| 45571. |
|
|
| 45572. |
- Lindgren, Anders E. G., et al.
(författare)
-
Chemical Probes to Study ADP-Ribosylation : Synthesis and Biochemical Evaluation of Inhibitors of the Human ADP-Ribosyltransferase ARTD3/PARP3
- 2013
-
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:23, s. 9556-9568
-
Tidskriftsartikel (refereegranskat)abstract
- The racemic 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-N-[1-(pyridin-2-yl)ethyl]propanamide, 1, has previously been identified as a potent but unselective inhibitor of diphtheria toxin-like ADP-ribosyltransferase 3 (ARTD3). Herein we describe synthesis and evaluation of SS compounds in this class. It was found that the stereochemistry is of great importance for both selectivity and potency and that substituents on the phenyl ring resulted in poor solubility. Certain variations at the meso position were tolerated and caused a large shift in the binding pose. Changes to the ethylene linker that connects the quinazolinone to the amide were also investigated but proved detrimental to binding. By combination of synthetic organic chemistry and structure-based design, two selective inhibitors of ARTD3 were discovered.
|
|
| 45573. |
- Lindgren, Anders E. G., et al.
(författare)
-
PARP Inhibitor with Selectivity Toward ADP-Ribosyltransferase ARTD3/PARP3
- 2013
-
Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 8:8, s. 1698-1703
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12, members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1.
|
|
| 45574. |
- Lindgren, Anders E G, et al.
(författare)
-
Statistical molecular design : a tool to follow up hits from small-molecule screening.
- 2014
-
Ingår i: Methods in Molecular Biology. - Totowa, NJ : Springer. - 1064-3745 .- 1940-6029. ; 1056, s. 169-188
-
Tidskriftsartikel (refereegranskat)abstract
- In high-throughput screening (HTS) a robust assay is used to interrogate a large collection of small organic molecules in order to find compounds, hits, with a desired biological activity. The hits are then further explored by an iterative process where new compounds are designed, purchased, or synthesized, followed by an evaluation in one or more assays. Statistical molecular design (SMD) is a useful method to select a balanced, varied, and information-rich compound collection based on hits from HTS in order to create a foundation for development of optimized compounds with improved properties. In this chapter, we describe the use of SMD to explore a hit obtained from small-molecule screening.
|
|
| 45575. |
- Lindgren, Anders E. G., et al.
(författare)
-
Total Synthesis of the Resveratrol Oligomers (+/-)-Ampelopsin B and (+/-)-E-Viniferin
- 2016
-
Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :3, s. 426-429
-
Tidskriftsartikel (refereegranskat)abstract
- The total synthesis of the resveratrol dimers (+/-)-ampelopsin B and (+/-)-E-viniferin is reported. Highlights of the approach include the use of cyclopropylmethyl groups to protect aromatic alcohols. This group allows an acid promoted three-step, one-pot deprotection-epimerization-cyclization of an advanced intermediate to give (+/-)-ampelopsin B. An important advantage with our strategy is the possibility of synthesizing analogs to these natural products to further study the chemistry and biology of resveratrol oligomers.
|
|
| 45576. |
- Lindgren, Anders, 1985-
(författare)
-
Synthesis of Small Molecules Targeting ADP-Ribosyltransferases and Total Synthesis of Resveratrol Based Natural Products
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diphtheria Toxin-like ADP-RibosyltransferasesThe Human ADP-ribosyl transferases (ARTDs) are a group of poorly studied enzymes which are believed to be involved in e.g. DNA repair, protein degradation, transcription regulation and cell death. Medicinal chemistry programmes aimed at developing selective inhibitors of these ARTDs were initiated. A suitable starting compound for one of these enzymes, ARTD3, was found by screening a library of NAD-mimics using a thermal shift assay. A virtual screening protocol was instead developed in order to find novel inhibitors of ARTD7, 8, and 10. The hit compounds were then further developed into selective inhibitors of the corresponding ARTDs by systematically varying different structural features using a combination of synthetic organic chemistry, computational chemistry and structural biology. Compounds were initially characterized using differential scanning fluorimetry which was later replaced with an enzymatic assay to obtain IC50 values. Biotinylated analogs were also synthesized in an attempt to develop an AlphaScreen assay. A selective ARTD3 inhibitor was ultimately identified and found to delay DNA repair in cells after γ-irradiation. These compounds are potentially valuable tools for elucidating the biological role of the poorly characterized ARTD-family of proteins.Total Synthesis of Resveratrol Based Natural ProductsThe polyphenolic natural product (-)-hopeaphenol was found to inhibit the type III secretion system present in certain gram-negative bacteria. (-)-Hopeaphenol is a tetramer of resveratrol and in order to investigate whether the entire structure was essential for inhibition two resveratrol dimers, ε-viniferin and ampelopsin B, were synthesized using a flexible and divergent synthetic route. Highlights of the synthetic strategy include the use of cyclopropylmethyl protecting groups, allowing an acid mediated three-step-one-pot deprotection-epimerization-cyclization of an advanced intermediate to form ampelopsin B. All previously reported syntheses of these two natural products include a dimerization of resveratrol which severly limits the possibilities to synthesize structural analogs. This new strategy enables the synthesis of a wide variety of analogs to ε-viniferin and ampelopsin B.
|
|
| 45577. |
|
|
| 45578. |
- Lindgren, Britt-Marie, et al.
(författare)
-
A Necessary Pain : A Literature Review of Young People’s Experiences of Self-Harm
- 2022
-
Ingår i: Issues in Mental Health Nursing. - : Taylor & Francis Group. - 0161-2840 .- 1096-4673. ; 43:2, s. 154-163
-
Forskningsöversikt (refereegranskat)abstract
- Background: Self-harm is defined as intentional self-injury without the wish to die. People who self-harm report feeling poorly treated by healthcare professionals, and nurses wish to know how best to respond to and care for them. Increased understanding of the meaning of self-harm can help nurses collaborate with young people who self-harm to achieve positive healthcare outcomes for them.Aim: This review aimed to synthesise qualitative research on young peoples' experiences of living with self-harm.Method: A literature search in CINAHL, PubMed, and PsycINFO resulted in the inclusion of 10 qualitative articles that were subjected to metasynthesis.Results: The results show that young people’s experiences of living with self-harm are multifaceted and felt to be a necessary pain. They used self-harm to make life manageable, reporting it provided relief, security, and a way to control overwhelming feelings. They suffered from feeling addicted to self-harm and from shame, guilt, and self-punishment. They felt alienated, lonely, and judged by people around them, from whom they tried to hide their real feelings. Instead of words, they used their wounds and scars as a cry for help.Conclusion: Young people who harm themselves view self-harm as a necessary pain; they suffer, but rarely get the help they need. Further research is necessary to learn how to offer these people the help they need.
|
|
| 45579. |
- Lindgren, Britt-Marie, et al.
(författare)
-
A qualitative study of young women's experiences of recovery from Bulimia Nervosa
- 2015
-
Ingår i: Journal of Advanced Nursing. - : Wiley. - 0309-2402 .- 1365-2648. ; 71:4, s. 860-869
-
Tidskriftsartikel (refereegranskat)abstract
- Aim To describe experiences of recovery from bulimia nervosa among young adult women.Background Most studies into recovery from eating disorders focus on anorexia nervosa, although some include both anorexia and bulimia nervosa. Recovery has been described as beginning with renewed self-esteem. DesignQualitative interview study.Methods Fourteen women were invited to participate; five women, between 23-26years of age, who assessed themselves as healthy for at least 2years agreed to take part in narrative interviews. Tape-recorded interviews lasting 45-60 minutes (median 49minutes) were conducted from February-April 2010 and transcribed verbatim. Data were analysed using qualitative content analysis.Findings The interviews revealed four themes in recovery from bulimia nervosa: feeling stuck in bulimia nervosa, getting ready to change, breaking free of bulimia nervosa and grasping a new reality, each comprising two or more subthemes. The process of recovery was not linear, but rather went back and forth between progress and relapse. The women expressed strong ambivalence about leaving the illness behind. An important part of their recovery was their ability to accept themselves. It was essential for their recovery to be supported in developing a unique explanation of the cause of their illness.Conclusion Women's ability to recover from bulimia nervosa and take control over their lives is based on their self-efficacy. Effective care should therefore strive to strengthen women's beliefs in their own abilities, to instil hope for recovery and thus to bolster their self-efficacy.
|
|
| 45580. |
- Lindgren, Britt-Marie, et al.
(författare)
-
A Systematic Literature Review of Experiences of Professional Care and Support Among People Who Self-Harm
- 2018
-
Ingår i: Archives of Suicide Research. - : Taylor & Francis. - 1381-1118 .- 1543-6136. ; 22:2, s. 173-192
-
Forskningsöversikt (refereegranskat)abstract
- Self-harm is an increasing phenomenon among young people, with potentially fatal outcomes. Patient's perceptions of treatment and support are poorly documented. The aim was to synthesise the experiences of those who self-harm, with special reference to professional care and support by family, friends, and the school system. A systematic review of the literature was conducted. Following retrieval of 1,623 abstracts, 14 studies were included in the final analysis, 11 of which are reported here. Two quantitative studies as well as 1 mixed method study on self-care could not be reported on here due to word limitations. Adult people who self-harm described the importance of quality in the caring relationship and a tailored care designed for each individual. There is a need for more studies into adolescents who self-harm but of importance is the adolescents' need for support from the adult world. A positive relationship between patient and healthcare professional can be crucial in motivating continued treatment of people who self-harm. A major priority is radical improvement in the attitudes of healthcare personnel.
|
|
