Total Synthesis of (–)-Anaferine: A Further Ramification in a Diversity-Oriented Approach

The piperidine ring is a widespread motif in several natural bioactive alkaloids of both vegetal and marine origin. In the last years, a diversity-oriented synthetic (DOS) approach, aimed at the generation of a library of piperidine-based derivatives, was developed in our research group, employing commercially available 2-piperidine ethanol as a versatile precursor. Here, we report the exploration of another ramification of our DOS approach, that led us to the stereoselective total synthesis of (\u2013)-anaferine, a bis-piperidine alkaloid present in Withania somnifera extract. This natural product was obtained in 9% overall yield over 13 steps, starting from a key homoallylic alcohol previously synthesised in our laboratory. Therefore, the collection of piperidine-derivatives accessible from 2-piperidine ethanol was enriched with a new, diverse scaffold

Predictive auto-scaling with OpenStack Monasca

Cloud auto-scaling mechanisms are typically based on reactive automation rules that scale a cluster whenever some metric, e.g., the average CPU usage among instances, exceeds a predefined threshold. Tuning these rules becomes particularly cumbersome when scaling-up a cluster involves non-negligible times to bootstrap new instances, as it happens frequently in production cloud services. To deal with this problem, we propose an architecture for auto-scaling cloud services based on the status in which the system is expected to evolve in the near future. Our approach leverages on time-series forecasting techniques, like those based on machine learning and artificial neural networks, to predict the future dynamics of key metrics, e.g., resource consumption metrics, and apply a threshold-based scaling policy on them. The result is a predictive automation policy that is able, for instance, to automatically anticipate peaks in the load of a cloud application and trigger ahead of time appropriate scaling actions to accommodate the expected increase in traffic. We prototyped our approach as an open-source OpenStack component, which relies on, and extends, the monitoring capabilities offered by Monasca, resulting in the addition of predictive metrics that can be leveraged by orchestration components like Heat or Senlin. We show experimental results using a recurrent neural network and a multi-layer perceptron as predictor, which are compared with a simple linear regression and a traditional non-predictive auto-scaling policy. However, the proposed framework allows for the easy customization of the prediction policy as needed

Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity

5noopenThe design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins. Based on these premises, the simultaneous inhibition of these targets may provide several benefits for the treatment of cancer. In this work, we set up a design strategy including the assembly and integration of molecular fragments known to be important for binding to the Hsp90, PDHK1 and B-Raf targets, aided by molecular docking for the selection of a set of compounds potentially able to exert Hsp90-B-Raf-PDHK1 multi-target activities. The designed compounds were synthesized and experimentally validated in vitro. According to the in vitro assays, compounds 4 a, 4 d and 4 e potently inhibited Hsp90 and moderately inhibited the PDHK1 kinase. Finally, molecular dynamics simulations were performed to provide further insights into the structural basis of their multi-target activity.openPinzi L.; Foschi F.; Christodoulou M.S.; Passarella D.; Rastelli G.Pinzi, L.; Foschi, F.; Christodoulou, M. S.; Passarella, D.; Rastelli, G

Histone Deacetylase and Microtubules as Targets for the Synthesis of Releasable Conjugate Compounds

Design and synthesis of an HDAC inhibitor and its merger with three tubulin binders to create releasable conjugate compounds is described. The biological evaluation includes: a) in vitro reactivity with glutathione, b) antiproliferative activity, c) cell cycle analysis and d) quantification of protein acetylation. The cellular pharmacology study indicated that the HDAC-inhibitor-drug conjugates retained antimitotic and proapoptotic activity with a reduced potenc

Survival and Functional Outcomes After Hip Fracture Among Nursing Home Residents

Importance Little is known regarding outcomes after hip fracture among long-term nursing home residents. Objective To describe patterns and predictors of mortality and functional decline in activities of daily living (ADLs) among nursing home residents after hip fracture. Design, Setting, and Participants Retrospective cohort study of 60 111 Medicare beneficiaries residing in nursing homes who were hospitalized with hip fractures between July 1, 2005, and June 30, 2009. Main Outcomes and Measures Data sources included Medicare claims and the Nursing Home Minimum Data Set. Main outcomes included death from any cause at 180 days after fracture and a composite outcome of death or new total dependence in locomotion at the latest available assessment within 180 days. Additional analyses described within-residents changes in function in 7 ADLs before and after fracture. Results Of 60 111 patients, 21 766 (36.2%) died by 180 days after fracture; among patients not totally dependent in locomotion at baseline, 53.5% died or developed new total dependence within 180 days. Within individual patients, function declined substantially after fracture across all ADL domains assessed. In adjusted analyses, the greatest decreases in survival after fracture occurred with age older than 90 years (vs ≤75 years: hazard ratio [HR], 2.17; 95% CI, 2.09-2.26 [P \u3c .001]), nonoperative fracture management (vs internal fixation: HR for death, 2.08; 95% CI, 2.01-2.15 [P \u3c .001]), and advanced comorbidity (Charlson score of ≥5 vs 0: HR, 1.66; 95% CI, 1.58-1.73 [P \u3c .001]). The combined risk of death or new total dependence in locomotion within 180 days was greatest among patients with very severe cognitive impairment (vs intact cognition: relative risk [RR], 1.66; 95% CI, 1.56-1.77 [P \u3c .001]), patients receiving nonoperative management (vs internal fixation: RR, 1.48; 95% CI, 1.45-1.51 [P \u3c .001]), and patients older than 90 years (vs ≤75 years: RR, 1.42; 95% CI, 1.37-1.46 [P \u3c .001]). Conclusions and Relevance Survival and functional outcomes are poor after hip fracture among nursing home residents, particularly for patients receiving nonoperative management, the oldest old, and patients with multiple comorbidities and advanced cognitive impairment. Care planning should incorporate appropriate prognostic information related to outcomes in this population

A small library of chalcones induce liver cancer cell death through Akt phosphorylation inhibition

Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity ([Formula: see text]) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NF[Formula: see text]B-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NF[Formula: see text]B-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development

Antiproliferative activity of yatein isolated from Austrocedrus chilensis against murine myeloma cells: Cytological studies and chemical investigations

Context: Fitzroya cupressoides (Molina) I. M. Johnst. and Austrocedrus chilensis (D. Don) Pic.Serm. & Bizzarri are two Chilean Cupressaceae that are naturally resistant to biodegradation. Secondary metabolites from these species display a variety of biological activities. Objective: To evaluate the antiproliferative activity of two lignans, a diterpene and a flavonol isolated from A. chilensis and F. cupressoides, to elucidate their cytological effects on P3X murine myeloma cells. Materials and methods: The antiproliferative activity of yatein, isotaxiresinol, ferruginol, and isorhamnetin was evaluated in vitro using the MTT assay. The effect of yatein at the cellular level, due to its high antiproliferative activity was evaluated. P3X cells treated for 24 h with 12.5 and 25 \u3bcg/mL of yatein were also examined at the cytological level using immunofluorescence and scanning and transmission electron microscopy. Results: Yatein, a lignan isolated from A. chilensis, potentially inhibited P3X murine myeloma cell proliferation, resulting in approximately 75% cell death in response to a 25 \u3bcg/mL treatment with the lignan. P3X cells lost membrane integrity at the nuclear and cytoplasmic levels, including organelles, in response to yatein treatment (12.5 \u3bcg/mL), and we observed changes in the cytoplasmic organization and distribution of microtubules. The other compounds tested had low activity. Discussion and conclusions: Yatein is a lignan precursor of podophyllotoxin, a key agent in anticancer drugs. Due to its structural similarities to podophyllotoxin, yatein could have similar cytoplasmic target(s), such as the microtubular apparatus. These findings suggest that yatein may be of potential pharmacological interest and warrants further investigation in human cell lines

Studies on the Laccase-Catalyzed Oxidation of 4-Hydroxy-Chalcones

The laccase-catalyzed oxidation of a series of substituted 4-hydroxy-chalcones has been investigated. The main isolated dimeric products were, as expected, racemic mixtures of trans-2,3-dihydrobenzofuran derivatives, always co-eluted with an additional isomeric dimer with an open structure. The two enantiomers, as well as the co-eluted dimeric isomer could be isolated by semi-preparative HPLC with a chiral column and were fully characterized. (Figure presented.)

2-Phenyloxazole-4-carboxamide as a Scaffold for Selective Inhibition of Human Monoamine Oxidase B

A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki ) values in the sub-micromolar range and a good selectivity index (Ki\u2009MAO-A /Ki\u2009MAO-B >50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4\u2009a) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity

Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB\u2013NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerizatio