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Indole- and azaindole-based glyoxylyl amide derivatives have been described as HIV-1 attachment inhibitors (AIs) that act by blocking the interaction between the viral gp120 coat protein and the human host cell CD4 receptor. As part of an effort to more deeply understand the role of the indole/azaindole heterocycle in the expression of antiviral activity, a survey of potential replacements was conducted using parallel synthesis methodology. The design and optimization was guided by a simple 2-dimensional overlay based on an overall planar topography between the indole/azaindole and C-7 substituents that had been deduced from structure-activity studies leading to the discovery of temsavir (3). 2-Substituted naphthalene- and quinoline-derived chemotypes emerged as the most interesting prototypes, with C-5 and C-6 substituents enhancing antiviral potency. Despite the fact that neither of these chemotypes incorporated a H-bond donor that has been shown to engage the side chain carboxylate of Asp 113 in gp120, the antiviral potency of several analogues met or exceeded that of 3 , demonstrating that engaging Asp 113 is not a prerequisite for potent antiviral activity. [ABSTRACT FROM AUTHOR]

BuChE inhibitors play important roles in treatment of patients with advanced Alzheimer's disease (AD). A series of tricyclic pyrazolo[1,5- d ][1,4]benzoxazepin-5(6H)-one derivatives were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Some derivatives showed selective BuChE inhibitory activity, which was influenced by the volumes of the substituted groups at the C6 position and halogen substituents at the benzene ring of tricyclic scaffold. Among them, compounds 3f and 3o with dihalogen and 6-ethyl substituent showed the most potent activity (IC 50  = 2.95, 2.04 μM, and mixed-type, non-competitive inhibition against BuChE, respectively). Eutomer (6 R )-3o exhibited better BuChE inhibitory activity than (6 S )-3o . Compound 3o exhibited nontoxic, good ADMET properties, and remarkable neuroprotective activity. Docking studies revealed the same binding orientation within the active site of target enzyme. Compound 3o was nicely bound to BuChE via three hydrogen bonds, one Alkyl interaction and three Pi-Alkyl interactions. The selective BuChE inhibitors had a potential use in progressive neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

To ascertain the relationship between receipt of antidepressant agents and the risk of subsequent dementia in migraine patients. A population-based case-control analysis, using the Taiwan National Health Insurance Research Database. We identified 1774 patients with dementia and 1774 matched nondementia controls from migraine patients enrolled in the Taiwan National Health Insurance program between 2005 and 2011. The proportional distributions of exposure to three classes of antidepressant were compared between dementia and nondementia groups. Univariable and multivariable logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of dementia based on antidepressant exposure. The proportions of subjects taking tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and new-generation antidepressants (NGAs) in dementia versus nondementia groups are 52.3 vs 51.2%, 25.5 vs 30.7%, and 18.8 vs 6.26%, respectively. The adjusted ORs of dementia were 1.02 (95% CI = 0.89, 1.17; P = 0.56) for TCAs, 0.58 (95% CI = 0.50, 0.69; P < 0.001) for SSRIs, and 4.23 (95% CI = 3.34, 5.37; P < 0.001) for NGAs. Treatment with SSRIs was associated with a decreased risk of dementia in migraine patients. TCAs showed no association with dementia risk, and NGAs showed increased risk. Given the possibility of confounding by indication, additional prospective trials and basic research are needed before drawing conclusions about the population-level risks for dementia onset conferred by antidepressant medications. [ABSTRACT FROM AUTHOR]

8,9-Dihydro-2,4,7,9a-tetraazabenzo[ cd ]azulen-6(7 H )-ones were designed and synthesized as a new class of PARP-1/2 inhibitors. The compounds displayed a variable pattern of PARP-1/2 enzymes inhibition profile that, in part, paralleled the antiproliferative activity in cell lines. Among them, compound 9e exhibited not only the significant IC 50 value of 28 nM in the PARP-1 and 7.7 nM in PARP-2 enzyme assay, but also a profound synergic efficacy combined with temozolomide with PF 50 values of 2.6, 2.5, and 6.5 against MDA-MB-468, SW-620 and A549 and cell line, respectively. [ABSTRACT FROM AUTHOR]

HCV NS5A inhibitors have demonstrated impressive in vitro potency profiles in HCV replicon assays and robust HCV RNA titer reduction in the clinic making them attractive components for inclusion in an all oral fixed dose combination regimen for the treatment of HCV infection. Herein, we describe research efforts that led to the discovery of a series of fused tricyclic core containing HCV NS5A inhibitors such as 24 , 39 , 40 , 43 , and 44 which have pan-genotype activity and are orally bioavailable in the rat. [ABSTRACT FROM AUTHOR]

The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling. [ABSTRACT FROM AUTHOR]

Background The existing literature provides contradictory evidence on antidepressant use and risk of suicide. Some studies have shown that the use of Selective Serotonin Reuptake Inhibitors (SSRIs) is associated with an increased risk of suicide, especially during the first months of treatment, whereas other studies did not confirm this association. For this reason, our objective was to investigate the association between antidepressant use and risk of suicide in incident antidepressant users in relation to time since starting therapy. Methods We conducted a population-based cohort study within the Dutch Integrated Primary Care Information (IPCI) database, in incident users of antidepressant therapy between 1994 and 2012 ( n =27,712). Cox proportional hazard models were used to study the association between current use of SSRIs, tricyclic antidepressants (TCA) and other antidepressants and risk of suicide or attempted suicide. Results During follow-up, a total of 280 incident antidepressant users attempted or committed suicide. Current use of SSRIs (hazard ratio (HR): 0.78, 95% CI: 0.57–1.07), TCAs (HR: 0.82, 95% CI: 0.48–1.42) or other antidepressants (HR: 0.75, 95% CI: 0.47–1.18) was not statistically significantly associated with suicide compared to past use of any of the antidepressants. Limitations Although a large healthcare database was used, the number of reported cases of suicide (attempt) was low. Conclusions This study did not indicate an increase in risk of suicide after starting treatment with SSRIs, TCAs or other antidepressants compared with past antidepressant use. [ABSTRACT FROM AUTHOR]

A new and efficient synthesis of tricyclic 4-pyridone analogs through the intramolecular Heck coupling cyclization was described. This reaction features mild conditions and good functional group tolerance allowing for the preparation of several novel tricyclic 4-pyridone analogs. [ABSTRACT FROM AUTHOR]

Highlights: [•] The UPLC–MS/MS method measures five tricyclic antidepressants in human urine. [•] Simple screening protocols and subsequent optimization delivered the final method. [•] The method was evaluated against current FDA guidelines. [•] The work includes an assessment of incurred sample reanalysis (ISR). [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We investigated the relationship between use of tricyclic antidepressants (TCAs) and risk of non-Hodgkin lymphoma (NHL). Previous studies provided some evidence of an association, but did not assess risk of NHL subtypes. Methods: Cases and controls were members of Group Health, an integrated healthcare delivery system. Cases were persons diagnosed with NHL between 1980 and 2011 at age 25 years or older; eight control subjects were matched to each case on age, sex, and length of enrollment. Information on previous TCA use was ascertained from automated pharmacy data. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for NHL, overall and for common subtypes, for various patterns of TCA use. Results: We identified 2768 cases and 22,127 matched control subjects. We did not observe an appreciably increased risk of NHL among TCA ever-users compared to non-users (OR, 1.1; 95% CI, 1.0–1.2). Overall risk of NHL was associated to at most a small degree with longer-term use (OR, 1.2; 95% CI, 1.0–1.4; ≥10 prescriptions), high-dose use (OR, 1.1; 95% CI, 0.8–1.5; ≥50 mg), or non-recent use (OR, 1.0; 95% CI, 0.9 = 1.2; >5 years previously). TCA use was not associated with NHL subtypes, except chronic lymphocytic leukemia/small lymphocytic lymphoma (OR, 1.5; 95% CI, 1.1–2.0; longer-term use). Conclusions: We found little evidence that the use of TCAs increases the risk of NHL overall or for specific common subtypes of NHL. [Copyright &y& Elsevier]

Abstract: Novel indeno[1,2-d]thiazole hydroxamic acids were designed, synthesized, and evaluated for histone deacetylases (HDACs) inhibition and antiproliferative activities on tumor cell lines. Most of the tested compounds exhibited HDAC inhibition and antiproliferative activity against both MCF7 and HCT116 cells with GI50 values in the sub-micromolar range. Among them, compound 6o showed good inhibitory activity against pan-HDAC with IC50 value of 0.14μM and significant growth inhibition on MCF7 and HCT116 cells with GI50 values of 0.869 and 0.535μM, respectively. [Copyright &y& Elsevier]

The purpose of this article is to review essential information about the pharmacokinetics of antidepressants in older adults and possible adverse drug reactions associated with each antidepressant class to avoid or minimize adverse drug events. [ABSTRACT FROM AUTHOR]

Abstract: Introducing structural diversity into the nucleoside scaffold for use as potential chemotherapeutics has long been considered an important approach to drug design. In that regard, we have designed and synthesized a number of innovative 2′-deoxy expanded nucleosides where a heteroaromatic thiophene spacer ring has been inserted in between the imidazole and pyrimidine ring systems of the natural purine scaffold. The synthetic efforts towards realizing the expanded 2′-deoxy-guanosine and -adenosine tricyclic analogues as well as the preliminary biological results are presented herein. [Copyright &y& Elsevier]

Abstract: This Letter describes the synthesis of a number of fused tricyclic and bicyclic triazolobenzodiazepines for the Vasopressin V1a antagonist programme. [Copyright &y& Elsevier]

Abstract: This report discloses the development of a series of tricyclic histamine H4 receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H4 receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model. [Copyright &y& Elsevier]

Abstract: A series of 3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-α-(hydroxymethyl)cyclopent-2-ene-1-α-yl]guanine (CBV) 5, (−)-β-D-(2R,4R)-1,3-dioxolane-guanosine (DXG) 6, 3′-azido-3′-deoxy-guanosine (AZG) 7, and 2′-C-methylguanosine 8. Their in vitro activity against HIV and HCV was evaluated and correlated to their ability to degrade to their purine counterpart. [Copyright &y& Elsevier]

Abstract: Mood disorders place substantial clinical, social, and economic burdens on individuals with the disorders, their families, and wider society. At the same time, the scarcity of health-care resources necessitates the efficiency of alternative treatments to be examined. Newer, more expensive, treatments always bring new cost concerns. However, costs alone are not an informative basis for decisions about the allocation of scarce resources. When broader perspectives are taken, such treatments can often demonstrate cost-effectiveness through improved clinical and/or quality-of-life outcomes, reduced use of other health-care resources, and improved participation in employment. [Copyright &y& Elsevier]

Abstract: Clinical studies have shown differential efficacy of several antidepressants in children and adolescents compared to adults, yet few animal studies have sought to characterize this phenomenon. We compared effects of fluoxetine and imipramine in two common behavioral assays that hold high predictive validity for antidepressant activity, tail suspension and forced swim test, using juvenile (5 weeks) and adult (12 weeks) mice from 3 strains. C57BL/6J-Tyrc-Brd (C57), hybrid C57BL/6J-Tyr c-Brd ×129S5/SvEvBrd (F2), and Balb/cAnNTac (Balb/C) mice were tested in forced swim test and tail suspension after i.p. dosing with either fluoxetine or imipramine. Brain tissues were analyzed to evaluate levels of VMAT2, a possible modulator of age-dependent sensitivity to antidepressants. Imipramine had more consistent antidepressant effect across age groups and strains. Imipramine increased struggle in mice of both ages. Fluoxetine did not have an effect on immobility in Balb/C of both ages in tail suspension. Fluoxetine also did not increase forced swim struggle behavior in juvenile mice of all strains, but was effective in increasing struggle in adults. Juvenile mice had higher immobility and lower struggle than adults in forced swim, and juveniles also had higher immobility in tail suspension test for Balb/C and C57. In addition, VMAT2 levels were increased in juveniles. These results confirm that standard antidepressants produce effects in both juveniles and adults but age-related differences were evident in both tests. Further examination of these effects is needed to determine whether it may be related to age-dependent difference in the clinical response to antidepressants of these classes. [Copyright &y& Elsevier]

Abstract: We report on the synthesis of a novel series of fluorinated acridones from 5-trifluoromethyl-1,3-cyclohexanedione. The cytotoxic activities of the compounds were studied in several cancer cells. Compounds 9a, 9c, 9e, 9f, and 9h exhibited significant anticancer activities in selected cell lines. Compound 9c is the most active showing GI50 that ranged in values from 0.13 to 26μM, covering a wide range of cancer cell lines. [Copyright &y& Elsevier]

Abstract: A series of C5-aza tricyclic HIV integrase inhibitors was prepared. A highly potent and orally bioavailable compound (compound 9) was identified and selected for development. [Copyright &y& Elsevier]

Abstract: A new high-performance liquid chromatography method is presented for the determination of 10 frequently prescribed tricyclic and nontricyclic antidepressants: imipramine, amitriptyline, clomipramine, fluoxetine, sertraline, paroxetine, citalopram, mirtazapine, moclobemide and duloxetine. The simple and accurate sample preparation step, consisted of liquid:liquid extraction with recoveries ranging between 72% and 86%, except for moclobemide (59%). Separation was obtained using a reverse phase Select B column under isocratic conditions with UV detection (230nm). The mobile phase consisted of 35% of a mixture of acetonitrile/methanol (92:8, v/v) and 65% of 0.25molL−1 sodium acetate buffer, pH 4.5. The standard curves were linear over a working range of 2.5–1000ngmL−1 for moclobemide, 5–2000ngmL−1 for citalopram, duloxetine, fluoxetine, 10–2000ngmL−1 for sertraline, imipramine, paroxetine, mirtazapine and clomipramine. The intra-assay and inter-assay precision and accuracy were studied at three concentrations (50, 200, and 500ngmL−1). The intra-assay coefficients of variation (CVs) for all compounds were less than 8.8%, and all inter-CVs were less than 10%. Limits of quantification were 2.5ngmL−1 for moclobemide, 5ngmL−1 for citalopram, duloxetine and amitriptyline, and 10ngmL−1 for mirtazapine, paroxetine, imipramine, fluoxetine, sertraline, and clomipramine. No interference of the drugs normally associated with antidepressants was observed. The method has been successfully applied to the analysis of real samples, for the drug monitoring of ten frequently prescribed tricyclic and non-tricyclic antidepressant drugs. [Copyright &y& Elsevier]

Abstract: In an effort to discover potent antibacterials based on the entropically favored ‘bioactive conformation’ approach, a series of novel tricyclic molecules mimicking the conformationally constrained structure of Linezolid is reported. Based on the initial tricyclic molecule 1, the benzazepine derivative 2 was designed where the tricyclic structure had more flexibility around C–N bond compared to 1. While, the molecule 2 was less active, the molecule 3 showed promising antibacterial activity presumably after having obtained rigidity due to pyrrole ring. The syntheses, SAR studies, and evaluation of 3 as a lead compound are reported. [Copyright &y& Elsevier]

Abstract: A series of conformationally constrained analogues of Linezolid were synthesised by employing a tandem SN2 and SNAr reaction as the key step and tested for antibacterial activity. While the hexahydroazolo-quinoxaline compounds were inactive, the tetrahydroazolo-benzothiazine compounds exhibited interesting antibacterial activity. The introduction of fluorine in the aromatic ring further made the compounds more potent in acetamide compounds resulting in an interesting analogue 32. However, the introduction of fluorine (analogue 34) on the already potent non-fluorine thiocarbamate 21 did not have any influence on the activity. [Copyright &y& Elsevier]

Abstract: Mood disorders place substantial clinical, social and economic burdens on individuals with the disorders, as well as on their families and wider society. At the same time, the scarcity of healthcare resources necessitates the efficiency of alternative treatments to be examined. Economic evaluations of the seemingly expensive SSRIs have tended to suggest that they are cost-effective compared with tricyclics due to better clinical outcomes and reduced hospitalizations. However, a third generation of antidepressants may bring new cost concerns. The high cost of psychological therapies may mean that they are only cost-effective for particular sub-groups of patients, as suggested by recent NICE guidelines. [Copyright &y& Elsevier]

Abstract: Structure–activity relationship (SAR) studies on the tricyclic isoxazole series of MRP1 modulators have resulted in the identification of potent and selective inhibitors containing cyclohexyl-based linkers. These studies ultimately identified compound 21b, which reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC50 =0.093μM), while showing no inherent cytotoxicity. Additionally, 21b inhibits ATP-dependent, MRP1-mediated LTC4 uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC50 =0.064μM) and shows selectivity (1115-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, 21b showed tumor regression and growth delay in MRP1-overexpressing tumors in vivo. [Copyright &y& Elsevier]

Dexamethasone, a synthetic corticosteroid, which can induce a range of mood disorders including depression and affective psychosis, is toxic to specific hippocampal and striatal neuronal populations. Chronic administration of antidepressants can induce neuroprotective effects, potentially by raising cellular levels of brain-derived neurotrophic factor (BDNF). We accordingly tested the hypothesis that chronic pretreatment of rats (Sprague–Dawley, male) with antidepressants would attenuate dexamethasone-induced neuronal damage as revealed by reductions in the level of neuronal death and in sublethal neuronal damage shown by the increase in the number of MAP-2 immunoreactive neurons. In support of this hypothesis, we demonstrate that chronic treatment with a range of antidepressants prior to dexamethasone administration (0.7 mg/kg, i.p.) attenuated the levels of neuronal death and loss of MAP-2 immunoreactivity in both the hippocampus and striatum. The antidepressants used were: desipramine (8 mg/kg, i.p., tricyclic), fluoxetine (8 mg/kg, i.p., selective serotonin reuptake inhibitor) and tranylcypromine (10 mg/kg, i.p., monoamine oxidase inhibitor) with each drug being injected once per day for 10 days. In contrast, acute injection of none of the antidepressants exerted a protective effect from dexamethasone-associated neuronal damage. Similarly, injection of neither cocaine nor chlordiazepoxide (benzodiazepine) exerted protective effects when injected either chronically or acutely. The observed protection from dexamethasone-induced neuronal damage is in keeping with the potential of chronic antidepressant medication to increase BDNF levels. The potential for dexamethasone to induce disorders of mood by damaging specific neuronal populations in the hippocampus and dorsomedial striatum is discussed. [Copyright &y& Elsevier]

Monoaminergic pathways are highly responsive to aversive stimuli and play a crucial role in the control of affect, cognition, endocrine secretion, chronobiotic rhythms, appetite, and motor function, all of which are profoundly disrupted in depressive states. Accordingly, a perturbation of monoaminergic transmission is implicated in the aetiology of depressive disorders, and all clinically available antidepressants increase corticolimbic availability of monoamines. However, their limited efficacy, delayed onset of action, and undesirable side effects underlie ongoing efforts to identify improved therapeutic agents. Sequencing the human genome has raised the hope not only of better symptomatic control of depression, but even of the prevention or cure of depressive states. In the pursuit of these goals, there is currently a tendency to focus on selective ligands of “novel” nonmonoaminergic targets. However, certain classes of novel agent (such as neurokinin1 receptor antagonists) indirectly modulate the activity of monoaminergic networks. Others may act “downstream” of them, converging onto common cellular substrates controlling gene expression, synaptic plasticity, and neurogenesis. Further, by analogy to the broad-based actions of currently employed drugs, multitarget agents may be better adapted than selective agents to the management of depression—a complex disorder with hereditary, developmental, and environmental origins. It is, thus, important to continue the creative exploration of clinically validated and innovative monoaminergic strategies within a multitarget framework. In this light, drugs combining monoaminergic and nonmonoaminergic mechanisms of action may be of particular interest. The present article provides a critical overview of monoaminergic strategies for the treatment of depressive states, both established and under development, and discusses interactions of novel “nonmonoaminergic” antidepressants with monoaminergic mechanisms. [Copyright &y& Elsevier]

We examined the effects of chronic activity wheel running and antidepressant treatment on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) in multiple brain regions—hippocampal formation (HF), ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and piriform cortex (PFx)—after bilateral olfactory bulbectomy (OBX). Male, Long-Evans rats (n=72) underwent either sham or OBX surgery and were randomly divided into eight experimental groups in a 2 (sham vs. OBX)×2 (sedentary vs. activity wheel)×2 (saline vs. imipramine) factorial design. Animals were killed after 21 days of treatment. Drug×exercise interaction effects were observed for HF (P=0.006–0.023) and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise, drug, or OBX (P>0.05). These results suggest that the effect of exercise on BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy, reported by other investigators, is time limited. [Copyright &y& Elsevier]

Echinofuran (1) was isolated in 1992 and was reported to inhibit cell division of fertilized sea urchin eggs. The synthesis of 1 was achieved by a Ring A→Ring AC→Ring ABC approach employing 3-methyl-4-(trimethylsilyl)furan (2) as a precursor. A Suzuki coupling reaction and a Lewis acid mediated Friedel-Crafts cyclization were the other key steps in the construction of the ring systems. In other preliminary model studies, two furan-containing 5,7,5-fused tricyclic molecules were also realized. [Copyright &y& Elsevier]

It has been suggested that early- and late-onset forms of obsessive–compulsive disorder (OCD) may stem from different neurobiological substrates manifesting themselves through particular phenotypic profiles. Our study aimed to assess the existence of clinical and therapeutic differences between adult patients with early- and late-onset OCD (EOCD and LOCD, respectively). Sixty-six patients with OCD were consecutively recruited among individuals seeking treatment in a university hospital clinic for anxiety and depressive disorders. Patients with EOCD (n=33) and LOCD (n=33) were compared and contrasted with regard to clinical and therapeutic characteristics using the two tailed t test for continuous variables and the Pearson''s goodness of fit Chi-square test for categorical ones; Fisher''s exact test was employed when indicated. We found that, compared to their LOCD counterparts, adult patients with EOCD were characterized by (1) male gender predominance, (2) greater number of clinically significant obsessions and compulsions, (3) higher frequency of rituals repetition, (4) increased severity of obsessive–compulsive symptoms at baseline, and (5) greater number of required therapeutic trials during the follow-up. However, no significant differences between groups were noted in the final treatment outcome. Our results are consistent with previous studies suggesting that EOCD may represent a more severe subtype of this disorder. [Copyright &y& Elsevier]

The “protein-only” mechanism by which infectious agents of prion diseases such as Creutzfeldt–Jakob disease and bovine spongiform encephalopathy replicate remains undetermined. The identification of several distinct classes of prion inhibitors has created an opportunity to investigate the mechanism of prion formation using pharmacological tools. These new inhibitors include substituted tricyclic derivatives, tetrapyrrole compounds, cysteine protease inhibitors, branched polyamines, and specific antibodies. Each inhibitor class contains at least one active compound that inhibits prion propagation in cell culture at sub-micromolar concentrations and several structurally related, inactive compounds. Work with branched polyamines and specific antibodies has already provided insight into the kinetics and cell biology of endogenous prion clearance mechanisms. Other anti-prion compounds do not appear to bind directly to the prion protein. Detailed investigation of the mechanism of drug action of these compounds may lead to the identification of novel prion propagation factors. [Copyright &y& Elsevier]

The chemotherapeutic drug Gemcitabine, 2′,2′-difluoro-2′-deoxycytidine, has long been the standard of care for a number of cancers. Gemcitabine’s chemotherapeutic properties stem from its 2′,2′-difluoro-2′-deoxyribose sugar, which mimics the natural nucleoside, but also disrupts nucleic acid synthesis, leading to cell death. As a result, numerous analogues have been prepared to further explore the biological implications for this structural modification. In that regard, a thieno-expanded guanosine analogue was of interest due to biological activity previously observed for the tricyclic heterobase scaffold. Several analogues were prepared, including the McGuigan ProTide, however the parent nucleoside exhibited the best chemotherapeutic activity, specifically against breast cancer cell lines (89.53% growth inhibition). [ABSTRACT FROM AUTHOR]

Abstract: SAR studies on the para-fluorobenzyl moiety of tricyclic HIV integrase inhibitors are discussed and lead compounds with potency and PK properties comparable to raltegravir were identified. [Copyright &y& Elsevier]

Abstract: A tricyclic ketone is formed from cyclohexanone and cyclohexenone in strong acid solutions. The structure is confirmed by X-ray crystallography. [Copyright &y& Elsevier]

Abstract: Perhydrophenanthrene-1,5,10-trione (6) was isolated from the reaction of methyl 3-(carboxymethyl)cyclohexanone and cyclohexenone in a tandem Michael–Claisen reaction. NMR and X-ray analysis confirmed the structure of the product. [Copyright &y& Elsevier]