STEREOSELECTIVE SYNTHESIS OF CYCLOPROPANES WITH QUATERNARY CARBON CENTRES

PhDMulti-substituted optically pure cyclopropanes are important motifs present in many agrochemicals, pharmaceuticals and materials employed in manifold applications. Their synthesis is challenging due to both the strained conformation and the need to control both the relative and absolute stereochemistry. This thesis describes an investigation of the scope of the Wadsworth-Emmons cyclopropanation, highlighting it as a potential efficient methodology for diastereoselective and enantiospecific synthesis of these valuable ring systems. Chapter 1 is an introduction to the cyclopropanation protocols and is split in two subsections. The first is a description of the currently most exploited synthetic pathways to cyclopropanes, with analysis of their substrate scope and critical analysis of their limitations as compared to potential of the Wadsworth-Emmons cyclopropanation (Sections 1.1 to 1.3). The latter section consists of a review on the history and the evolution of this procedure and introduces the preconditions for the development of the project (Sections 1.4 to 1.17). Chapter 2 describes the results and discussion, introducing the use of novel alkyl-substituted triethyl phosphonoacetates to yield cyclopropyl-esters containing quaternary stereocentres. The high yields and the excellent trans-diastereoselectivity values obtained (proved by X-ray crystallography) allowed the proposal of a suggested reaction mechanism, which is supported by the subsequent experiments carried out in the presence of other functional groups, e.g. other carbonyls, nitriles, hetero-aromatics, substituted phenyl rings. This study was further extended to examine the effect of fluorine atom, due to its importance in biologically active environments. The study on the stereochemistry of the Wadsworth-Emmons cyclopropanation has been strongly supported by a range of X-ray crystal structures of the cyclopropane products. The chapter ends with an empirical set of guidelines, helpful for the design of successful cyclopropanations. Chapter 3, describes the experimental methods in full as well as full characterisation of the products obtained. Literature references, noted throughout the thesis, are listed in the final chapter.EPSR

Sultones and Sultines via a Julia-Kocienski Reaction of Epoxides

We thank the EPSRC/Syngenta for a CASE Ph.D. Studentship (to G.M.T.S. under grant EP/J50029X/1), the EPSRC UK National Mass Spectrometry Facility at Swansea University and the EPSRC UK National Crystallography Service Facility at Southampton University.37 We are indebted to Andrew Plant and Janice Black (Syngenta) for the initial suggestion of using the combination of LiN(SiMe3)2/CH2Cl2 and Matthew Reid (Syngenta) for NMR assistance

Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results

Quinazolinecarboline alkaloid evodiamine as scaffold for targeting topoisomerase I and sirtuins

This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results

Risk factors and action thresholds for the novel coronavirus pandemic. Insights from the Italian Society of Nephrology COVID-19 Survey

Background and aim: Over 80% (365/454) of the nation’s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment. Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules. Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20–1.51], positive healthcare workers (IRR 1.09, 95% CI 1.02–1.17), test-all policy (IRR 5.94, 95% CI 3.36–10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001–1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94–0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers. Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center’s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely

Risk factors and action thresholds for the novel coronavirus pandemic. Insights from the Italian Society of Nephrology COVID-19 Survey

365noBackground and aim: Over 80% (365/454) of the nation’s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment. Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules. Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20–1.51], positive healthcare workers (IRR 1.09, 95% CI 1.02–1.17), test-all policy (IRR 5.94, 95% CI 3.36–10.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001–1.003) (all p < 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94–0.98) (p < 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence ≥ 229 per 100,000 and at ≥ 3 positive healthcare workers. Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center’s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely.nonenoneNordio M.; Reboldi G.; Di Napoli A.; Quintaliani G.; Alberici F.; Postorino M.; Aucella F.; Messa P.; Brunori G.; Brunori G.; Bosco M.; Malberti F.; Mandreoli M.; Mazzaferro S.; Movilli E.; Ravera M.; Salomone M.; Santoro D.; PostorinoLimido M.A.; Bonomini M.; Stingone A.; Maccarone M.; Di Loreto E.; Stacchiotti L.; Malandra R.; Chiarella S.; D'Agostino F.; Fuiano G.; Nicodemo L.; Bonofiglio R.; Greco S.; Mallamaci F.; Barreca E.; Caserta C.; Bruzzese V.; Galati D.; Tramontana D.; Viscione M.; Chiuchiolo L.; Tuccillo S.; Sepe M.; Vitale F.; Ciriana E.; Santoro D.; Martignetti V.; Caserta D.; Stizzo A.; Romano A.; Iulianiello G.; Cascone E.; Minicone P.; Chiricone D.; Delgado G.; Barbato A.; Celentano S.; Molfino I.; Coppola S.; Raiola I.; Abategiovanni M.; Borrelli S.; Margherita C.; Bruno F.; Ida M.; Aliperti E.; Potito D.; Cuomo G.; De Luca M.; Merola M.; Botta C.; Garofalo G.; Alinei P.; Paglionico C.; Roano M.; Vitale S.; Ierardi R.; Fimiani V.; Conte G.; Di Natale G.; Romano M.; Di Marino V.; Scafarto A.; Meccariello S.; Pecoraro C.; Di Stazio E.; Di Meglio E.; Cuomo A.; Maresca B.; Rotaia E.; Capasso G.; Auricchio M.; Pluvio C.; Maddalena L.; De Maio A.; Palladino G.; Buono F.; Gigliotti G.; Mandreoli M.; Mancini E.; La Manna G.; Storari A.; Mosconi G.; Cappelli G.; Scarpioni R.; Gregorini M.; Rigotti A.; Mancini W.; Bianco F.; Boscutti G.; Amici G.; Tosto M.; Fini R.; Pace G.; Cioffi A.; Boccia E.; Di Lullo L.; Di Zazzo G.; Simonelli R.; Bondatti F.; Miglio L.; Rifici N.; Treglia A.; Muci M.; Baldinelli G.; Rizzi E.; Lonzi M.; De Cicco C.; Forte F.; De Paolis P.; Grandaliano G.; Cuzziol C.; Torre V.M.; Sfregola P.; Rossi V.; Fabio G.; Flammini A.; Filippini A.; Onorato L.; Vendola F.; Di Daniela N.; Alfarone C.; Scabbia L.; Ferrazzano M.; Grotta B.D.; Gamberini M.; Fazzari L.; Mene P.; Morgia A.; Catucci A.; Palumbo R.; Puliti M.; Marinelli R.; Polito P.; Marrocco F.; Morabito S.; Rocca R.; Nazzaro L.; Lavini R.; Iamundo V.; Chiappini M.; Casarci M.; Morosetti M.; Hassan S.; Alfarone C.; Ferrazzano M.; Firmi G.; Galliani M.; Serraiocco M.; Feriozzi S.; Valentini W.; Sacco P.; Garibotto G.; Cappelli V.; Saffioti C.; Repetto M.; Rolla D.; Lorenz M.; Pedrini L.; Polonioli D.; Galli E.; Ruggenenti P.; Scolari F.; Bove S.; Costantino E.; Bracchi M.; Mangano S.; Depetri G.; Malberti F.; La Milia V.; Farina M.; Zecchini S.; Savino R.; Melandri M.; Guastoni C.; Paparella M.; Gallieni M.; Minetti E.; Bisegna S.; Messa P.; Righetti M.; Badalamenti S.; Guastoni C.; Alberghini E.; Bertoli S.; Fabbrini P.; Albrizio P.; Rampino T.; Colturi C.; Rombola G.; Lucatello A.; Guerrini E.; Ranghino A.; Lenci F.; Fanciulli E.; Santarelli S.; Damiani C.; Garofalo D.; Sopranzi F.; Santoferrara A.; Di Luca M.; Galiotta P.; Brigante M.; Manganaro M.; Maffei S.; Berto I.; Besso L.; Viglino G.; Besso L.; Cusinato S.; ChiarinottiChiappero D.F.; Tognarelli G.; Gianoglio B.; Salomone M.; Forneris G.; Biancone L.; Savoldi S.; Vitale C.; Boero R.; Filiberti O.; Borzumati M.; Gesualdo L.; Lomonte C.; Gernone G.; Pallotta G.; Di Paolo S.; Vernaglione L.; Specchio A.; Stallone G.; Dell'Aquila R.; Aucella F.; Sandri G.; Russo F.; Napoli M.; Marangi A.; Morrone L.; Di Stratis C.; Fresu A.; Cicu F.; Murtas S.; Manca O.; Pani A.; Pilloni M.; Pistis R.; Cadoni M.; Contu B.; Logias F.; Ivaldi R.; Fancello S.; Cossu M.; Lepori G.; Lepori G.; Vittoria S.; Battiati E.; Arnone M.; Rome M.; Barbera A.; Granata A.; Collura G.; Dico C.L.; Pugliese G.; Di Natale E.; Rizzari G.; Cottone L.; Longo N.; Battaglia G.; Marcantoni C.; Giannetto G.; Tumino G.; Randazzo F.; Bellissimo L.; Faro F.L.; Grippaldi F.; Urso S.; Quattrone G.; Todaro I.; Vincenzo D.; Murgo A.; Masuzzo M.; Pisacane A.; Monardo P.; Santoro D.; Pontorierro M.; Quari C.; Bauro A.; Chimenz R.R.; Alfio D.; Girasole F.; Cascio A.L.; Caviglia A.; Tornese F.; Sirna F.; Altieri C.; Cusumano R.; Saveriano V.; La Corte A.; Locascio G.; Rotolo U.; Rome M.; Musso S.; Risuglia L.; Blanco G.; Minardo G.; Castellino S.; Zappulla Z.; Randone S.; Di Francesca M.; Cassetti C.C.; Oddo G.; Buscaino G.; Mucaria F.; Barraco V.I.; Di Martino A.; Mucaria F.; Rallo D.; Dani L.; Campolo G.; Manescalchi F.; Biagini M.; Agate M.; Panichi V.; Casani A.; Traversari L.; Garosi G.; Brunori G.; Tabbi M.; Selvi A.; Cencioni L.; Fagugli R.; Timio F.; Leveque A.; Manes M.; Mennella G.; Calo L.; Fiorini F.; Abaterusso C.; Calzavara P.; Nordio M.; Meneghel G.; Bonesso C.; Gambaro G.; Gammaro L.; Rugiu C.; Dell'Aquila R.; Dell'Aquila R.; Ronco C.; Rugiu C.Nordio, M.; Reboldi, G.; Di Napoli, A.; Quintaliani, G.; Alberici, F.; Postorino, M.; Aucella, F.; Messa, P.; Brunori, G.; Brunori, G.; Bosco, M.; Malberti, F.; Mandreoli, M.; Mazzaferro, S.; Movilli, E.; Ravera, M.; Salomone, M.; Santoro, D.; Postorinolimido, M. A.; Bonomini, M.; Stingone, A.; Maccarone, M.; Di Loreto, E.; Stacchiotti, L.; Malandra, R.; Chiarella, S.; D'Agostino, F.; Fuiano, G.; Nicodemo, L.; Bonofiglio, R.; Greco, S.; Mallamaci, F.; Barreca, E.; Caserta, C.; Bruzzese, V.; Galati, D.; Tramontana, D.; Viscione, M.; Chiuchiolo, L.; Tuccillo, S.; Sepe, M.; Vitale, F.; Ciriana, E.; Santoro, D.; Martignetti, V.; Caserta, D.; Stizzo, A.; Romano, A.; Iulianiello, G.; Cascone, E.; Minicone, P.; Chiricone, D.; Delgado, G.; Barbato, A.; Celentano, S.; Molfino, I.; Coppola, S.; Raiola, I.; Abategiovanni, M.; Borrelli, S.; Margherita, C.; Bruno, F.; Ida, M.; Aliperti, E.; Potito, D.; Cuomo, G.; De Luca, M.; Merola, M.; Botta, C.; Garofalo, G.; Alinei, P.; Paglionico, C.; Roano, M.; Vitale, S.; Ierardi, R.; Fimiani, V.; Conte, G.; Di Natale, G.; Romano, M.; Di Marino, V.; Scafarto, A.; Meccariello, S.; Pecoraro, C.; Di Stazio, E.; Di Meglio, E.; Cuomo, A.; Maresca, B.; Rotaia, E.; Capasso, G.; Auricchio, M.; Pluvio, C.; Maddalena, L.; De Maio, A.; Palladino, G.; Buono, F.; Gigliotti, G.; Mandreoli, M.; Mancini, E.; La Manna, G.; Storari, A.; Mosconi, G.; Cappelli, G.; Scarpioni, R.; Gregorini, M.; Rigotti, A.; Mancini, W.; Bianco, F.; Boscutti, G.; Amici, G.; Tosto, M.; Fini, R.; Pace, G.; Cioffi, A.; Boccia, E.; Di Lullo, L.; Di Zazzo, G.; Simonelli, R.; Bondatti, F.; Miglio, L.; Rifici, N.; Treglia, A.; Muci, M.; Baldinelli, G.; Rizzi, E.; Lonzi, M.; De Cicco, C.; Forte, F.; De Paolis, P.; Grandaliano, G.; Cuzziol, C.; Torre, V. M.; Sfregola, P.; Rossi, V.; Fabio, G.; Flammini, A.; Filippini, A.; Onorato, L.; Vendola, F.; Di Daniela, N.; Alfarone, C.; Scabbia, L.; Ferrazzano, M.; Grotta, B. D.; Gamberini, M.; Fazzari, L.; Mene, P.; Morgia, A.; Catucci, A.; Palumbo, R.; Puliti, M.; Marinelli, R.; Polito, P.; Marrocco, F.; Morabito, S.; Rocca, R.; Nazzaro, L.; Lavini, R.; Iamundo, V.; Chiappini, M.; Casarci, M.; Morosetti, M.; Hassan, S.; Alfarone, C.; Ferrazzano, M.; Firmi, G.; Galliani, M.; Serraiocco, M.; Feriozzi, S.; Valentini, W.; Sacco, P.; Garibotto, G.; Cappelli, V.; Saffioti, C.; Repetto, M.; Rolla, D.; Lorenz, M.; Pedrini, L.; Polonioli, D.; Galli, E.; Ruggenenti, P.; Scolari, F.; Bove, S.; Costantino, E.; Bracchi, M.; Mangano, S.; Depetri, G.; Malberti, F.; La Milia, V.; Farina, M.; Zecchini, S.; Savino, R.; Melandri, M.; Guastoni, C.; Paparella, M.; Gallieni, M.; Minetti, E.; Bisegna, S.; Messa, P.; Righetti, M.; Badalamenti, S.; Guastoni, C.; Alberghini, E.; Bertoli, S.; Fabbrini, P.; Albrizio, P.; Rampino, T.; Colturi, C.; Rombola, G.; Lucatello, A.; Guerrini, E.; Ranghino, A.; Lenci, F.; Fanciulli, E.; Santarelli, S.; Damiani, C.; Garofalo, D.; Sopranzi, F.; Santoferrara, A.; Di Luca, M.; Galiotta, P.; Brigante, M.; Manganaro, M.; Maffei, S.; Berto, I.; Besso, L.; Viglino, G.; Besso, L.; Cusinato, S.; Chiarinottichiappero, D. F.; Tognarelli, G.; Gianoglio, B.; Salomone, M.; Forneris, G.; Biancone, L.; Savoldi, S.; Vitale, C.; Boero, R.; Filiberti, O.; Borzumati, M.; Gesualdo, L.; Lomonte, C.; Gernone, G.; Pallotta, G.; Di Paolo, S.; Vernaglione, L.; Specchio, A.; Stallone, G.; Dell'Aquila, R.; Aucella, F.; Sandri, G.; Russo, F.; Napoli, M.; Marangi, A.; Morrone, L.; Di Stratis, C.; Fresu, A.; Cicu, F.; Murtas, S.; Manca, O.; Pani, A.; Pilloni, M.; Pistis, R.; Cadoni, M.; Contu, B.; Logias, F.; Ivaldi, R.; Fancello, S.; Cossu, M.; Lepori, G.; Lepori, G.; Vittoria, S.; Battiati, E.; Arnone, M.; Rome, M.; Barbera, A.; Granata, A.; Collura, G.; Dico, C. L.; Pugliese, G.; Di Natale, E.; Rizzari, G.; Cottone, L.; Longo, N.; Battaglia, G.; Marcantoni, C.; Giannetto, G.; Tumino, G.; Randazzo, F.; Bellissimo, L.; Faro, F. L.; Grippaldi, F.; Urso, S.; Quattrone, G.; Todaro, I.; Vincenzo, D.; Murgo, A.; Masuzzo, M.; Pisacane, A.; Monardo, P.; Santoro, D.; Pontorierro, M.; Quari, C.; Bauro, A.; Chimenz, R. R.; Alfio, D.; Girasole, F.; Cascio, A. L.; Caviglia, A.; Tornese, F.; Sirna, F.; Altieri, C.; Cusumano, R.; Saveriano, V.; La Corte, A.; Locascio, G.; Rotolo, U.; Rome, M.; Musso, S.; Risuglia, L.; Blanco, G.; Minardo, G.; Castellino, S.; Zappulla, Z.; Randone, S.; Di Francesca, M.; Cassetti, C. C.; Oddo, G.; Buscaino, G.; Mucaria, F.; Barraco, V. I.; Di Martino, A.; Mucaria, F.; Rallo, D.; Dani, L.; Campolo, G.; Manescalchi, F.; Biagini, M.; Agate, M.; Panichi, V.; Casani, A.; Traversari, L.; Garosi, G.; Brunori, G.; Tabbi, M.; Selvi, A.; Cencioni, L.; Fagugli, R.; Timio, F.; Leveque, A.; Manes, M.; Mennella, G.; Calo, L.; Fiorini, F.; Abaterusso, C.; Calzavara, P.; Nordio, M.; Meneghel, G.; Bonesso, C.; Gambaro, G.; Gammaro, L.; Rugiu, C.; Dell'Aquila, R.; Dell'Aquila, R.; Ronco, C.; Rugiu, C

Risk factors and action thresholds for the novel coronavirus pandemic. Insights from the Italian Society of Nephrology COVID-19 Survey

Background and aim: Over 80% (365/454) of the nation\u2019s centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment. Methods: We investigated fixed factors and contextual effects by multilevel modeling. Classification and Regression Tree (CART) analysis was used to develop decision rules. Results: Increased positivity among hemodialysis patients was predicted by center location [incidence rate ratio (IRR) 1.34, 95% confidence interval (CI) 1.20\u20131.51], positive healthcare workers (IRR 1.09, 95% CI 1.02\u20131.17), test-all policy (IRR 5.94, 95% CI 3.36\u201310.45), and infected proportion in the general population (IRR 1.002, 95% CI 1.001\u20131.003) (all p &lt; 0.01). Conversely, lockdown duration exerted a protective effect (IRR 0.95, 95% CI 0.94\u20130.98) (p &lt; 0.01). The province-contextual effects accounted for 10% of the total variability. Predictive factors for peritoneal dialysis and transplant cases were center location and infected proportion in the general population. Using recursive partitioning, we identified decision thresholds at general population incidence 65 229 per 100,000 and at 65 3 positive healthcare workers. Conclusions: Beyond fixed risk factors, shared with the general population, the increased and heterogeneous proportion of positive patients is related to the center\u2019s testing policy, the number of positive patients and healthcare workers, and to contextual effects at the province level. Nephrology centers may adopt simple decision rules to strengthen containment measures timely

Risk factors and action thresholds for the novel coronavirus pandemic. Insights from the Italian Society of Nephrology COVID-19 Survey

Over 80% (365/454) of the nation's centers participated in the Italian Society of Nephrology COVID-19 Survey. Out of 60,441 surveyed patients, 1368 were infected as of April 23rd, 2020. However, center-specific proportions showed substantial heterogeneity. We therefore undertook new analyses to identify explanatory factors, contextual effects, and decision rules for infection containment