| 1. |
- Andersson, Hans, 1978-
(författare)
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Reaction Between Grignard reagents and Heterocyclic N-oxides : Synthesis of Substituted Pyridines, Piperidines and Piperazines
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the development of new synthetic methodologies for preparation of bioactive interesting compounds, e.g. substituted pyridines, piperidines or piparazines. Thesecompounds are synthesized from commercially available, cheap and easily prepared reagents, videlicet the reaction between Grignard reagents and heterocyclic N-oxides. The first part of this thesis deals with an improvement for synthesis of dienal-oximes and substituted pyridines. This was accomplished by a rapid addition of Grignard reagents to pyridine N-oxides at rt. yielding a diverse set of substituted dienal-oximes. During these studies, it was observed that the obtained dienal-oxmies are prone to ring-close upon heating. By taking advantage of this, a practical synthesis of substituted pyridines was developed. In the second part, an ortho-metalation of pyridine N-oxides using Grignard reagents is discussed. The method can be used for incorporation of a range of different electrophiles, including aldehydes, ketones and halogens. Furthermore, the importance for incorporation of halogens are exemplified through a Suzuki–Miyaura coupling reaction of 2-iodo pyridine N-oxides and different boronic acids. Later it was discovered that if the reaction temperature is kept below -20 °C, the undesired ringopening can be avoided. Thus, the synthesis of 2,3-dihydropyridine N-oxide, by reacting Grignard reagents with pyridine N-oxides at -40 °C followed by sequential addition of aldehyde or ketone, was accomplished. The reaction provides complete regio- and stereoselectivity yielding trans-2,3-dihydropyridine N-oxides in good yields. These intermediate products could then be used for synthesis of either substituted piperidines, by reduction, or reacted in a Diels–Alder cycloaddtion to give the aza-bicyclo compound. In the last part of this thesis, the discovered reactivity for pyridine N-oxides, is applied on pyrazine N-oxides in effort to synthesize substituted piperazines. These substances are obtained by the reaction of Grignard reagents and pyrazine N-oxides at -78 °C followed by reduction and protection, using a one-pot procedure. The product, a protected piperazine, that easily can be orthogonally deprotected, allowing synthetic modifications at either nitrogens in a fast and step efficient manner. Finally, an enantioselective procedure using a combination of PhMgCl and (-)-sparteine is discussed, giving opportunity for a stereoselective synthesis of substituted piperazines.
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| 2. |
- Buitrago, Elina, et al.
(författare)
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High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones : Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine
- 2012
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Ingår i: ChemCatChem. - : Wiley. - 1867-3880 .- 1867-3899. ; 4:12, s. 2082-2089
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Tidskriftsartikel (refereegranskat)abstract
- A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p-cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2-propanol. The reactions were performed on a Chemspeed automated high-throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)-fluoxetine and (S)-duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94?%) and excellent product enantioselectivities (>99?% ee) of the formed 1,3-amino alcohols.
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| 3. |
- Buitrago, Elina, et al.
(författare)
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Selective reduction of heteroaromatic ketones: A combinatorial approach
- 2011
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The enantioselective reduction of prochiral ketones is a most productiveway towards enantio enriched secondary alcohols used in the preparation of biologically active compounds. There are numerous transition metal catalyzed methods for this transformation, particularly based on Ru(II)-and Rh(I)-complexes, but there is a demand for a larger substrate scope. Heteroaromatic ketones are traditionally more challenging substrates. Normally a catalyst is developed for one benchmark substrate, and asubstrate screen is made with the best performing catalyst. Using this methodology, there is a high probability that for different substrates, another catalyst could outperform the one used. We have executed a multiple screen, containing a variety of different ligands together with both Ru and Rh, and heteroaromatic ketones to fine-tune, and find the optimum catalyst depending on the substrate. The acquired information was used to synthesize known, biologically active compounds, where the key reduction steps were performed with high enantioselectivities and yields.
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| 4. |
- Fall, Katja, et al.
(författare)
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Prostate-specific antigen levels as a predictor of lethal prostate cancer
- 2007
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Ingår i: Journal of the National Cancer Institute. - Oxford : Oxford Univ. Press. - 0027-8874 .- 1460-2105. ; 99:7, s. 526-532
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Tidskriftsartikel (refereegranskat)abstract
- Background: Rates of long-term survival among patients with untreated localized prostate cancer are high. To avoid unnecessary treatment, tools are needed to identify the small proportion of patients who are destined to develop lethal prostate cancer. Methods: To evaluate the accuracy of early changes in prostate-specific antigen (PSA) levels as predictors of prostate cancer outcome, we assessed serial measurements of PSA level among 267 men with localized prostate cancer in a Scandinavian cohort of men who were diagnosed between 1989 and 1999 and who were managed by watchful waiting. We then 1) fitted individual regression lines to the PSA values assessed for each patient during the first 2 years of follow-up by using three different models, 2) evaluated early PSA curve characteristics as determinants of the cumulative incidence of lethal prostate cancer and calculated hazard ratios for baseline PSA value and rate of change in PSA level to prostate cancer outcome, and 3) plotted time-dependent receiver operating characteristic (ROC) curves. All P values are two-sided. Results: During complete follow-up for a mean of 8.5 years, 34 patients (13%) died from prostate cancer, and 18 (7%) developed metastases but were still alive at end of follow-up. In a log-linear model, both PSA value at baseline (P = .05) and the rate of PSA change (P<.001) were associated with the development of lethal prostate cancer. In the ROC analysis, however, the accuracy of classifying the disease as either indolent or destined to progress was low, regardless of the cut point chosen for initial PSA level or rate of change in PSA level. Conclusions: Although baseline PSA value and rate of PSA change are prognostic factors for lethal prostate cancer, they are poor predictors of lethal prostate cancer among patients with localized prostate cancer who are managed by watchful waiting.
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| 5. |
- Holmberg, Lars, et al.
(författare)
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Season of diagnosis and prognosis in breast and prostate cancer
- 2009
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Ingår i: Cancer Causes and Control. - : Springer Science and Business Media LLC. - 0957-5243 .- 1573-7225. ; 20:5, s. 633-670
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with breast or prostate cancer diagnosed during the summer season have been observed to have better survival. The extent to which this is due to biological and/or health care system related factors is unclear. METHODS: Using the Swedish Cancer Register and clinical databases, we analyzed overall survival by month of diagnosis among the incident cases of breast (n = 89,630) cancer and prostate (n = 72,375) cancer diagnosed from 1960 to 2004. We retrieved data on tumor stage from 1976 for breast cancer and 1997 for prostate cancer. Cox proportional hazards models were used to calculate relative risk of survival by the season of diagnosis. RESULTS: There was a higher hazard ratio of death in men and women diagnosed with cancer in the summer with a relative hazard of 1.20 (95% confidence interval 1.15-1.25) for July for prostate cancer and 1.14 (95% confidence interval 1.09-1.19) for August for breast cancer when compared to being diagnosed in January. This difference coincided with a lower mean number of cases diagnosed per day, and a higher proportion of advanced cases diagnosed in the summer. This pattern of presentation was stronger in the later years. CONCLUSION: The difference in stage distribution explains the seasonal variation in prognosis seen in this study. The variation may be because of structure of the health care system and a strong tradition of vacationing from mid June to mid August. Thus, the health care infrastructure and the late presentation of symptomatic disease may influence cancer survival studied by season of diagnosis substantially.
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| 6. |
- Tilling, Kate, et al.
(författare)
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Development of a new method for monitoring prostate-specific antigen changes in men with localised prostate cancer : a comparison of observational cohorts
- 2010
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 57:3, s. 446-452
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate-specific antigen (PSA) measurements are increasingly used to monitor men with localised prostate cancer (PCa), but there is little consensus about the method to use. OBJECTIVE: To apply age-specific predictions of PSA level (developed in men without cancer) to one cohort of men with clinically identified PCa and one cohort of men with PSA-detected PCa. We hypothesise that among men with clinically identified cancer, the annual increase in PSA level would be steeper than in men with PSA-detected cancer. DESIGN, SETTING, AND PARTICIPANTS: The Scandinavian Prostate Cancer Group 4 (SPCG-4) cohort consisted of 321 men assigned to the watchful waiting arm of the SPCG-4 trial. The UK cohort consisted of 320 men with PSA-detected PCa in the Prostate testing for cancer and Treatment (ProtecT) study who opted for monitoring. Multilevel models describing changes in PSA level were fitted to the two cohorts, and average PSA level at age 50, change in PSA level with age, and predicted PSA values were derived. MEASUREMENTS: PSA level. RESULTS AND LIMITATIONS: In the SPCG-4 cohort, mean PSA at age 50 was similar to the cancer-free cohort but with a steeper yearly increase in PSA level (16.4% vs 4.0%). In the UK cohort, mean PSA level was higher than that in the cancer-free cohort (due to a PSA biopsy threshold of 3.0 ng/ml) but with a similar yearly increase in PSA level (4.1%). Predictions were less accurate for the SPCG-4 cohort (median difference between observed and predicted PSA level: -2.0 ng/ml; interquartile range [IQR]: -7.6-0.7 ng/ml) than for the UK cohort (median difference between observed and predicted PSA level: -0.8 ng/ml; IQR: -2.1-0.1 ng/ml). CONCLUSIONS: In PSA-detected men, yearly change in PSA was similar to that in cancer-free men, whereas in men with symptomatic PCa, the yearly change in PSA level was considerably higher. Our method needs further evaluation but has promise for refining active monitoring protocols.
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| 7. |
- Wiklund, Fredrik, et al.
(författare)
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Association of Reported Prostate Cancer Risk Alleles With PSA Levels Among Men Without a Diagnosis of Prostate Cancer
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:4, s. 419-427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS. We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS. Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P <= 0.05) were found for six SNPs. These six SNP's had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS. Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening. Prostate 69: 419-427, 2009. (C) 2008 Wiley-Liss, Inc.
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| 8. |
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| 9. |
- Adolfsson, Hans, et al.
(författare)
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Betyg i högre utbildning
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- SUHF:s arbetsgrupp för betygsfrågor har varit verksam under perioden 1 mars 2014 – 31 december 2015. Uppdraget har varit att undersöka behovet av betygssystem med fler betygs-steg i högskolan mot bakgrund av den konkurrenssituation som en internationaliserad utbildnings- och arbetsmarknad medför. Uppdraget har också varit att sprida erfarenheter kring flergradiga betygsskalor inkluderande både nationella erfarenheter och exempel från andra europeiska länder. Arbetsgruppen har också uppmanats att föreslå rekommendationer om betygssystem till SUHF:s medlemslärosäten. Arbetsgruppen har främst inhämtat underlag genom intervjuer, en enkät till lärosätena och Ladok-statistik omfattande drygt tre miljoner betygssättningar som renderat godkända betyg över en period av tre år. Resultatet av utredningen visar att svenska lärosäten har en stark tradition av målrelaterad betygssättning som samtliga involverade i utredningen upplever som positiv och viktig att bevara, oavsett antal grader i betygsskalan. Gruppens arbete bekräftar att det finns olika problem med de svenska betygssystemen ur ett internationaliseringsperspektiv. Det går dock inte att säga att det finns någon tydlig samsyn mellan lärosätena om exakt vilka dessa problem är eller hur stora de anses vara. Det är svårt att entydigt koppla problemen till valet av betygsskala. Det finns också andra faktorer för valet av betygsskala som verkar väga minst lika tungt som internationaliseringsperspektivet och som gör att lärosäten inte inför betygsskalor med fler grader. Utredningen visar vidare att flera olika betygssystem används i svensk högskola och heterogeniteten framträder som betydande, såväl mellan lärosäten som inom ett lärosäte. Det finns starka ämnesmässiga traditioner och god argumentation kring enskilda lärosätens val av skala men nationellt saknas det gemensamma ramar för betygssättning, samordning och uppföljning. Huvudsakligen används fortfarande fågradiga betygsskalor i Sverige men 43% av alla betyg sätts numera i betygsskalor med minst tre godkända betygssteg. Ett antal lärosäten har de senaste tio åren gått över till en sjugradig skala för all utbildning eller för viss utbildning som riktar sig till en internationell målgrupp. Under perioden 2011−2014 är A–F-skalan den enda betygsskala som ökat i omfattning medan exempelvis användningen av G–U-skalan minskat med 18,5 %. Att ha en flergradig betygsskala ses som positivt ur flera aspekter: det underlättar internationellt studentutbyte, det kommunicerar tydligare utbildnings-resultaten och är ett bättre instrument för urval för både vidare utbildning och rekrytering på arbetsmarknaden. Flergradiga betyg ställer höga krav på tydliga betygskriterier och genom-tänkta pedagogiska metoder för målrelaterad bedömning. Flera av de problem som rapporten påvisar skulle kunna lösas genom att en gemensam nationell flergradig betygsskala implementerades. I nuläget bedömer arbetsgruppen dock inte att det är realistiskt att rekommendera detta. De svenska lärosätena använder flera olika betygsskalor. De problem fågradiga betyg kan skapa för internationellt studentutbyte verkar upp-vägas av andra värden för många lärosäten. Ett relativt stort antal lärosäten har redan valt att införa en sjugradig betygsskala för utbildning med internationell inriktning. Ett önskemål som lyfts fram i flera enkätsvar och intervjuer är att ett meritvärde eller betyg för hel utbildning, motsvarande grade point average (GPA) införs. GPA upplevs fungera väl för internationell jämförelse. Ladok-statistiken visar på skillnader mellan lärosätena i användningen av betygsskalorna som – åtminstone i avsaknad av fördjupat underlag – ter sig anmärkningsvärt stora. Dessa skillnader bör ses mot bakgrund av att betygssättning är myndighetsutövning och att betyg är ett myndighetsbeslut som studenterna inte kan överklaga. Undersökningen visar på stora skillnader i betygsfördelningen mellan olika betygsskalor även då antalet steg är identiska (5-U respektive AB-U). Det gäller även inom en och samma betygsskala såväl mellan lärosäten som inom lärosäten. Andelen studenter som exempelvis får högsta betyg kan skilja stort. Stickprov inom lärosäten visar på samma variationer i betygssättningen mellan olika kurser. Det finns också en genusskillnad, dock liten. En bättre uppföljning med årlig betygsstatistik kunde införas, dels för alla lärosäten för att ge en nationell överblick och nationella betygsutfall för varje betygsskala, dels för vissa specifika ämnesområden för att kunna jämföra betygsutfall t ex i större utbildningsprogram som ges vid många lärosäten, såsom juristprogrammet, ingenjörsutbildning, lärarutbildning, psykologutbildning, ekonomiutbildning, socionomutbildning. Sådant underlag skulle stimulera till utveckling av examination och bedömning inom högskolan. Arbetsgruppen föreslår därför att.....
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