A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC50 =0.16 µM, EC50 =0.3 µM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.

The Asymmetric Aza-silyl-Prins Reaction: Synthesis of Enantiopure Piperidines.

The design and development of the first asymmetric aza-silyl-Prins reaction is reported, giving rise to valuable and diverse piperidines and pipecolic acid derivatives in both high yields and as single enantiomers. The creation of a novel chiral auxiliary-homoallylic amine for the aza-silyl-Prins reaction is essential to its success.

Selective recognition of oxalate in water: effect of pH on binding strength and sensing mechanisms.

Bicyclic receptors bearing anthracene as a strap were designed for selective oxalate binding in a buffered aqueous solution. The receptors were found to possess two mechanisms of fluorescence response depending on the pH of a buffered solution. Receptor 2 binds oxalate at pH 6.2 showing a 10-fold fluorescence enhancement and a two orders of magnitude selectivity over other anions.

Naphthalimide-Based Polyammonium Chemosensors for Anions: Study of Binding Properties and Sensing Mechanisms.

New naphthalimide-based receptors for anions have been synthesized. Efficient synthetic routes have been discovered to functionalize the naphthalimide core with branched polyamines. Binding and sensing properties of the receptors were studied by potentiometric, NMR and fluorescence titrations. The receptors bind selectively to the pyrophosphate anion in buffered aqueous solutions. The receptors with more than six amine groups in the structure demonstrated the highest affinities for pyrophosphate. The fluorescence response towards anions was found to be dependent on the position of the amine groups relative to the naphthalimide core, and on the pH of the buffered solution. Three sensing mechanisms have been found that explain fluorescence responses of receptors towards anions in an aqueous solution.

Design of anion-selective PET probes based on azacryptands: the effect of pH on binding and fluorescence properties.

Design of PET probes for anions working in an aqueous buffered solution is described. The design has been used to develop selective fluorescent probes for sulfate and pyrophosphate. The relationship between the selectivity of receptors towards anions, their conformation, fluorescence response and the pH of the solution has been studied in detail.

Rational design, synthesis, and structure-activity relationships of 5-amino-1H-pyrazole-4-carboxylic acid derivatives as protein tyrosine phosphatase 1B inhibitors.

A series of novel amino-carboxylic based pyrazole as protein tyrosine phosphatase 1B (PTP1B) inhibitors were designed on the basis of structure-based pharmacophore model and molecular docking. Compounds containing different hydrophobic tail (1,2-diphenyl ethanone, oxdiadizole and dibenzyl amines) were synthesized and evaluated in PTP1B enzymatic assay. Structure-activity relationship based optimization resulted in identification of several potent, metabolically stable and cell permeable PTP1B inhibitors.

Mutational, proteomic and metabolomic analysis of a plant growth promoting copper-resistant Pseudomonas spp.

Pseudomonas sp. TLC6-6.5-4 is a multiple metal resistant plant growth-promoting bacteria isolated from copper-contaminated lake sediments. In this study, a comprehensive analysis of genes involved in copper resistance was performed by generating a library of transposon (Tn5) mutants. Two copper-sensitive mutants with significant reduction in copper resistance were identified: CSM1, a mutant disrupted in trpA gene (tryptophan synthase alpha subunit), and CSM2, a mutant disrupted in clpA gene (ATP-dependent Clp protease). Proteomic and metabolomic analyses were performed to identify biochemical and molecular mechanisms involved in copper resistance using CSM2 due to its lower minimum inhibitory concentration compared with CSM1 and the wild type. Proteomic analysis revealed that disruption of Clp protease gene up-regulated molecular chaperones and down-regulated the expression of enzymes related to tRNA modification, whereas metabolomic analysis showed that amino acid and oligosaccharide transporters that are part of ATP-binding cassette (ABC) transporters pathways were down-regulated. Further, copper stress altered metabolic pathways including the tricarboxylic acid cycle, protein absorption and glyoxylate metabolism.

Aftercare of depressed inpatients--service delivery and unmet needs.

BACKGROUND: In contrast to acute treatment, delivery of aftercare to depressed patients has not been well studied. Poor care may contribute to poor outcomes for treated depression. METHODS: One hundred and two patients discharged from hospital with unipolar depression were followed up 18 months later and were interviewed in detail regarding aftercare and treatment received. Unmet needs were assessed on the community version of the MRC Needs for Care Assessment. RESULTS: In the first month after discharge approximately 70 % of subjects received contacts with mental health services and in the first 3 months over 80 % received at least one contact. About 40 % were in contact with mental health services at 18 months. Needs assessment found comparatively low unmet needs, reaching highest levels (around 25 % in any 6-month period) for medication. Two-thirds of unmet needs for medication and psychotherapy were due to patient refusal or non-compliance. Aftercare levels were higher in those with more previous admissions and were unrelated to presence of personality disorder. CONCLUSIONS: There were some deficiencies in service aftercare for depressed patients in a British NHS setting, although unmet need was not high. Some aftercare failures reflect patient reluctance to receive further treatment, representing a challenge to overcome in patients entitled to autonomous choices.

Medication received by patients with depression following the acute episode: adequacy and relation to outcome.

BACKGROUND: The adequacy of pharmacotherapy received in practice by patients after an acute episode of depression has been little studied. AIMS: To describe and assess adequacy of drug continuation and maintenance in patients with depression. METHOD: Patients with depression were interviewed 18 months after discharge from hospital. Quantitative assessments of drug treatment doses and compliance were made monthly over this period, and qualitative ratings in continuation and maintenance phases. RESULTS: About 20% of patients were prescribed low drug doses after discharge and 10% were prescribed no drugs at all. Reported compliance was around 70%. About 30% failed to receive adequate longer-term treatment, mostly due to the continuation phase being too short. Deficiencies of dosage and compliance were greater in patients who never achieved full recovery. Patient refusal was the most common reason for not using antidepressants. Further episodes of depression were not particularly associated with inadequate treatment. CONCLUSIONS: There were deficiencies in drug treatment that did not appear to be the principal cause of further episodes but may be important in non-recovery. Patient fears require discussion.

Expressed emotion and depression. A longitudinal study.

BACKGROUND: Previous studies show that criticism by relatives during acute depressive illness predicts relapse over nine months, but the course of criticism over time and its relation to the course of illness, have not been examined in depressed patients. METHOD: Thirty-nine depressed patients and their partners, were interviewed separately at three-monthly intervals over about one year. Illness was assessed by Research Diagnostic Criteria and Hamilton Depression Rating Scale. Criticism was measured by the Camberwell Family Interview. RESULTS: Criticism when patients were most depressed predicted neither remission nor subsequent relapse. Patients who fully recovered, with or without later relapse, had partners who were consistently uncritical, or critical only at presentation. Patients with residual symptoms during remission had more persistently critical partners. CONCLUSIONS: The nature of the association between criticism and depression could not be unequivocally established, although it appeared likely that continuing criticism was a result of continuing depression. Relatives' understanding of the illness may mediate between levels of criticism and the course of depression.

Direct somatic embryogenesis and transformation in Cicer arietinum L.

Somatic embryos were induced directly from immature cotyledons of the genotype of chickpea ICC 4918 (annigiri) on B5 medium supplemented with 2,4,5-T or 2,4-D in combination with BA or KN. Successful transformation was achieved via somatic embryogenesis using Agrobacterium tumefaciens strain LBA4404, carrying a binary plasmid vector system containing neomycin phosphotransferase (NPT II) gene as the selectable marker and beta-glucuronidase (GUS) as a reporter gene. Histochemical staining for GUS expression was observed as primary evidence for transformation.

Life events, social support and marital relationships in the outcome of severe depression.

The effects of life events, social support and marital relationships on outcome were examined in a predominantly recurrent in-patient sample of depressives studied longitudinally every 3 months to remission and up to 15 months thereafter. Outcomes examined were length of time to remission, presence of residual symptoms at remission, and subsequent relapse. There were few associations between these outcomes and the social variables. These findings add to other recent evidence that psychosocial factors are relatively unimportant in the subsequent course of severe and recurrent depressions, in contrast to their contribution to onset of such depressions and subsequent outcome of milder depressions.

Remission and relapse in major depression: a two-year prospective follow-up study.

This paper reports the course with respect to remission and relapse of a cohort of predominantly in-patient RDC major depressive subjects, who were followed at 3-monthly intervals to remission and for up to 15 months thereafter. Remission was comparatively rapid with 70% of subjects remitting within 6 months. Only 6% failed to do so by 15 months. However, 40% relapsed over the subsequent 15 months, with all the relapses occurring in the first 10 months. Greater severity of the depression and longer duration of the illness predicted a longer time to remission. Greater initial severity of depression also predicted relapse. Subjects with a worse outcome had not received less adequate treatment than the remainder. Our results confirm the comparatively poor outcome subsequent to remission that has been reported in recent literature, in spite of the availability of modern methods of treatment. The clustering of relapses in the first 10 months gives some support to the distinction between relapse and later recurrence.

Residual symptoms after partial remission: an important outcome in depression.

This paper draws attention to an important adverse outcome in depression, the occurrence of residual symptoms after partial remission. Among patients with definite major depression followed every 3 months to remission and thereafter, residual symptoms reaching 8 or more on the Hamilton Depression Scale 17-item total were present in 32% (19) of the 60 who remitted below major depression by 15 months. The pattern was of mild but typical depressive symptoms. Residual symptoms were more common in subjects with more severe initial illness, but were not related to any other predictors, including longer prior illness, dysthymia, or lower dose of drug treatment during the illness episode. There were weak associations with personality that might have been consequences of symptom presence. Residual symptoms were very strong predictors of subsequent early relapse, which occurred in 76% (13/17) of those with residual symptoms and 25% (10/40) of those without.

The epidemiology of bipolar affective disorder.

This paper reviews the current position of studies on the epidemiology of bipolar affective disorder. A disorder that cannot be recognized until sometime after its onset poses special difficulties for epidemiological study. These are discussed and attempts made to solve them. Community psychiatric surveys suggest a morbid risk of bipolar disorder of around 2-2.5%, but probably include many false-positives. Studies of treated cases indicate a morbid risk of 0.5%, but will miss untreated cases. It is probably reasonable to suggest a compromise value of 1-1.5%; bipolar disorder is thus still a rare condition. It is possible to quantify the unipolar-bipolar conversion rate, which is of the order of 5%, and is of particular interest that female sufferers have proportionately fewer manic episodes. Age at onset, possible cohort phenomena, comorbidity, and sociodemographic correlates are discussed.

Social influences on bipolar affective disorders.

The impact of psychosocial adversity on the onset and course of bipolar disorder has been assessed in studies that have relied on methods of eliciting life event histories and evaluating family atmosphere. The results of life event studies have been inconsistent, perhaps because the relationship between bipolar disorder and major stress is only pronounced in first or early episodes. If this is so, this phenomenon itself invites explanation, whether in social or biological terms. The two studies to data of family atmosphere suggest an association between high expressed emotion and relapse. The relationship between psychosocial stress and bipolar disorder requires further and more detailed research.

EMS-induced streptomycin resistance in Solanum melongena.

Streptomycin-resistant mutations were induced in Solanum melongena by exposing seeds to ethyl methane sulphonate (EMS). Seed mutagenesis resulted in a high frequency of chlorophyll-deficient mutations and a low frequency of resistant shoots, both of which retained their resistance on subsequent testing. Reciprocal crosses between streptomycin-resistant and -sensitive plants showed a non-Mendelian transmission of the resistance trait. Streptomycin resistance is the first selectable and maternally inherited organelle marker described in brinjal.

Classification of affective disorders.

The classification of affective disorders has provoked much controversy in the past. Current classification systems, ICD-10 and DSM-IIIR, define operational criteria for diagnosis and recognize the presence of more chronic and milder forms. They reflect a growing consensus on the subject.