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- Pettersson, Birgitta, et al.
(författare)
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Synthetic studies towards 1,5-benzodiazocines
- 2013
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Ingår i: Tetrahedron. - : Elsevier BV. - 0040-4020 .- 1464-5416. ; 69:12, s. 2647-2654
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Tidskriftsartikel (refereegranskat)abstract
- Anthranilonitrile reacted with phenylmagnesium bromide to yield a dianion, which when heated (similar to 120 degrees C) yielded the condensation product 2-(2-aminophenyl)-2,4-dipheny1-1,2-dihydroquinazoline 8. This heterocycle, when treated with palladium acetate, was converted into 6,12-diphenyldibenzo[b,f][1,5] diazocine 9. Methylmagnesium bromide and anthranilonitrile, under similar conditions directly gave a nitrogen-bridged diazocine, whose structure was determined by X-ray crystallography and also proven to be an analogue of Troger's base. Acid-induced condensation of 2-amino-3-methoxybenzaldehyde gave the trimeric product 45 rather than a dibenzo[b,f][1,5]diazocine.
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| 2. |
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| 4. |
- Sorbe, Bengt, et al.
(författare)
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External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation Alone as Postoperative Therapy in Medium-risk Endometrial Carcinoma-A Prospective Randomized Study.
- 2012
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 82:3, s. 1249-1255
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity. METHODS AND MATERIALS: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity. RESULTS: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone. CONCLUSIONS: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.
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| 5. |
- Sorbe, Bengt Göran, et al.
(författare)
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External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation Alone as Postoperative Therapy in Medium-Risk Endometrial Carcinoma A Prospective, Randomized Study-Quality-of-Life Analysis
- 2012
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Ingår i: International Journal of Gynecological Cancer. - Philadelphia : Lippincott Williams & Wilkins. - 1048-891X .- 1525-1438. ; 22:7, s. 1281-1288
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Tidskriftsartikel (refereegranskat)abstract
- Background: A combination of vaginal brachytherapy and external beam radiotherapy was compared with brachytherapy alone in medium-risk endometrial carcinomas. Quality-of-life analysis is an important part of a randomized study to find out the optimal adjuvant treatment for this group of patients. Objective: To evaluate the value of adjuvant external beam pelvic radiotherapy in adjunct to vaginal brachytherapy in medium-risk endometrial carcinoma. Quality-of-life evaluation is the main topic of this report. Methods: A consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study end points were locoregional recurrences and overall survival. Secondary end points were recurrence-free survival, toxicity, and quality-of-life. European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 modules were used to evaluate global health status, functional scales, and symptom scales. Results: Five-year locoregional relapse rates were 1.5% after external beam (ERT) plus vaginal irradiation (VBT) and 5% after vaginal irradiation alone (P = 0.013), and 5-year overall survival (OS) rates were 89% and 90%, respectively. External beam radiotherapy was associated with a higher rate of adverse effects from the intestine and the bladder, and quality-of-life parameters deteriorated at the end of radiotherapy but recovered to normal levels within a few months. There was a significant difference in favor of VBT alone with regard to adverse effects of the bowel and urinary tract, and quality-of-life. Conclusions: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded; but increased late toxicity from the intestine and the bladder. External beam irradiation decreased global health status during and after treatment, and 3 functional scale items (physical, role, and social). Six of 11 symptom items showed a pattern favoring vaginal brachytherapy alone.
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| 6. |
- Pettersson, Birgitta
(författare)
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Synthetic studies towards 7- and 8-membered N-heterocycles, particularly 1,4-pyrrolobenzodiazepines : total synthesis of fuligocandin A and B
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This dissertation is concerned with the synthesis of 7- and 8-membered N-heterocycles, particularly 1,4-pyrrolobenzodiazepines. A non-chromatographic method for conversion of carbonyl-functionalities to the corresponding thiocarbonyls is described. A formal total synthesis of the pyrrolobenzodiazepine natural product DC-81 was developed starting from vanillin. The tricyclic core structure was successfully obtained in 6 steps and several approaches for transformation of this key diamide to obtain the target molecule DC-81 was investigated. A convergent and concise synthesis of the pyrrolobenzodiazepine natural products fuligocandin A and B was developed employing Eschenmoser sulfide contraction as a key step. Fuligocandin B could be obtained in optically active form and the method was applied to obtain a number of vinologous amides. The thionating power of a reagent obtained from P4S10 and pyridine was investigated and the actual structure of the crystalline reagent could for the first time be conclusively determined and confirmed by X-ray crystallography. A range of carbonyl compounds have been converted to the corresponding thiocarbonyl derivatives without the need for chromatographic purification. The final part of this thesis features synthetic studies towards 7- and 8-membered heterocycles starting from anthranilnitrile. Accordingly, addition of Grignard reagents to N-acylderivatives of anthranilonitrile resulted in the formation of 1,4-benzodiazepin-3-ones and the method was also applied to obtain the higher homologue 1,5-benzodiazocin-4-one. Furthermore, the imino-intermediates initially formed by reaction of anthranilonitrile and Grignard reagents could be transformed to dibenzo-1,5-diazocines. Thus, an unusual briged N-heterocycle was isolated and its structure was confirmed by X-ray crystallography.
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| 8. |
- Lotfi, Kourosh, et al.
(författare)
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Biochemical Pharmacology and Resistance to 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells
- 1999
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 5:9, s. 2438-2444
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Tidskriftsartikel (refereegranskat)abstract
- The objective of the present study was to investigate the biochemical pharmacology of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFdA) — a fluorinated analogue of cladribine [2-chloro-2′-deoxyadenosine, Leustatin (CdA)] with improved acid and metabolic stability — in human leukemic cell lines and in mononuclear cells isolated from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). We have also made and characterized two cell lines that are not sensitive to the growth inhibitory and cytotoxic effects of CAFdA. Incubation of cells isolated from the blood of CLL and AML patients with various concentrations of CdA or of CAFdA accumulated CdA and CAFdA nucleotides in a dose-dependent manner. A significantly higher rate of phosphorylation to monophosphates was observed for CAFdA than for CdA in cells from CLL patients (n = 14; P = 0.04). The differences in the phosphorylation were even more pronounced for the respective triphosphates in both CLL (n = 14; P = 0.001) and AML (n = 4; P = 0.04) cells. Retention of CAFdA 5′-triphosphate (CAFdATP) was also longer than that for CdA 5′-triphosphate (CdATP) in cells from leukemic patients. The relative efficacy of CAFdA as a substrate for purified recombinant deoxycytidine kinase (dCK), the key enzyme in the activation of nucleoside analogues, was very high and exceeded that of CdA as well as the natural substrate, deoxycytidine, by a factor of 2 and 8, respectively. The Km for CAFdA with dCK was also lower than that for CdA, as measured in crude extracts from the human acute lymphoblastic leukemia cell line CCRF-CEM and the promyelocytic leukemia cell line HL60. Acquired resistance to CAFdA in HL60 and in CCRF-CEM cell lines was directly correlated to the decreased activity of the nucleoside phosphorylating enzyme, dCK. Resistant cells also showed a considerable degree of cross-resistance to analogues that were activated by dCK. These observations demonstrated that dCK phosphorylates CAFdA more efficiently than CdA. Furthermore, CAFdATP is apparently more stable than CdATP and the mechanisms of resistance to CAFdA are similar to those leading to CdA resistance. These results encourage studies on the clinical effect of CAFdA in lymphoproliferative diseases.
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