Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives.

A continuous flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alcohol into easily separable benzyl butyrate. The resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity.

Supporting the role of community members employed as research staff: Perspectives of community researchers working in addiction research.

Community researchers are laypersons who conduct research activities in their own communities. In addiction and HIV research, community researchers are valued for their insider status and knowledge. At the same time, their presence on the research team raises concerns about coercion and confidentiality when community researchers and participants know each other personally, and the work of navigating between the worlds of research and community leads to moral distress and burnout for some community researchers.

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response.

When a cell encounters external stressors, such as lack of nutrients, elevated temperatures, changes in pH or other stressful environments, a key set of evolutionarily conserved proteins, the heat shock proteins (hsps), become overexpressed. Hsps are classified into six major families with the hsp90 family being the best understood; an increase in cell stress leads to increased levels of hsp90, which leads to cellular protection. A hallmark of hsp90 inhibitors is that they induce a cell rescue mechanism, the heat shock response.

Moral Stress, Moral Practice, and Ethical Climate in Community-Based Drug-Use Research: Views From the Front Line.

Background: The role of front-line researchers, those whose responsibilities include face-to-face contact with participants, is critical to ensuring the responsible conduct of community-based drug use research. To date, there has been little empirical examination of how front-line researchers perceive the effectiveness of ethical procedures in their real-world application and the moral stress they may experience when adherence to scientific procedures appears to conflict with participant protections.

Methods: This study represents a first step in applying psychological science to examine the work-related attitudes, ethics climate, and moral dilemmas experienced by a national sample of 275 front-line staff members whose responsibilities include face-to-face interaction with participants in community-based drug-use research.

An Hsp90 modulator that exhibits a unique mechanistic profile.

Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound-Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90.

Case managers' perspectives on the therapeutic alliance: a qualitative study.

Purpose: In order to understand the nature of the therapeutic alliance in intensive case management, this study used qualitative methods to assess the dynamics of the case managers' relationships with their consumers by examining their perspectives on their own and their consumers' likeability, how helpful consumers perceive them to be, as well as their expectations for their relationships with their consumers.

Methods: The study employed content analysis of open-ended responses from 49 intensive case managers about their consumers.

Results: From case managers' responses, four themes emerged describing the dynamics of the case manager/consumer relationship: motivation, monitoring, creating dependency, and being there.

Synthesis of sansalvamide A peptidomimetics: triazole, oxazole, thiazole, and pseudoproline containing compounds.

Peptidomimetic-based macrocycles typically have improved pharmacokinetic properties over those observed with peptide analogs. Described are the syntheses of 13 peptidomimetic derivatives that are based on active Sansalvamide A structures, where these analogs incorporate heterocycles (triazoles, oxazoles, thiazoles, or pseudoprolines) along the macrocyclic backbone. The syntheses of these derivatives employ several approaches that can be applied to convert a macrocyclic peptide into its peptidomimetic counterpart.

A small molecule that preferentially binds the closed conformation of Hsp90.

Described is the synthesis of three different fluorescein-tagged derivatives of a macrocycle, and their binding affinity to heat shock protein 90 (Hsp90). Using fluorescence polarization anisotropy, we report the binding affinity of these fluorescein-labeled compounds to Hsp90 in its open state and ATP-dependent closed state. We show that the compounds demonstrate a conformation-dependent preference for binding to the closed state.

Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins.

Heat shock protein 90 (Hsp90) accounts for 1-2% of the total proteins in normal cells and functions as a molecular chaperone that folds, assembles, and stabilizes client proteins. Hsp90 is overexpressed (3- to 6-fold increase) in stressed cells, including cancer cells, and regulates over 200 client and co-chaperone proteins. Hsp90 client proteins are involved in a plethora of cellular signaling events including numerous growth and apoptotic pathways.

Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90.

Described are the syntheses of three sansalvamide A derivatives that contain biotinylated tags at individual positions around the macrocycle. The tagged derivatives indicated in protein pull-down assays that they bind to Hsp90 at the same binding site (N-Middle domain) as the San A-amide peptide. Further, these compounds inhibit binding between Hsp90 and multiple C-terminal client proteins.

Misbehaviors of front-line research personnel and the integrity of community-based research.

There has been little empirical research into misconduct and misbehavior among community research workers who recruit and collect data in vulnerable and marginalized health populations and are also members of those same communities. We conducted qualitative interviews with community research workers and traditional research assistants to understand the context and consequences of misbehaviors that pose a threat to research ethics and data integrity. In our sample, more community research workers acknowledged engaging in research wrongdoing than did traditional research assistants.

Histone Deacetylase Inhibitors: Synthesis of Cyclic Tetrapeptides and their Triazole Analogues.

Synthesis of nine macrocyclic peptide HDAC inhibitors and three triazole derivatives are described. HDAC inhibitory activity of these compounds against HeLa cell lysate is evaluated. The biological data demonstrates that incorporation of a triazole unit improves the HDAC inhibitory activity.

Design and synthesis of Hsp90 inhibitors: exploring the SAR of Sansalvamide A derivatives.

Utilizing the structure-activity relationship we have developed during the synthesis of the first two generations and mechanism of action studies that point to the interaction of these molecules with the key oncogenic protein Hsp90, we report here the design of 32 new Sansalvamide A derivatives and their synthesis. Our new structures, designed from previously reported potent compounds, were tested for cytotoxicity on the HCT116 colon cancer cell line, and their binding to the biological target was analyzed using computational studies involving blind docking of derivatives using Autodock. Further, we show new evidence that our molecules bind directly to Hsp90 and modulate Hsp90's binding with client proteins.

Macrocyclic inhibitors of hsp90.

Heat shock proteins (HSP) are a family of highly conserved proteins, whose expression increases in response to stresses that may threaten cell survival. Over the past decade, heat shock protein 90 (Hsp90) has emerged as a potential therapeutic target for cancer as it plays a vital role in normal cell maturation and acts as a molecular chaperone for proper folding, assembly, and stabilization of many oncogenic proteins. To date, a majority of Hsp90 inhibitors that have been discovered are macrocycles.

Evaluation of di-sansalvamide A derivatives: synthesis, structure-activity relationship, and mechanism of action.

Described is the SAR of 18 di-sansalvamide A derivatives and the mechanism of action of the most potent compound. We show that this scaffold is a promising lead in the development of novel cancer therapeutics because it is cytotoxic at nanomolar potency, inhibits a well-established oncogenic target (Hsp90), and does not share structural motifs with current drugs on the market.

Termination of parental rights proceedings: legal considerations and practical strategies for parents with psychiatric disabilities and the practitioners who serve them.

Topic: This article examines the issue of parenting with a psychiatric disability and the risk of custody loss for these parents.

Purpose: The purpose of this article is to examine the parental rights of parents with psychiatric disabilities and the use of the Americans with Disabilities Act as a legal defense. The current status of the law on terminating parental rights for people with mental illnesses is reviewed and the use of the ADA as a defense is described.

The relationship of case managers' expressed emotion to clients' outcomes.

Background: Expressed emotion (EE) has been studied in families of a relative with schizophrenia as well as other psychiatric disorders; and high EE (hostile, critical, and overinvolved) families have been found to be strongly related to relapse among their relatives. EE has been assessed on a limited basis among non-familial care providers and determined that providers can also have high EE which results in poor quality of life and negative consequences for their clients.

Methods: The present study assessed 42 case managers serving clients with schizophrenia spectrum disorder regarding their EE for specific clients enrolled in a larger study examining the reliability and validity of two alliance measures.

Conformationally based design of macrocycles as antitumor agents.

A key feature for any chemotherapeutic agent is a favorable conformation when it is presenting itself to its intended target. Numerous macrocycles have been identified as having antitumor activity and have been a source of lead compounds in anticancer research. The macrocyclic scaffold restricts bond rotation, therefore macrocycles maintain a relatively rigid conformation compared to their linear counterparts.

Neglected voices: consumers with serious mental illness speak about intensive case management.

This study explores early alliance formation between adult consumers with schizophrenic-spectrum disorders and their case managers from the consumers' perspectives using a prospective, cohort design. While quantitative studies have demonstrated positive links between the alliance and some client outcomes, such methods cannot reveal in concrete and authentic ways what consumers want in the case management relationship. This study finds that consumers can provide tangible and insightful information about the specifics of their case management relationships, confirming previous findings about the desire for connection with others, while extending it to include the desire for connection to the social world through the case manager relationship.

The working alliance in pediatric chronic disease management: a pilot study of instrument reliability and feasibility.

Findings are presented from a pilot study to determine the reliability, relevance, and feasibility of child and adult versions of the Working Alliance Inventory, adapted from psychotherapy research for use in the management of chronic childhood hematologic disorders. Thirty-four children, 13 adolescents, 43 parent/guardians, and 4 health-care providers participated. The adapted scales, called the Working Alliance Inventories for Chronic Care, had strong internal consistencies for all versions; retest reliabilities were generally acceptable.

A family of trust: African American parents' stories of adoption disclosure.

Dramatic increases in same-race adoptions of African American children have stimulated interest in the experiences of these families, including those related to disclosure. Data from interviews with 27 African American adoptive parents (7 mothers and fathers interviewed conjointly, 13 mothers interviewed alone) from 20 different families revealed the following themes: (a) efforts to prevent trauma to the child; (b) respect for the child's differentness and birth history; (c) developmental decisions in disclosure; (d) children's questions as motivations for disclosure; and (e) parents' feelings about disclosure. Findings confirm the importance of psychoeducation regarding methods and timing of disclosure and provide support for comparative research on contemporary disclosure, including racial differences in process and content.