Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for G signaling to measure agonistic activation of the orexin receptor type 2 (OXR). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OXR coupled G signaling.

The structure of importin α and the nuclear localization peptide of ChREBP, and small compound inhibitors of ChREBP-importin α interactions.

The carbohydrate response element binding protein (ChREBP) is a glucose-responsive transcription factor that plays a critical role in glucose-mediated induction of genes involved in hepatic glycolysis and lipogenesis. In response to fluctuating blood glucose levels ChREBP activity is regulated mainly by nucleocytoplasmic shuttling of ChREBP. Under high glucose ChREBP binds to importin α and importin β and translocates into the nucleus to initiate transcription.

Mental disorders and the desire for death in patients receiving palliative care for cancer.

Objectives: The desire for death in terminally ill patients is associated with depression and anxiety, but not all patients who report it meet criteria for mental disorders. We examined the characteristics of subgroups of palliative cancer patients who expressed a desire for death that occurred either with or without a concurrent depressive or anxiety disorder.

Design: Cross-sectional survey.

In silico derived small molecules bind the filovirus VP35 protein and inhibit its polymerase cofactor activity.

The Ebola virus (EBOV) genome only encodes a single viral polypeptide with enzymatic activity, the viral large (L) RNA-dependent RNA polymerase protein. However, currently, there is limited information about the L protein, which has hampered the development of antivirals. Therefore, antifiloviral therapeutic efforts must include additional targets such as protein-protein interfaces.

Development of proneurogenic, neuroprotective small molecules.

Degeneration of the hippocampus is associated with Alzheimer's disease and occurs very early in the progression of the disease. Current options for treating the cognitive symptoms associated with Alzheimer's are inadequate, giving urgency to the search for novel therapeutic strategies. Pharmacologic agents that safely enhance hippocampal neurogenesis may provide new therapeutic approaches.

Discovery of a proneurogenic, neuroprotective chemical.

An in vivo screen was performed in search of chemicals capable of enhancing neuron formation in the hippocampus of adult mice. Eight of 1000 small molecules tested enhanced neuron formation in the subgranular zone of the dentate gyrus. Among these was an aminopropyl carbazole, designated P7C3, endowed with favorable pharmacological properties.

Synthesis and evaluation of duocarmycin SA analogs incorporating the methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) alkylation subunit.

The design, synthesis and evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]oxazolo[2,3-e]indol-4-one-6-carboxylate (COI) derivatives are detailed representing analogs of duocarmycin SA containing an oxazole replacement for the fused pyrrole found in the alkylation subunit.

Synthesis and Preliminary Evaluation of Duocarmycin Analogues Incorporating the 1,2,11,11a-Tetrahydrocyclopropa[c]naphtho[2,3-e]indol-4-one (CNI) and 1,2,11,11a-Tetrahydrocyclopropa[c]naphtho[1,2-e]indol-4-one (iso-CNI) Alkylation Subunits.

Efficient syntheses and a preliminary evaluation of 1,2,11,11a-tetrahydrocyclopropa[c]-naphtho[2,3-e]indole (CNI) and 1,2,11,11a-tetrahydrocyclopropa[c]naphtho[1,2-e]indole (iso-CNI), and their derivatives containing an anthracene and phenanthrene variant of the CC-1065 or duocarmycin alkylation subunit are detailed.

Synthesis and evaluation of a thio analogue of duocarmycin SA.

The design, synthesis, and preliminary evaluation of methyl 1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one-6-carboxylate (CTI) derivatives are detailed representing a single atom change (N to S) embedded in the duocarmycin SA alkylation subunit.

Prevalence and correlates of pain in the Canadian National Palliative Care Survey.

Background: Pain is a common problem for people with cancer who are nearing the ends of their lives.

Objective: In the present multicentre Canadian study of palliative cancer care, the prevalence of pain, its perceived severity and its correlates across a range of physical, social, psychological, and existential symptoms and concerns were examined.

Methods: Semistructured interviews were conducted with 381 patients.

Prognostic acceptance and the well-being of patients receiving palliative care for cancer.

Purpose: To identify the impact of prognostic acceptance/nonacceptance on the physical, psychological, and existential well-being of patients with advanced cancer.

Patients And Methods: A Canadian multicenter prospective national survey was conducted of patients diagnosed with advanced cancer with an estimated survival duration of 6 months or less (n = 381) receiving palliative care services.

Results: Of the total number of participants, 74% reported accepting their situation and 8.

An additional spirocyclization for duocarmycin SA.

A unique alternative to the -spirocyclization for activation of compounds containing the duocarmycin SA alkylation subunit was established involving indole NH deprotonation and subsequent cyclopropane formation. The structural characterization of an alternative spirocyclization product, and the establishment of its relative reactivity, intrinsic reaction regioselectivity, biological activity, and DNA alkylation properties (selectivity, rate, and efficiency) including the isolation, characterization, and quantitation of its adenine N3 adduct, are disclosed.

Potent cytotoxic C-11 modified geldanamycin analogues.

17-Allylamino-17-demethoxygeldanamycin (17-AAG) inhibits the activity of Hsp90, an important target for treatment of cancers. In an effort to identify analogues of geldanamycin (GDM) with properties superior to those of 17-AAG, we synthesized C-11 modified derivatives of GDM including ethers, esters, carbazates, ketones, and oximes and measured their affinity for Hsp90 and their ability to inhibit growth of human cancer cells. In accordance with crystal structures reported for complexes of GDMs with Hsp90, bulky groups attached to C-11 interfered with Hsp90 binding while smaller groups such as 11-O-methyl allowed Hsp90 binding.

Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin.

The total synthesis and evaluation of iso-duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity.

Pathways to competence: parental adversity and the roles of parenting quality and social support.

The authors studied a representative Canadian cohort from the National Longitudinal Study of Children and Youth at 3 points in time, when the participants were aged 10-11 years (n = 2,147), 12-13 years (n = 1,976), and 14-15 years (n = 1,762). The presence of parent-related adversity appeared detrimental to young people's emotional and behavioral competence. Parents' self-reports of adversity predicted children's self-reports of their own behavioral functioning 2 years later.

Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins.

The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) alkylation subunit and its isomer 6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one (iso-MeCTI) were found to be 5-6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potency of the corresponding DSA derivatives, consistent with projections made on the basis of the parabolic relationship.

Systematic exploration of the structural features of yatakemycin impacting DNA alkylation and biological activity.

A systematic examination of the impact of the yatakemycin left and right subunits and their substituents is detailed along with a study of its unique three subunit arrangement (sandwiched vs extended and reversed analogues). The examination of the ca. 50 analogues prepared illustrate that within the yatakemycin three subunit structure, the subunit substituents are relatively unimportant and that it is the unique sandwiched arrangement that substantially increases the rate and optimizes the efficiency of its DNA alkylation reaction.

Suffering with advanced cancer.

Purpose: The alleviation of suffering is a central goal of palliative care, but little research has addressed the construct of suffering as a global experience of the whole person. We inquired into the sense of suffering among patients with advanced cancer to investigate its causes and correlates.

Patients And Methods: Semistructured interviews were administered to 381 patients.

Depression and anxiety disorders in palliative cancer care.

Depression and anxiety disorders are thought to be common in palliative cancer care, but there is inconsistent evidence regarding their relevance for other aspects of quality of life. In the Canadian National Palliative Care Survey, semi-structured interviews assessing depression and anxiety disorders were administered to 381 patients who were receiving palliative care for cancer. There were 212 women and 169 men, with a median survival of 63 days.

Palliative care nurses' perceptions of the Edmonton Symptom Assessment Scale: a pilot survey.

Aim: to evaluate, at a pilot level, palliative care nurses' perceptions of the Edmonton Symptom Assessment Scale's (ESAS's) feasibility and usefulness.

Methods: all nurses working within the Edmonton Palliative Care Programme were provided with a one-page document containing five statements about the benefits and feasibility of the ESAS, and invited to rate each statement on a five-point Likert scale (1=strongly agree; 5=strongly disagree).

Results: of the 74 nursing staff employed in the programme, 48 (64.

Chemobiosynthesis of novel 6-deoxyerythronolide B analogues by mutation of the loading module of 6-deoxyerythronolide B synthase 1.

Chemobiosynthesis (J. R. Jacobsen, C.

Neurologic complications following treatment of canine hypoadrenocorticism.

After treatment for hypoadrenocorticism, an 18-month-old dog exhibited marked ataxia and intermittent muscle tremors, progressing to head pressing, dysphagia, and quadraparesis. Serum sodium increased by 38.9 mmol in 48 hours, suggesting myelinolysis.