antigen recognition is believed to exert a profound influence on both the type of disease caused by the infecting agent and the final outcome of the viral infection. To characterize the cytokine pattern associated with spontaneous resolution of acute hepatitis B, we analyzed interferon gamma (IFN-gamma), interleukin (IL)-4, and IL-5 production by a wide series of hepatitis B virus (HBV) nucleocapsid-specific T-cell lines (34 lines) and T-cell clones (71 clones) derived from the peripheral blood of 13 patients during the acute or recovery phase of hepatitis B (2 and 7 of them were studied only in the recovery or the acute phase, respectively, and 4 during both). Most T-cell lines (67%) and clones (77%) isolated during the acute phase of infection expressed a T-helper (Th) 1 cytokine profile dominated by the production of IFN-gamma. A larger proportion (74%) of T-cell lines produced several years after resolution of hepatitis was able to secrete not only IFN-gamma, but also IL-4 and IL-5 (Th0-like cells). Results indicate that the antigen-specific fraction of peripheral blood T cells in acute self-limited hepatitis B selectively secrete Th1-type eytokines, suggesting that Th1-mediated effects may contribute not only to liver cell injury, but probably also to recovery from disease and successful control of infection

Baseline serum TSH levels predict the absence of thyroid dysfunction in cancer patients treated with immunotherapy

Purpose Immunotherapy against immune checkpoints has significantly improved survival both in metastatic and adjuvant setting in several types of cancers. Thyroid dysfunction is the most common endocrine adverse event reported. Patients who are at risk of developing thyroid dysfunction remain to be defined. We aimed to identify predictive factors for the develop- ment of thyroid dysfunction during immunotherapy. Methods This is a retrospective study including a total of 68 patients who were treated with immune checkpoint inhibi- tors (ICIs) for metastatic or unresectable advanced cancers. The majority of patients were treated with anti-PD1 drugs in monotherapy or in combination with anti-CTLA4 inhibitors. Thyroid function and anti-thyroid antibodies, before starting immunotherapy and during treatment, were evaluated. Thyroid ultrasound was also performed in a subgroup of patients at the time of enrolment in the study. Results Eleven out of 68 patients (16.1%) developed immune-related overt thyroid dysfunction. By ROC curve analysis, we found that a serum TSH cut-off of 1.72 mUI/l, at baseline, had a good diagnostic accuracy in identifying patients without overt thyroid dysfunction (NPV = 100%, p = 0.0029). At multivariate analysis, both TSH and positive anti-thyroid antibod- ies (ATAbs) levels, before ICIs treatment, were independently associated with the development of overt thyroid dysfunction during immunotherapy (p = 0.0001 and p = 0.009, respectively). Conclusions Pre-treatment serum TSH and ATAbs levels may help to identify patients at high risk for primary thyroid dysfunction. Our study suggests guidance for an appropriate timely screening and for a tailored management of thyroid dysfunctions in patients treated with ICIs

A concise total synthesis of (R)-fluoxetine, a potent and selective serotonin reuptake inhibitor

(R)-Fluoxetine, potent and selective serotonin reuptake inhibitor, has been synthesized in six steps, 50% overall yield and 99% ee from benzaldehyde via catalytic asymmetric allylation with Maruoka's catalyst.(R)-Fluoxetina, um inibidor potente e seletivo da recaptação da serotonina, foi sintetizada em seis etapas, 50% de rendimento total e 99% de excesso enantiomérico a partir do benzaldeído via alilação catalítica assimétrica empregando-se o sistema catalítico desenvolvido por Maruoka e colaboradores.495499Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq