Your browser doesn't support javascript.
loading
: 20 | 50 | 100
1 - 20 de 30
1.
J Gerontol Nurs ; 50(2): 5-9, 2024 Feb.
Article En | MEDLINE | ID: mdl-38290101

PURPOSE: To assess implementation context prior to the implementation of Dementia Collaborative Coaching (DCC), a person-centered, communication coaching intervention for speech-language pathologists, certified nursing assistants, and people living with dementia in nursing homes. METHODS: This was a pre-implementation, content analysis of focus groups. Focus group questions and subsequent analysis were guided by the Practical, Robust Implementation and Sustainability Model. RESULTS: Employees (N = 27) from three nursing homes participated in five focus groups. Five themes from directed content analysis included (a) Dementia Care Needs Improvement; (b) Dementia Collaborative Coaching Appears Promising; (c) Awareness of Necessary Implementation and Sustainability Plans; (d) Regulations Need Accurate Interpretation and Local Dissemination; and (e) Appropriate Staffing Concerns. CONCLUSION/IMPLICATIONS: Key factors related to the implementation of DCC included a perceived tension for change from staff to improve dementia care, concerns about appropriate staffing, and the need for explicit implementation and sustainability plans. The importance of continuing education with specific attention to temporary staff was also found to be a necessary element to support better uptake of the person-centered intervention. [Journal of Gerontological Nursing, 50(2), 5-9.].


Dementia , Humans , Nursing Homes , Focus Groups , Patient-Centered Care , Quality of Life
2.
Am J Speech Lang Pathol ; 33(1): 349-368, 2024 Jan 03.
Article En | MEDLINE | ID: mdl-38048335

PURPOSE: Aphasia may decrease the capacity to develop and maintain friendships. The aim of this study was to better understand the perspectives of people with aphasia on why some friendship bonds remain strong and some do not. Furthermore, we wanted to explore how age and aphasia severity shape views on friendship. METHOD: We interviewed 27 people with aphasia about their experiences of friendship before and after the onset of aphasia. We then used framework analysis and reflexive thematic analysis to interpret the interview data. RESULTS: From the interviews, we created four major themes concerning how friend relationships had been impacted by aphasia: (a) Not all bonds have the same chance of surviving the onset of aphasia; (b) people with aphasia's closest friends took active steps to keep relationships strong; (c) if friends knew some basic information about aphasia, bonds would stay stronger; (d) positive affective aspects of friendship play an important role in keeping bonds strong. We also noted differences in friendship experiences that appeared to be influenced by age and aphasia severity of participants. CONCLUSIONS: Interview data provided actionable ideas including focusing on friends who are likely to be responsive to help with maintaining the friendship, providing them with strategies to keep the friendship active and communication meaningful, and acknowledging the positive impact that this will have on the friend recovering from aphasia. More research is needed to develop programs that empower people with aphasia to maintain their friendships. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24688671.


Aphasia , Friends , Female , Humans , Friends/psychology , Interpersonal Relations , Aphasia/diagnosis , Aphasia/psychology , Siblings , Communication
3.
J Am Geriatr Soc ; 71(11): 3554-3565, 2023 11.
Article En | MEDLINE | ID: mdl-37736669

The growing number of people living with dementia (PLWD) requires a coordinated clinical response to deliver pragmatic, evidence-based interventions in frontline care settings. However, infrastructure to support such a response is lacking. Moreover, there are too few researchers conducting rigorous embedded pragmatic clinical trials (ePCTs) to make the vision of high quality, widely accessible dementia care a reality. National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer's disease and Related Dementias Clinical Trials (IMPACT) Collaboratory seeks to improve the pipeline of early career researchers qualified to lead ePCTs by funding career development awards. Even with support from the Collaboratory, awardees face practical and methodological challenges to success, recently exacerbated by the COVID-19 pandemic. We first describe the training opportunities and support network for the IMPACT CDA recipients. This report then describes the unique career development challenges faced by early-career researchers involved in ePCTs for dementia care. Topics addressed include challenges in establishing a laboratory, academic promotion, mentoring and professional development, and work-life balance. Concrete suggestions to address these challenges are offered for early-career investigators, their mentors, and their supporting institutions. While some of these challenges are faced by researchers in other fields, this report seeks to provide a roadmap for expanding the work of the IMPACT Collaboratory and initiating future efforts to recruit, train, and retain talented early-career researchers involved in ePCTs for dementia care.


Dementia , Mentoring , Humans , Pandemics , Mentors
4.
Am J Speech Lang Pathol ; 32(5): 2146-2157, 2023 09 11.
Article En | MEDLINE | ID: mdl-37437528

PURPOSE: The primary purpose of this study was to obtain preliminary evidence for a communication coaching intervention, Dementia Collaborative Coaching. The secondary aim of this study was to assess the acceptability, appropriateness, and feasibility of the intervention according to routine care providers. METHOD: In a pre-/posttest design, speech-language pathologists (SLPs) delivered Dementia Collaborative Coaching to certified nursing assistants (CNAs) and people living with dementia (PLWD) in six different skilled nursing facilities over a period of 6 weeks. A self-perceived knowledge and efficacy measure regarding the use of external memory aids to support communication in PLWD was administered to CNA and SLP participants. The Cohen-Mansfield Agitation Inventory was administered to PLWD participants. The Acceptability of Intervention Measure, Intervention Appropriateness Measure, and Feasibility of Intervention Measure were administered post-intervention. RESULTS: For CNAs, self-perceived knowledge and efficacy increased from pre-intervention (M = 3.73, SD = 0.69) to post-intervention (M = 4.07, SD = 0.44), t(11) = -1.97, one-sided p = .037. There was a significant improvement (e.g., reduction) in scores on the Cohen-Mansfield Agitation Inventory for PLWD (n = 10) from pre-intervention (M = 73.10, SD = 29.98) to post-intervention (M = 58.6, SD = 18.82), t(9) = 2.83, p = .01. CNA participants (n = 12) rated the intervention as acceptable (M = 4.48, SD = 0.48), appropriate (M = 4.33, SD = 0.61), and feasible (M = 4.19, SD = 0.48). SLPs rated the intervention as slightly more acceptable, appropriate, and feasible than CNAs with scores of M = 4.54, SD = 0.51; M = 4.54, SD = 0.51; and M = 4.46, SD = 0.51, respectively. CONCLUSIONS: Dementia Collaborative Coaching showed preliminary positive outcomes for CNAs and PLWD. The intervention was acceptable, appropriate, and feasible for routine providers and warrants further study.


Dementia , Mentoring , Nursing Assistants , Humans , Certification , Communication , Dementia/diagnosis , Dementia/therapy
5.
Phys Ther ; 103(4)2023 04 04.
Article En | MEDLINE | ID: mdl-37079888

OBJECTIVE: The Learning Health Systems Rehabilitation Research Network (LeaRRn), an NIH-funded rehabilitation research resource center, aims to advance the research capacity of learning health systems (LHSs) within the rehabilitation community. A needs assessment survey was administered to inform development of educational resources. METHODS: The online survey included 55 items addressing interest in and knowledge of 33 LHS research core competencies in 7 domains and additional items on respondent characteristics. Recruitment targeting rehabilitation researchers and health system collaborators was conducted by LeaRRn, LeaRRn health system partners, rehabilitation professional organizations, and research university program directors using email, listservs, and social media announcements. RESULTS: Of the 650 people who initiated the survey, 410 respondents constituted the study sample. Respondents indicated interest in LHS research and responded to at least 1 competency item and/or demographic question. Two-thirds of the study sample had doctoral research degrees, and one-third reported research as their profession. The most common clinical disciplines were physical therapy (38%), communication sciences and disorders (22%), and occupational therapy (10%). Across all 55 competency items, 95% of respondents expressed "a lot" or "some" interest in learning more, but only 19% reported "a lot" of knowledge. Respondents reported "a lot" of interest in a range of topics, including selecting outcome measures that are meaningful to patients (78%) and implementing research evidence in health systems (75%). "None" or "some" knowledge was reported most often in Systems Science areas such as understanding the interrelationships between financing, organization, delivery, and rehabilitation outcomes (93%) and assessing the extent to which research activities will improve the equity of health systems (93%). CONCLUSION: Results from this large survey of the rehabilitation research community indicate strong interest in LHS research competencies and opportunities to advance skills and training. IMPACT: Competencies where respondents indicated high interest and limited knowledge can inform development of LHS educational content that is most needed.


Learning Health System , Rehabilitation Research , Humans , Surveys and Questionnaires , Learning
6.
Chem ; 9(2): 343-362, 2023 Feb 09.
Article En | MEDLINE | ID: mdl-36777049

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C and 13C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [11C]nitriles into arenes. The aryl [11C]nitriles can be further derivatized to [11C]carboxylic acids, [11C]amides, and [11C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.

7.
Am J Speech Lang Pathol ; 32(2): 803-810, 2023 03 09.
Article En | MEDLINE | ID: mdl-36763851

PURPOSE: The purpose of this article is to contend that there is a power differential between researchers and clinicians where researchers are the primary creators of knowledge and clinicians are the primary consumers of knowledge. Rooted in a sociological model illustrating interacting levels of power at macro-, meso-, and microlevels, we argue that authentic research-practice partnerships and clinician-researcher collaborations can mitigate this power differential. CONCLUSIONS: Clinicians and researchers in our field have vastly different responsibilities and priorities that impact our ability to work collaboratively to solve the most pressing problems for the clients we serve. Although some current research practices may reinforce a power differential causing clinicians to feel less than and to only consume knowledge, there are examples of successful collaborations where this power differential is mitigated. These examples can contribute meaningfully to the dialogue on research-practice partnerships, with the goal of improving outcomes for the clients we serve.


Evidence Gaps , Professional Practice Gaps , Humans
8.
JBI Evid Synth ; 21(1): 207-213, 2023 01 01.
Article En | MEDLINE | ID: mdl-36036561

OBJECTIVE: The objective of this review is to evaluate the effectiveness of physical rehabilitation versus non-rehabilitation control in improving physical functioning and quality of life in long-term care residents with dementia. INTRODUCTION: Many long-term-care residents live with dementia and have impaired physical function and poor quality of life. Physical rehabilitation can improve physical function and quality of life for people living with dementia, yet many long-term-care residents with dementia do not receive this intervention, and health care providers are unsure of which rehabilitation interventions are effective. Studies synthesizing effective rehabilitation programs are needed to guide practice in the long-term-care sector where many residents live with dementia. Previous studies have focused broadly on long-term care, specific professions, interventions or outcomes, or people with dementia in the community. Our review will focus on long-term-care residents living with dementia and a broader definition of physical rehabilitation. INCLUSION CRITERIA: This review will include studies that evaluate physical rehabilitation in comparison with non-rehabilitation controls among long-term-care residents with any severity of dementia. We will include studies that measure the effect on performance-based physical functioning and self- or proxy-reported quality of life. METHODS: Searches will be conducted in APA PsycINFO (EBSCO), CINAHL (EBSCO), MEDLINE (Ovid), Embase, Scopus, and the Cochrane CENTRAL database with no date or language limitations. Two independent reviewers will conduct a critical appraisal of eligible studies, assess methodological quality, and extract the data. Where possible, studies will be pooled in a statistical meta-analysis. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42022308444.


Dementia , Long-Term Care , Neurological Rehabilitation , Physical Therapy Modalities , Quality of Life , Humans , Dementia/rehabilitation , Meta-Analysis as Topic , Review Literature as Topic , Neurological Rehabilitation/methods , Recovery of Function , Systematic Reviews as Topic
9.
Disabil Rehabil ; 45(18): 3012-3031, 2023 09.
Article En | MEDLINE | ID: mdl-36170126

PURPOSE: Map the landscape of friendship interventions/programs for older adults to guide intervention/program development inclusive of the unique needs of older people with aphasia (PWA). METHODS: A search query of multiple databases was completed for articles published before 4 January 2021. Studies included all the following: (1) participants aged 55 years or older; (2) addressed an intervention/program designed to prevent social isolation and/or friendship loss; (3) used an outcome variable related to social isolation and/or friendship; and (4) published in a peer-reviewed journal. Title and abstract screening were conducted using Covidence software, which tracked disagreements across the study team. All studies included in the full-text review were identified as relevant by a minimum of two study authors, and a consensus was reached on all full-text reviews. Data were extracted according to (1) theoretical frameworks used; (2) interventionist and discipline; (3) participant characteristics; (4) intervention/program replicability; (5) format of intervention/program; (6) measures used in the intervention/programs; (7) and, reported effects of intervention/programs on individuals. RESULTS: A total of 40 articles with 42 intervention/programs were included and represented 4584 intervention/program participants ranging in age from 40 to 104 years. Intervention/programs involved a wide range of theoretical frameworks (e.g., theories of loneliness, feminist theory, positive psychology). Disciplines such as psychology and exercise science informed intervention/programs. Interventionists included many types of individuals like therapists, volunteers and home health aides. Intervention/programs often lacked adequate description for replication and included individual and group formats, most commonly delievered in the participants homes. Outcomes usually included self-report measures of loneliness, social networks, or well-being, and intervention/programming was primarily educational, activity-based, or networking-based in nature. CONCLUSIONS: The intervention/programs reviewed yield important lessons to support innovation in developing friendship intervention/programs for older PWA as most yielded positive results and were acceptable to participants.IMPLICATIONS FOR REHABILITATIONPeople with aphasia want their friendships addressed as part of their rehabilitation; however, the research literature has little guidance in this area.Studies reviewed of friendship intervention/programs for older adults yielded helpful lessons for consideration in developing this type of intervention/programming for people with aphasia.Interprofessional teams made up of rehabilitation professionals should address friendship for people with aphasia in both research and clinical practice.


Aphasia , Friends , Humans , Aged , Social Isolation/psychology , Loneliness/psychology , Behavior Therapy
10.
J Speech Lang Hear Res ; 65(11): 4172-4180, 2022 11 17.
Article En | MEDLINE | ID: mdl-36306509

PURPOSE: The purpose of this tutorial is threefold: (a) to bring attention to the role and value of dissemination research in communication sciences and disorders (CSD), (b) to introduce a model that can be used to guide dissemination research, and (c) to demonstrate strategic steps toward generating research questions and planning methods for dissemination research using an example from the authors' work. METHOD: This tutorial begins with a discussion of the role of dissemination in clinical research, with emphasis on differentiating the unique value of dissemination within the broader context of dissemination and implementation (D&I) research. The tutorial next presents a model of dissemination from the extant literature and describes how this model can be applied in CSD using examples from the authors' respective programs of clinical research. This is followed by an example that illustrates how the model can be used to determine research questions and guide the development of methods. Finally, the tutorial ends by discussing the potential impact of dissemination research for advancing efforts in CSD for closing the research-to-practice gap. CONCLUSIONS: Dissemination research is an often overlooked but critical component of D&I efforts. When approached systematically and rigorously, dissemination can make meaningful contributions to clinical research in CSD.


Communication Disorders , Humans , Communication , Information Dissemination
11.
J Gerontol Nurs ; 48(8): 6-9, 2022 Aug.
Article En | MEDLINE | ID: mdl-35914076

Montessori for Dementia and Ageing (MDA) is a philosophy to support person-centered care (PCC) and autonomy of older adults. This quality improvement project documented outcomes of implementation of the MDA philosophy in a long-term care memory neighborhood. After an initial training session, MDA was implemented with weekly, 2-hour on-site coaching sessions over the course of two semesters (28 weeks) with a community of 20 female persons living with dementia (PWD). Primary outcomes were negative responsive behaviors of PWD, whereas the secondary outcome included percentage of active engagement of PWD. Mean number of negative responsive behaviors was 62.21 at baseline, which decreased to 33.82 at the end of the project per the Cohen-Mansfield Agitation Inventory. At baseline, PWD were actively engaged in 18.15% of observed opportunities, according to the Engage portion of the Resident-Centered Assessment of Interactions with Staff and Engagement Tool. At the end of the project, PWD were actively engaged in 40.56% of observed opportunities. Results suggest that MDA is feasible to implement PCC in a long-term care memory neighborhood. [Journal of Gerontological Nursing, 48(8), 6-9.].


Dementia , Aged , Aging , Anxiety , Dementia/therapy , Female , Humans , Long-Term Care , Quality Improvement
12.
Am J Speech Lang Pathol ; 31(3): 1023-1025, 2022 05 10.
Article En | MEDLINE | ID: mdl-35344451

In this prologue, we introduce readers to the Forum: Clinicians and Researchers Navigating Implementation Science in CSD. Implementation science (IS), or the study of the adoption of evidence-based practice in real-world settings, is a key area of development in communication sciences and disorders (CSD). The goal of this forum was to show by example how researchers and clinicians are collaborating to begin to apply IS in CSD. This goal culminated in a scoping review of IS in CSD, a tutorial on incorporating IS into clinical practice research, three articles on stakeholder engagement, and three examples of IS studies in CSD included in this forum. We hope this forum helps clinicians and researchers to begin wherever they are in their knowledge and understanding of IS in CSD.


Communication Disorders , Implementation Science , Humans , Motivation
13.
Am J Speech Lang Pathol ; 31(3): 1054-1083, 2022 05 10.
Article En | MEDLINE | ID: mdl-35104415

PURPOSE: The purpose of this study was to complete a scoping review of implementation science (IS) research in communication sciences and disorders (CSD) over time and to determine characteristics of IS research in CSD. METHOD: A scoping review was conducted of PubMed and Education Resources Information Center for sources published in English that (a) included CSD practitioners, (b) addressed IS research, and (c) identified a specific evidence-based practice. Resulting sources were systematically examined for study aim, patient populations, implementation framework utilized, setting of the study, implementation strategy examined, and implementation outcome measured. RESULTS: The majority of the 82 studies that underwent a full-text review (80.5%) were published in 2014 or later. One fourth of the studies were concept papers, and another one fourth focused on context assessment (25.6% of studies, each), 11% focused on designing implementation strategies, and 36.6% focused on testing implementation strategies. The patient population most frequently represented aphasia (21.3%), and most studies (34.4%) were conducted in inpatient medical settings. Nearly half (42.6%) of the nonconcept studies lacked an IS framework. Among implementation strategies identified, approximately one third of studies focused on education and/or training plus another strategy and one fourth focused on education and/or training alone. Implementation outcomes measured typically represented early stages of implementation. CONCLUSIONS: This scoping review of IS research in CSD described the landscape of IS studies in CSD. IS is intersecting with CSD at a rapid rate, especially since 2014. Future IS research in CSD should adopt an implementation framework a priori and consider the broad range of implementation strategies and outcomes to support the uptake of research into typical practice settings.


Aphasia , Implementation Science , Communication , Evidence-Based Practice , Humans
14.
Chem Rev ; 122(2): 1925-2016, 2022 01 26.
Article En | MEDLINE | ID: mdl-34585909

The fields of C-H functionalization and photoredox catalysis have garnered enormous interest and utility in the past several decades. Many different scientific disciplines have relied on C-H functionalization and photoredox strategies including natural product synthesis, drug discovery, radiolabeling, bioconjugation, materials, and fine chemical synthesis. In this Review, we highlight the use of photoredox catalysis in C-H functionalization reactions. We separate the review into inorganic/organometallic photoredox catalysts and organic-based photoredox catalytic systems. Further subdivision by reaction class─either sp2 or sp3 C-H functionalization─lends perspective and tactical strategies for use of these methods in synthetic applications.


Organic Chemicals , Catalysis
15.
Am J Speech Lang Pathol ; 31(3): 1039-1053, 2022 05 10.
Article En | MEDLINE | ID: mdl-34735294

PURPOSE: Most evidence-based clinical research findings in communication sciences and disorders never achieve full implementation by practicing clinicians. To address this almost universal problem, this tutorial focuses on the initial planning steps of including implementation methodologies as part of clinical practice research programs. Integrating the principles and methodologies of implementation science can shift the current reality, leading to better uptake of evidence-based interventions. METHOD: A step-by-step approach to integrating implementation science into new or existing research projects is provided, including the construction of a logic model, the selection of an implementation framework, and the selection of research methodologies. A detailed example of an augmentative and alternative communication research program is provided to illustrate the process. CONCLUSIONS: Readily available online tools can help researchers start the process of integrating implementation science into clinical practice research, and existing frameworks can assist with developing and guiding research programs to ensure maximal impact. If the ultimate goal is to improve the daily lives of individuals with communication disorders through the use of evidence-based practices, clinical practice researchers must integrate these approaches into their research programs.


Communication Disorders , Implementation Science , Communication , Communication Disorders/diagnosis , Communication Disorders/therapy , Evidence-Based Practice , Humans , Research Design
16.
Am J Speech Lang Pathol ; 30(1): 239-252, 2021 01 27.
Article En | MEDLINE | ID: mdl-33472008

Purpose This study investigated whether a 6-week coaching strategy resulted in positive changes in self-perceived knowledge and efficacy (SPKE) and positive communication behaviors in certified nursing assistants (CNAs) working with people with dementia in a skilled nursing facility. It also assessed the impact of the coaching strategy on negative responsive behaviors of people with dementia, such as yelling out, hitting, or spitting. Method Seven CNAs and seven people with dementia completed this study. Pretesting and posttesting were conducted for CNAs' SPKE. A single-subject, multiple-baseline design across five communication behaviors, the positive communication approach checklist, was completed to assess CNA communication behaviors after completion of a coaching strategy. Pretesting and posttesting of responsive behaviors of people with dementia were completed with the Cohen-Mansfield Agitation Inventory. Results Six out of seven CNAs improved their SPKE from pre- to postcoaching; however, this difference was not statistically significant. Per the positive communication approach checklist, there was a statistically significant increase, from baseline to follow-up, in CNA positive communication behaviors when interacting with people with dementia. The frequency of overall responsive behaviors of people with dementia significantly decreased from pre- to postcoaching, per the Cohen-Mansfield Agitation Inventory. Conclusions There is preliminary evidence to support the feasibility of a coaching strategy for the implementation of positive communication behaviors by CNAs when communicating with people with dementia. Negative responsive behaviors of people with dementia also decreased. Speech-language pathologists should consider acting as coaches to support positive communication for people with dementia. Supplemental Material https://doi.org/10.23641/asha.13564811.


Dementia , Mentoring , Nursing Assistants , Communication , Dementia/diagnosis , Feasibility Studies , Humans , Nursing Homes
17.
ACS Catal ; 11(5): 3153-3158, 2021 Mar 05.
Article En | MEDLINE | ID: mdl-36093286

The direct ß-functionalization of saturated aza-heterocycles has remained a synthetic challenge because of the remote and unactivated nature of ß-C-H bonds in these motifs. Herein, we demonstrate the ß-functionalization of saturated aza-heterocycles enabled by a two-step organic photoredox catalysis approach. Initially, a photoredox-catalyzed copper-mediated dehydrogenation of saturated aza-heterocycles produces ene-carbamates. This is followed by an anti-Markovnikov hydrofunctionalization of the ene-carbamates with a range of heteroatom-containing nucleophiles furnishing an array of C-C, C-O, and C-N aza-heterocycles at the ß-position.

18.
PLoS One ; 15(8): e0236839, 2020.
Article En | MEDLINE | ID: mdl-32780746

The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a KD value of 119 ± 2 µM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.


Cell Proliferation/drug effects , GRB2 Adaptor Protein/antagonists & inhibitors , Quinoxalines/pharmacology , Animals , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/metabolism , GRB2 Adaptor Protein/chemistry , GRB2 Adaptor Protein/metabolism , Humans , K562 Cells , Kidney/cytology , Kinetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Protein Binding , Quinoxalines/chemistry , Quinoxalines/metabolism , Stromal Cells/cytology , Stromal Cells/drug effects , Stromal Cells/metabolism , Surface Plasmon Resonance , Zebrafish , src Homology Domains
20.
Angew Chem Int Ed Engl ; 59(19): 7425-7429, 2020 05 04.
Article En | MEDLINE | ID: mdl-32068943

Expanding the toolbox of C-H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C-H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C-H functionalization reactions with diazoacetate derivatives, furnishing sp2 -sp3 coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.


Alkylation , Photochemistry , Catalysis , Cations , Diazonium Compounds/chemical synthesis , Drug Development , Free Radicals , Hydrocarbons, Aromatic/chemical synthesis , Metals/chemistry , Methane/analogs & derivatives
...