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Brain rhythms provide the timing for recruitment of brain activity required for linking together neuronal ensembles engaged in specific tasks. The γ-oscillations (30 to 120 Hz) orchestrate neuronal circuits underlying cognitive processes and working memory. These oscillations are reduced in numerous neurological and psychiatric disorders, including early cognitive decline in Alzheimers disease (AD). Here, we report on a potent brain-permeable small molecule, DDL-920 that increases γ-oscillations and improves cognition/memory in a mouse model of AD, thus showing promise as a class of therapeutics for AD. We employed anatomical, in vitro and in vivo electrophysiological, and behavioral methods to examine the effects of our lead therapeutic candidate small molecule. As a novel in central nervous system pharmacotherapy, our lead molecule acts as a potent, efficacious, and selective negative allosteric modulator of the γ-aminobutyric acid type A receptors most likely assembled from α1β2δ subunits. These receptors, identified through anatomical and pharmacological means, underlie the tonic inhibition of parvalbumin (PV) expressing interneurons (PV+INs) critically involved in the generation of γ-oscillations. When orally administered twice daily for 2 wk, DDL-920 restored the cognitive/memory impairments of 3- to 4-mo-old AD model mice as measured by their performance in the Barnes maze. Our approach is unique as it is meant to enhance cognitive performance and working memory in a state-dependent manner by engaging and amplifying the brains endogenous γ-oscillations through enhancing the function of PV+INs.

Heteroatom‐embedded helical nanographenes (NGs) constitute an important and appealing class of intrinsically chiral materials. In this work, a series of B,N‐embedded helical NGs (BN‐HNGs) bearing azepines was synthesized via stepwise regioselective cyclodehydrogenation. First, the phenyl‐ or nitrogen‐bridged dimers were efficiently clipped into highly congested model compounds 1 and 2. Later, the controllable Scholl reactions of the tetraphenyl‐tethered precursor generated 1, 7 or 8 new C−C bonds, thereby establishing a robust method for the preparation of nonalternant BN‐HNGs with up to 31 fused rings. The helical bilayer nature was unambiguously verified by X‐ray diffraction analysis. The helical chirality was transferred to the stereogenic boron centers upon fluoride coordination, with a concave‐concave structure to comply with the bilayer skeleton. Notably, the largest nonalternant BN‐HNG (6) spontaneously resolved into a homochiral 41 helix structure as a molecular spiral staircase during crystallization via conglomerate formation at the single‐crystal scale. The large twisted C2‐symmetric π‐surface and the dynamic chiral skeleton induced by curved azepines might have synergistic effects on self‐recognition of enantiomers of 6 to achieve the intriguing spontaneous resolution behavior. The chiroptical properties of the enantiomer of 6 were further investigated, revealing that 6 had a strong chiroptical response in the visible range (400–700 nm). [ABSTRACT FROM AUTHOR]

Background: Rauvolfia vomitoria (R. vomitoria) is a plant of economic importance due to its diverse ethnomedicinal properties, including the anticonvulsant effect. In this study, we studied the antiseizure and neuroprotective potentials of R. vomitoria extracts against pentylenetetrazol (PTZ)-induced kindling. Methods: Twenty-five adult Swiss mice (25–30 g) were assigned to five groups (n = 5): control group, PTZ treatment group, and PTZ treatment after receiving oral R. vomitoria crude extract (100 mg/kg), R. vomitoria phenol extract (50 mg/kg) or sodium valproate (15 mg/kg) every 48 h for 28 days. Seizure scores, cognitive behavioral tests including novel object test, Y-maze test, and the elevated plus maze test, as well as brain neurochemicals and histomorphology studies, were performed. Results: Compared with the control group, the PTZ group showed comparable body weight and durations in closed and open arms (P > 0.05), but preference for familiar objects, significant (P < 0.05) spontaneous alternation, increased monoamine oxidase activity and nitric oxide level, and Nissl chromatolysis in the temporal lobe structures including the cortex, hippocampus, and amygdala. R. vomitoria phenol extract pretreatment significantly (P < 0.05) reduced seizures, prevented adverse cognitive behaviors, decreased the nitric oxide level, and reduced the temporal lobe Nissl chromatolysis compared with the R. vomitoria crude extract pretreatment group and the sodium valproate pretreatment groups. Conclusions: Thus, R. vomitoria phenol extract showed promising results against seizures and potential for general brain protection, suggesting that the anticonvulsant property of R. vomitoria may be attributed to its phenol constituent. More studies are needed to delineate the mechanisms of its action. [ABSTRACT FROM AUTHOR]

This paper outlines a novel strategy for the preparation of seven-membered-ring lactams from simple nitroarenes. The approach is based on a photochemical dearomative ring expansion starting with the conversion of the nitro group into a singlet nitrene. This process is mediated by blue light, occurs at room temperature and overall enables the insertion of the nitro N -atom into the benzenoid framework. This step transforms the aromatic starting material into a seven-membered ring azepine that, following hydrogenation and hydrolysis, is converted into the desired caprolactams in just three steps. [ABSTRACT FROM AUTHOR]

A new and efficient strategy for the stereoselective synthesis of tetrahydropyridino- and deazepanopyrrolo[1,2- c ]imidazolidines has been developed. Annulation of acylethynylpyrroles with six- and seven-membered cyclic imines (MeCN/THF, 20–25 °C, 24–72 h) leads to tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2- a ]pyridines and hexahydropyrrolo[1′,2′:3,4]imidazo[1,2- a ]azepines with (E)-acylethenyl moiety in 28–96% yields. [ABSTRACT FROM AUTHOR]

Vitamin B7(biotin) is not synthesized in our body and is retrieved from some food products like eggs, liver, pork and leafy vegetables and as well as microbes of gut. Deficiency of biotin majorly leads to loss of hair, rashes over skin, lethargy and seizures. It is noted that biotin is an anti-oxidant and negates free radical effects. Biotin is also involved in carbon dioxide metabolism and it might alter seizure threshold. Studies also suggest its effect on lipid metabolism as well. So, the primary objective of this study was to assess the efficacy of biotin in maximal electric shock (MES) induced generalized tonic-clonic seizures (GTCS) and pentylenetetrazole (PTZ) induced absence seizures. The secondary objective is to study the effect of combined treatment of biotin and sodium valproate on seizures as well as plasma lipid profile in rats. In our study 30 albino Wistar rats each were used in MES and PTZ model respectively. 30 rats were divided equally into following groups: I – distilled water (negative control) II – distilled water (positive control) III – sodium valproate (300 mg/kg) IV – biotin (10 mg/kg/day) V – biotin (10 mg/kg) + sodium valproate (150 mg/kg). We observed that the tonic hind limb extension was significantly reduced in the treatment group in MES model. Nitric oxide levels were also seen raised in combination group in MES model and all the treated groups in PTZ model. Biotin treated group showed increased high-density lipoproteins and reduced low density lipoproteins and triglycerides. Biotin had an additive effect to sodium valproate in both the models of epilepsy in rats. Further, it was also able to counteract hyperlipidemia cause by sodium valproate. [ABSTRACT FROM AUTHOR]

BACKGROUND: Recurrent atypical teratoid/rhabdoid tumor (AT/RT) is, most often, a fatal pediatric malignancy with limited curative options. METHODS: We conducted a phase II study of Aurora kinase A inhibitor alisertib in patients aged 12 months. PFS did not differ by AT/RT molecular groups. Neutropenia was the most common adverse effect (n = 23/30, 77%). The 22 patients who received liquid formulation had a higher mean maximum concentration (Cmax) of 10.1 ± 3.0 µM and faster time to Cmax (Tmax = 1.2 ± 0.7 h) than those who received tablets (Cmax = 5.7 ± 2.4 µM, Tmax = 3.4 ± 1.4 h). CONCLUSIONS: Although the study did not meet predetermined efficacy end point, single-agent alisertib was well tolerated by children with recurrent AT/RT, and SD or PR was observed in approximately a third of the patients.

The research focused on the photolysis of ortho‐ and para‐substituted aryl azides and the preparation of 2‐arylamino‐substituted azepines. The best results were achieved in 1,4‐dioxane for ortho‐substituted azides and in ethanol for para‐substituted azides, respectively. It was found that reactions with arylamines, which have electron‐donating groups, typically produce higher yields of heterocycles than those with electron‐withdrawing groups. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The azepine ring is a prominent structural scaffold in biologically significant molecules. In this study, we present a Ni(II)‐catalyzed asymmetric difunctionalization of alkynes, involving intermolecular regioselective arylation and intramolecular nitrile addition, enabling the synthesis of enantioenriched azepine derivatives. This reaction simultaneously installs an all‐carbon quaternary stereocenter and introduces an unprotected imine functionality, showing great promise for subsequent transformations. The reaction exhibits good tolerance toward various functional groups, resulting in high yields and enantioselectivities. The synthetic utility of this methodology is further demonstrated through gram‐scale synthesis and product derivatization. This research offers an efficient approach to the synthesis of seven‐membered nitrogen heterocycles. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The azepine ring is a prominent structural scaffold in biologically significant molecules. In this study, we present a Ni(II)‐catalyzed asymmetric difunctionalization of alkynes, involving intermolecular regioselective arylation and intramolecular nitrile addition, enabling the synthesis of enantioenriched azepine derivatives. This reaction simultaneously installs an all‐carbon quaternary stereocenter and introduces an unprotected imine functionality, showing great promise for subsequent transformations. The reaction exhibits good tolerance toward various functional groups, resulting in high yields and enantioselectivities. The synthetic utility of this methodology is further demonstrated through gram‐scale synthesis and product derivatization. This research offers an efficient approach to the synthesis of seven‐membered nitrogen heterocycles. [ABSTRACT FROM AUTHOR]

In this article, a hitherto unreported catalyst-free ring expansion reaction of tetrahydroisoquinolines with o-alkynylarylaldehydes for the construction of the dibenzo[b,d]azepine skeleton is described. Using air as a "green" oxidant, some important biologically active dibenzo[b,d]azepines were produced with favorable functional group tolerance and a wide substrate scope. The synthetic potential was further confirmed by facile scale-up reactions and the synthesis of isoindoline derivatives. [ABSTRACT FROM AUTHOR]

Dibenzoazepine, dibenzoxazepine and dibenzothiazepine scaffolds are an important class of N‐heterocycles that possess multiple biological activities. Due to the widespread application of these motifs in drug discovery, the synthesis of tri‐cyclic seven‐membered imines/amines has gained huge attention of chemists. In the present review, we have highlighted recent advances in functionalization and cyclization reactions of these valuable organic compounds over the last six years. [ABSTRACT FROM AUTHOR]

A novel strategy in which palladium(II)-catalyzed tandem cyclization is used to obtain N-heterocyclic architectures containing a seven-membered ring has been developed and used to synthesize a series of derivatives. The reaction uses an eco-friendly mixed solvent (water : EtOH = 2 : 1) instead of DMSO and maintains a high yield (91%). Its potential application value and reaction mechanism have also been explored. [ABSTRACT FROM AUTHOR]

PurposeAurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion.MethodsKey inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles.ResultsIn total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration.ConclusionsThis trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.

A series of novel azepine derivatives based on quinazolinone moiety was synthesized through the reaction of quinazolinone chalcones (2a–d) either with 2-amino aniline in acidic medium to give diazepines (3a–d) or with 2-aminophenol to offer oxazepine (4a–d). The structure of the synthesized compounds was confirmed via melting points, elemental analyses, and different spectroscopic techniques. Moreover, these newly compounds mode of action was investigated in-silico using molecular docking against the outer membrane protein A (OMPA), exo-1,3-beta-glucanase for their antimicrobial activity, and against Smoothened (SMO), transcription factor glioma-associated homology (SUFU/GLI-1), the main proteins of Hedgehog signaling pathway to inspect their anticancer potential. Our results showed that, diazepine (3a) and oxazepine (4a) offered the highest binding energy against the target OMPA/ exo-1,3-beta-glucanase proteins and exhibited the potent antimicrobial activities against E. coli, P. aeruginosa, S. aureus, B. subtilis, C. Albicans and A. flavus. As well, diazepine (3a) and oxazepine (4a) achieved the best results among the other compounds, in their binding energy against the target SMO, SUFU/GLI-1 proteins. The in-vitro cytotoxic study was done for them on panel of cancer cell lines HCT-116, HepG2, and MCF-7 and normal cell line WI-38. Conclusively, it was revealed that molecular docking in-silico simulations and the in-vitro experiments were agreed. As a result, our findings elucidated that diazepine (3a) and oxazepine (4a), have the potential to be used as antimicrobial agents and as possible cancer treatment medications. [ABSTRACT FROM AUTHOR]

The first enantioselective reduction of 2‐substituted cyclic imines to the corresponding amines (pyrrolidines, piperidines, and azepines) by imine reductases (IREDs) in non‐conventional solvents is reported. The best results were obtained in a glycerol/phosphate buffer 1 : 1 mixture, in which heterocyclic amines were produced with full conversions (>99 %), moderate to good yields (22–84 %) and excellent S‐enantioselectivities (up to >99 % ee). Remarkably, the process can be performed at a 100 mM substrate loading, which, for the model compound, means a concentration of 14.5 g L−1. A fed‐batch protocol was also developed for a convenient scale‐up transformation, and one millimole of substrate 1 a was readily converted into 120 mg of enantiopure amine (S)‐2 a with a remarkable 80 % overall yield. This aspect strongly contributes to making the process potentially attractive for large‐scale applications in terms of economic and environmental sustainability for a good number of substrates used to produce enantiopure cyclic amines of high pharmaceutical interest. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: A phosphine‐catalyzed [4+3] annulation between dinucleophilic indole derivatives and Morita−Baylis−Hillman (MBH) carbonates was discovered by using the N1 and N4′/C4′ nucleophilicities of the indole precursors, in which indoles act as four atom synthons. This protocol provides an efficient and facile access to indole‐1,2‐fused 1,4‐diazepinones and azepines in good to high yields in one step, which illustrates potential synthetic utilities in drug discovery. [ABSTRACT FROM AUTHOR]

This review article discusses the recent progress in synthesizing seven-membered ring 1,3,5-triazepine and benzo[f][1,3,5]triazepine derivatives. These derivatives can be either unsaturated, saturated, fused, or separated. This review covers strategies and procedures developed over the past two decades, including cyclo-condensation, cyclization, methylation, chlorination, alkylation, addition, cross-coupling, ring expansions, and ring-closing metathesis. This review discusses the synthesis of 1,3,5-triazepine derivatives using nucleophilic or electrophilic substitution reactions with various reagents such as o-phenylenediamine, 2-aminobenzamide, isothiocyanates, pyrazoles, thiazoles, oxadiazoles, oxadiazepines, and hydrazonoyl chloride. This article systematically presents new approaches and techniques for preparing these compounds. It also highlights the biological importance of benzo[f][1,3,5]triazepine derivatives, which have been used as drugs for treating nervous system diseases. This review aims to provide researchers with the necessary information to create and develop new derivatives of these compounds as quickly as possible. [ABSTRACT FROM AUTHOR]

Objective: This study involved the synthesis of new Schiff bases and 1,3-oxazepine derivatives from the baclofen drug and study the anticancer activities. Methods: Baclofen was initially reacted with aromatic aldehydes to create Schiff base derivatives (Ia–Ib), which were then closed in the next step using anhydrous acids to form oxazepine derivatives (IIa–IId). Results: The title compounds were synthesized successfully and identified using FT-IR, 1H NMR, and 13C NMR spectroscopy. Additionally, compound (IIc)'s (3-(4-chloro-phenyl)-4-[2-(4nitro-phenyl)-4,7-dioxo-4,7-dihydro-[1,3] oxazepin-3-yl]butyric acid) anticancer activity was assessed using MTT assay against FTC-133 (thyroid cancer) compared with WRL-68 (normal cell line). Discussion: The results showed that the viability of the FTC-133 cell was found to be greatest at 12.5 g/mL (96.52 ± 0.70) and lowest at 400 g/mL (35.378 ± 5.07). The effect of compound (IIc) on the normalizing of the WRL-68 cell line resulted in an IC50 for 62.39 ϻg/mL. Conclusions: It has been found that the compound (IIc) has good efficiency against thyroid cancer (FTC-133). [ABSTRACT FROM AUTHOR]

This perspective article describes the recent progress in the total syntheses of iheyamines A and B. Since iheyamine A possesses a highly unique unsymmetrical azepino‐2,2'‐bisindole scaffold, novel strategies to construct the basic scaffold have been developed, and unique total syntheses have been reported based on these strategies. In addition, because iheyamine B bears vicinal 2‐oxopropyl moieties with a trans‐configuration in the azepine scaffold of iheyamine A, the first asymmetric total synthesis of iheyamine B took a substantially longer time than iheyamine A to complete. Due to the unusual structure of iheyamine B and some discrepancies in the experimental data between the isolated and synthesized iheyamine B, some controversial issues regarding whether iheyamine B is a natural product or an artifact have been raised and will be discussed. [ABSTRACT FROM AUTHOR]

A novel series of 5-[(1-aryl-1H-1,2,3-triazol-4-yl)methyl]-10,11-dihydro-5H-dibenzo[b,f]azepine derivatives were synthesized by employing click chemistry approach starting from 10,11-dihydro-5H-dibenzo-[b,f]azepine and evaluated for their cytotoxicity against a panel of three cancer cell lines (SiHa, MDA-MB-231, PANC-1). Many of the tested compounds exhibited significant anticancer activity, and compound 4g was found to be the most promising analogue in this series. [ABSTRACT FROM AUTHOR]

Peganum harmala L. and Lavandula angustifolia are two traditional herbs with probable antiseizure effects. This study evaluated the effects of these two herbal extracts on pentylenetetrazol- (PTZ-) induced seizures in mice. We prepared hydroalcoholic extracts using P. harmala seeds and the aerial parts of L. angustifolia and then randomly divided 190 mice into 19 groups. Normal saline (10 mg/kg), diazepam (2 mg/kg), P. harmala (2.5, 5, 10, 15, 30, 45, and 60 mg/kg), and L. angustifolia (200, 400, 600, and 800 mg/kg) were intraperitoneally (IP) administrated 30 min before an IP administration of PTZ (90 mg/kg). Animals were observed for behavioral changes for one hour. In addition, the effects of flumazenil and naloxone on the antiseizure activity of P. harmala and L. angustifolia were assessed. P. harmala showed antiseizure activity at the dose of 10 mg/kg; it prolonged the seizure latency and decreased the seizure duration. The mortality protection rate was 90% for this herbal extract. L. angustifolia (600 mg/kg) prolonged the seizure latency and decreased both seizure duration and mortality. Neither flumazenil nor naloxone significantly reversed the antiseizure activities of P. harmala and L. angustifolia. In mice, the hydroalcoholic extracts of P. harmala and L. angustifolia showed antiseizure activity against PTZ-induced seizures. We could not delineate the exact antiseizure mechanisms of these extracts in the current study. [ABSTRACT FROM AUTHOR]

A cascade [4+3] annulation of o‐alkenyl bromoarenes and o‐bromoaniline derivatives was described. Various dibenzo[b,f]azepines with substitutions on the 10/11 position were obtained in 14–97% yields. The synthetic versatility of this protocol is highlighted by the preparation of a precursor of the drug molecule oxcarbazepine, a gram‐scale synthesis, and two product transformations. Unlike previous amination/Heck sequence, this cascade process is supposed to undergo a C(vinyl), C(aryl)‐palladacycle involved pathway. [ABSTRACT FROM AUTHOR]

We here disclose that the incorporation of thiophene rings into a seven‐membered 8π azepine in a fused fashion produces a useful antiaromatic core for near‐infrared (NIR) dyes. In contrast to dibenzazepine derivatives with bent structures, dithieno‐fused derivatives with electron‐accepting groups adopt flat conformations in the ground state. The dithieno‐fused derivatives exhibited broad absorption spectra that cover the visible region as well as sharp emission bands in the NIR region, which are considerably red‐shifted relative to those of the dibenzo‐fused congeners. Theoretical study revealed two contradictory effects of the less‐aromatic thiophene‐fused structure, i.e. the enhancement of the antiaromaticity of the adjacent azepine ring and the relief of the antiaromaticity through the contribution of a quinoidal resonance form. The combination of the dithienoazepine core with cationic electron‐accepting groups produced a NIR fluorescent dye with an emission at 878 nm in solution. [ABSTRACT FROM AUTHOR]

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a–g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e). Two novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. 5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM). 5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM). In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment. [ABSTRACT FROM AUTHOR]

A one-pot synthesis approach to access sulfonamide-containing derivatives of dibenzo[1,4]thiazepine using primary amines and 2-[(2-nitro-4-sulfamoylphenyl)sulfanyl]benzoic acid as precursors was developed. The approach is based on a sequence of amidation steps and the subsequent tandem of the Smiles rearrangement and denitrocyclization reaction. The resulting tricyclic systems showed pronounced activity as inhibitors of bovine carbonic anhydrase isoform II. [ABSTRACT FROM AUTHOR]

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug-sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by >30-fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.

C40H39ClN2, monoclinic, P21/c (no. 14), a = 14.6448(2) Å, b = 11.1193(2) Å, c = 19.9769(4) Å, β = 98.741(2)°, V = 3215.25(10) Å3, Z = 4, Rgt(F) = 0.0559, wRref(F2) = 0.1614, T = 200 K. [ABSTRACT FROM AUTHOR]

C40H39ClN2, monoclinic, P21/c (no. 14), a = 14.6448(2) Å, b = 11.1193(2) Å, c = 19.9769(4) Å, β = 98.741(2)°, V = 3215.25(10) Å3, Z = 4, Rgt(F) = 0.0559, wRref(F2) = 0.1614, T = 200 K. [ABSTRACT FROM AUTHOR]

[Display omitted] A simple and effective stereoselective synthesis of unique azaspirocyclic 2,3,4,7-tetrahydro-1 H -azepine derivatives, namely, 7-azaspiro[4.6]undec-9-ene and 8-azaspiro[5.6]- dodec-10-ene, from simple commercially available reagents was accomplished. Their key 1,2-epoxy derivatives as individual diastereomers were obtained in nine steps with 31–32% overall yields. The possibility of synthesizing a library of small spiroheterocyclic molecules was exemplified by the N -Boc-protected (1 RS ,2 SR ,6 RS)-1,2-epoxy-8-aza- spiro[5.6]dodec-10-ene scaffold through simple chemical modifications of its epoxide function. [ABSTRACT FROM AUTHOR]

IntroductionInsomnia diagnosis has been associated with a significant clinical and economic burden on patients and healthcare systems. This study examined changes in healthcare resource use (HCRU) and costs in insomnia patients before and after initiation of suvorexant treatment.MethodsThis retrospective cohort study analyzed Optum Clinformatics Data Mart claims data (Jan 2010-Dec 2018). Patients with ≥ 2 insomnia diagnosis claims and ≥ 1 prescription for suvorexant were included. Prevalent and incident insomnia patients were analyzed separately. The change in the trends of HCRU and costs were examined for 12 months before and 12 months after suvorexant initiation. An interrupted time series (ITS) analysis was conducted to assess the level and slope changes. Subgroups of patients with mental health comorbidities were examined.ResultsThe study included 18,919 and 5939 patients in the prevalent and incident insomnia cohorts, respectively. For the prevalent cohort, mean (SD) age was 64.5 (14.1) years, 65% were female, 74% had Medicare Advantage coverage, and 61% had a Charlson comorbidity index score ≥ 1. Characteristics for the incident cohort were similar. The ITS results suggested that the trend for monthly total healthcare cost (THC) was increasing before suvorexant initiation (US$52.51 in the prevalent cohort, $74.93 in incident insomnia cohort), but, after suvorexant initiation, the monthly total cost showed a decreasing trend in both cohorts. The decrease in slope for THC after suvorexant initiation were $72.66 and $112.07 per month in the prevalent and incident cohorts, respectively. The monthly trends in HCRU rates also decreased. The subgroup analysis showed that decreases were 1.5-3 times greater for patients with mental health comorbidities.ConclusionsIn this real-world study, suvorexant initiation was associated with immediate and continued decreases in HCRU and costs in insomnia patients. Further research is needed to understand the effect of suvorexant initiation on direct medical costs as well as costs associated with lost productivity in other real-world settings.

Background: Epilepsy is a chronic neurological condition that disrupts the normal functioning of the brain and it is characterized by seizures. Research suggests the involvement of the Gut-Brain axis in epilepsy. This study seeks to determine the role of the gut microbiota in the anticonvulsant effect of basil oil (BO) using antibiotic-depleted and altered germ-free mice against naïve mice in Pentylenetetrazole (PTZ) induced seizure model. There is an ever growing interest in improvement of treatment outcomes in epilepsy and also in the development of newer therapeutic options, especially in the population of patients that do not attain seizure relief from available antiseizure medications (ASMs). According to research, gut microbiota can alter brain function and development. Increasing evidence suggests disrupting the delicate symbiotic balance existing between the gut and brain results in disease conditions. Also, the oil from Ocimum basilicum L., (BO) has been proven scientifically to significantly block clonic seizures induced by PTZ and picrotoxin in seizure models. Methods: The microbiota of mice were depleted or altered by administering cocktail antibiotics and individual antibiotics respectively. DNA was isolated from mouse stool, and then the 16S ribosomal ribonucleic acid (16S rRNA) gene was quantitatively amplified using reverse transcription-polymerase chain reaction (RT-PCR). Amplicons were sequenced to determine the phylogenetic make-up of the bacteria involved. Metabolic profiles of the serum and stool of mice were determined using Proton (1H) Nuclear Magnetic Resonance (NMR) spectroscopy. Results: Cocktail antibiotic pre-treatment significantly reversed the anticonvulsant effect of BO by increasing frequency and duration of seizures but did not affect latency to seizure. In mice pre-treated with single antibiotics, the anticonvulsant effect of BO was lost as latency to seizures, frequency and duration of seizures increased compared to mice that received only BO. Assessment of the phylogenetic make-up of the microbiota in antibiotic pre-treated mice showed a distorted composition of the microbiota compared to the control group. Conclusion: Depletion of the microbiota significantly reversed the anticonvulsant actions of BO. The concentrations of short chain fatty acids (SCFAs) was higher in stool than in the serum of the mice. Administration of BO probably does not influence the microbial composition within the mouse microbiota. The elevated ratio of Firmicutes to Bacteroidetes in microbiota-depleted groups might have contributed to the reversal of anticonvulsant actions of BO. [ABSTRACT FROM AUTHOR]

A new two-step, one-pot synthesis of benzo[f][1,2]thiazepine 1,1-dioxides was developed, which contains a visible-light mediated aza Paternò–Büchi reaction of benzo[d]isothiazole 1,1-dioxides with alkenes and a Lewis acid catalyzed ring-expansion of azetidine. In this work, the mechanism of the aza Paternò–Büchi reaction was also investigated. [ABSTRACT FROM AUTHOR]

The objective of this work was to synthesize new 1,3-oxazepine derivatives and evaluate the antioxidant activity of the synthesized compounds. The synthesis of Schiff's base of oxazepine was achieved in four steps involving condensation of aniline and benzaldehyde followed by (2+5) cycloaddition occurs between the imine and anhydride leading to the formation of 1,3-oxazepine-4,7-dione. Later the oxazepine dione undergoes condensation with thiosemicarbazide and finally nucleophilic addition of active carbonyl group to form Schiff's bases. The synthesized compounds 8a-e were obtained in yield ranging from 69-77%. The antioxidant activity of the compounds was evaluated at various concentrations (100-500 µg/mL) using DPPH radical scavenging assay and hydroxy radical scavenging assay. The compounds had IC50 in the range of 34.297 µg to 131.04 µg in the DPPH scavenging assay whereas the IC50 ranged of 49.943 µg to 153.13 µg in the hydroxy radical scavenging assay. [ABSTRACT FROM AUTHOR]

Energy-intensive compounds AzCH3, 7-methyl-7Н-trifurazano[3,4-b:3′,4′-f:3″,4″-d]azepine, and Az(O)CH3, 7-methyl-7Н-difurazano[ 3,4-b:3′,4′-f]furoxano[3″,4″-d]azepine, are extensively studied as potential dispersants in gas-generating fuels. The main parameters of the crystal lattice are determined by X‑ray diffraction analysis and experimental data on the heats of combustion and enthalpies of the formation of AzCH3 and Az(O)CH3 are obtained. A thermodynamic analysis of the effectiveness of these compounds in gas-generating fuels is carried out. It is shown that AzCH3 and Az(O)CH3 are very effective as potential dispersants of solid fuels for gas generator engines. [ABSTRACT FROM AUTHOR]

SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 8.09 (d, I J i = 8.7 Hz, 1 H), 7.77 (d, I J i = 8.0 Hz, 1 H), 7.69 (d, I J i = 8.8 Hz, 1 H), 7.49 (t, I J i = 7.3 Hz, 1 H), 7.38-7.30 (m, 2 H), 4.32 (s, 1 H), 3.86-3.63 (m, 2 H), 3.22-3.14 (m, 1 H), 3.14-3.03 (m, 1 H), 3.00 (s, 3 H), 2.72-2.58 (m, 2 H), 2.14-1.97 (m, 2 H), 1.71 (t, I J i = 12.7 Hz, 1 H), 1.66-1.57 (m, 1 H), 1.04 (t, I J i = 7.1 Hz, 3 H). SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 6.97 (d, I J i = 7.8 Hz, 1 H), 6.84 (d, I J i = 9.7 Hz, 2 H), 4.10-3.91 (m, 2 H), 3.25 (p, I J i = 6.0 Hz, 1 H), 3.03-2.85 (m, 2 H), 2.82 (s, 3 H), 2.71 (t, I J i = 11.9 Hz, 1 H), 2.51-2.38 (m, 1 H), 2.27 (s, 3 H), 1.93-1.68 (m, 3 H), 1.60 (d, I J i = 13.1 Hz, 1 H), 1.23 (t, I J i = 7.0 Hz, 3 H). SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = (isomer 1) = 7.18 (q, I J i = 7.9 Hz, 1 H), 7.11-7.05 (m, 1 H), 6.98-6.87 (m, 2 H), 4.93 (ddd, I J i = 49.2, 7.8, 4.9 Hz, 1 H), 4.23-4.09 (m, 2 H), 3.34-3.25 (m, 1 H), 3.02-2.91 (m, 1 H), 2.90-2.79 (m, 1 H), 2.85 (s, 3 H), 2.79-2.62 (m, 1 H), 2.51-2.29 (m, 1 H), 1.85-1.72 (m, 2 H), 1.71-1.58 (m, 2 H), 1.28 (t, I J i = 7.1 Hz, 3 H); (isomer 2) = 7.18 (q, I J i = 7.8 Hz, 1 H), 7.11-7.05 (m, 1 H), 6.98-6.87 (m, 2 H), 4.54 (ddd, I J i = 49.8, 10.7, 2.6 Hz, 1 H), 4.23-4.09 (m, 2 H), 3.34-3.25 (m, 1 H), 3.02-2.91 (m, 1 H), 2.90-2.79 (m, 1 H), 2.84 (s, 3 H), 2.51-2.29 (m, 1 H), 2.06-1.92 (m, 1 H), 1.85-1.72 (m, 2 H), 1.71-1.58 (m, 2 H), 1.27 (t, I J i = 7.1 Hz, 3 H). SP 1 sp H NMR (400 MHz, CDCl SB 3 sb ): = 7.17 (dd, I J i = 8.5, 2.0 Hz, 1 H), 7.07 (d, I J i = 2.0 Hz, 1 H), 6.71 (d, I J i = 8.5 Hz, 1 H), 4.01 (q, I J i = 7.0 Hz, 2 H), 3.18 (p, I J i = 5.3 Hz, 1 H), 2.95-2.76 (m, 2 H), 2.73 (s, 3 H), 2.72-2.63 (m, 1 H), 2.38-2.25 (m, 1 H), 1.78-1.60 (m, 3 H), 1.59-1.50 (m, 1 H), 1.19 (t, I J i = 7.1 Hz, 3 H). [Extracted from the article]

PurposeAurora kinases are overexpressed or amplified in numerous malignancies. This study was designed to determine the safety and tolerability of the Aurora A kinase inhibitor alisertib (MLN8237) when combined with weekly irinotecan.MethodsIn this single-center phase 1 study, adult patients with refractory advanced solid tumors received 100 mg/m2 irinotecan intravenously on day 1 and 8 of a 21-day cycle. Alisertib at planned escalating dose levels of 20-60 mg was administered orally twice per day on days 1-3 and 8-10. Patients homozygous for UGT1A1*28 were excluded. The primary objective was the safety of alisertib when combined with irinotecan to determine the maximum tolerated dose (MTD). Secondary objectives included overall response rate by RECIST and pharmacokinetics in a planned expansion cohort of patients with colorectal cancer treated at the MTD.ResultsA total of 17 patients enrolled at three dose levels. Dose-limiting toxicities included diarrhea, dehydration, and neutropenia. The MTD of alisertib combined with weekly irinotecan was 20 mg twice per day on days 1-3 and 8-10. One fatal cardiac arrest at the highest dose level tested was deemed possibly related to drug treatment. One partial response in 11 efficacy evaluable patients (9%) occurred in a patient with small cell lung cancer. The study was terminated prior to the planned expansion in patients with colorectal cancer.ConclusionIn contrast to prior results in a pediatric population, adult patients did not tolerate alisertib combined with irinotecan at clinically meaningful doses due to hematologic and gastrointestinal toxicities. The study was registered with ClinicalTrials.gov under study number NCT01923337 on Aug 15, 2013.

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined for their ability to compete with JQ1 in BRDT and BRD4 bromodomain AlphaScreen assays. These studies identified CDD-1102 as a selective BRDT-BD2 inhibitor with low nanomolar potency and >1,000-fold selectivity over BRDT-BD1. Structure-activity relationship studies of CDD-1102 produced a series of additional BRDT-BD2/BRD4-BD2 selective inhibitors, including CDD-1302, a truncated analog of CDD-1102 with similar activity, and CDD-1349, an analog with sixfold selectivity for BRDT-BD2 versus BRD4-BD2. BROMOscan bromodomain profiling confirmed the great affinity and selectivity of CDD-1102 and CDD-1302 on all BET BD2 versus BD1 with the highest affinity for BRDT-BD2. Cocrystals of BRDT-BD2 with CDD-1102 and CDD-1302 were determined at 2.27 and 1.90 Å resolution, respectively, and revealed BRDT-BD2 specific contacts that explain the high affinity and selectivity of these compounds. These BD2-specific compounds and their binding to BRDT-BD2 are unique compared with recent reports and enable further evaluation of their nonhormonal contraceptive potential in vitro and in vivo.

ObjectiveJoint injury rapidly induces expression of primary response genes (PRGs), which activate a cascade of secondary genes that destroy joint tissues and initiate post-traumatic osteoarthritis (PTOA). Bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9) cooperatively control the rate-limiting step of PRG transactivation, including pro-inflammatory genes. This study investigated whether Brd4 and CDK9 inhibitors suppress inflammation and prevent PTOA development in vitro and in a mouse PTOA model.MethodsThe effects of Brd4 and CDK9 inhibitors (JQ1 and Flavopiridol) on PRG and associated secondary damage were rigorously tested in different settings. Short-term effects of inflammatory stimuli (IL-1β, IL-6, TNF) on human chondrocyte PRG expression were assessed by RT-PCR and microarray after 5-h. We quantified glycosaminoglycan release from IL-1β-treated bovine cartilage explants after 3-6 days, and osteoarthritic changes in mice after ACL-rupture using RT-PCR (2-24hrs), in vivo imaging of MMP activity (24hrs), AFM-nanoindentation (3-7days), and histology (3days-4wks).ResultsFlavopiridol and JQ1 inhibitors act synergistically, and a combination of both almost completely prevented the activation of most IL-1β-induced PRGs in vitro by microarray analysis, and prevented IL-1β-induced glycosaminoglycan release from cartilage explants. Mice given the drug combination showed reduced IL-1β and IL-6 expression, less in vivo MMP activity, and lower synovitis (1.5 vs 4.9) and OARSI scores (2.8 vs 6.0) than untreated mice with ACL-rupture.ConclusionsJQ1 and Flavopiridol work synergistically to reduce injury response after joint trauma, suggesting that targeting Brd4 and/or CDK9 could be a viable strategy for PTOA prevention and treatment of early OA.

Targeted protein degradation (TPD) has emerged as a powerful tool in drug discovery for the perturbation of protein levels using heterobifunctional small molecules. E3 ligase recruiters remain central to this process yet relatively few have been identified relative to the ~ 600 predicted human E3 ligases. While, initial recruiters have utilized non-covalent chemistry for protein binding, very recently covalent engagement to novel E3's has proven fruitful in TPD application. Herein we demonstrate efficient proteasome-mediated degradation of BRD4 by a bifunctional small molecule linking the KEAP1-Nrf2 activator bardoxolone to a BRD4 inhibitor JQ1.

The novel synthetic approach was employed to synthesize a series of 1,8‐dihydropyrazolo[3,4‐b]azepine derivatives from 5‐aminopyrazoles in three‐step synthesis. The structures of the individual derivatives were unambiguously confirmed by spectral methods, including heteronuclear 1H−13C HMBC spectra and other necessary 2D NMR experiments. The obtained pyrazoloazepines and starting aminopyrazoles were subsequently investigated for their potential cytotoxic effect using mouse and human leukemia cell models. The original L1210 (mouse lymphoblastic), MOLM‐13, and SKM‐1 (both human myeloblastic) cell lines and their P‐glycoprotein (P‐gp) expressing cell variants were used. Aminopyrazole 8 was the most effective on murine leukemic lymphoblasts (L1210), while it had a greater effect on P‐gp expressing cells. In contrast, on human leukemic myeloblasts (MOLM‐13, SKM‐1), Aminopyrazoles 10 showed the most pronounced effect, but this was independent of the presence of P‐gp in the cells. [ABSTRACT FROM AUTHOR]

Highly efficient asymmetric hydrogenation of dibenzo[b,f][1,4]oxazepine, dibenzo[b,f][1,4]thiazepine and dibenzo[b,e]azepine derivatives with chiral cationic ruthenium diamine catalysts has been developed, giving diverse chiral seven-membered N-heterocycles with excellent results (up to 99% yield and 99% ee). Moreover, it was found that the catalyst counteranion regulated the enantioselectivity obviously in the hydrogenation of dibenzo[b,f][1,4]thiazepine and dibenzo[b,e]azepine derivatives. [ABSTRACT FROM AUTHOR]

We report an unprecedented atom-economic one-pot Cp*Rh(III)-catalyzed regioselective [3+2]-spiroannulation reaction between dibenz(ox)azepines and ynones, allowing the synthesis of biologically relevant novel spirocyclic dibenz(ox)azepines under operationally simple and mild reaction conditions. The reaction proceeds without any silver additive or external oxidant implementing a redox-neutral pathway. A broad substrate scope with diverse functional group tolerance permitted the regioselective synthesis of a wide spectrum of indene-containing spirocyclic dibenz(ox)azepines in good to excellent yields. Also, we showcased detailed mechanistic studies to justify the formation of spirocycles. In addition, the synthetic utility of this process was also demonstrated by the modular synthesis of various steroid conjugates. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the oldest and most widely used groups of drugs nowadays. However, the problem of searching for and creating new NSAIDs remains open, primarily due to the risks owing to their short- and long-term use. In this context, triazole-azepine hybrid molecules are attractive and prospective objects for the rational design of novel potential NSAIDs. In the present work studies of 3-aryl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepines as potential non-steroidal anti-inflammatory agents are reported. Evaluation of drug-like properties for all tested triazole-azepine hybrids was performed in silico using SwissADME. The screening of analgesic and anti-inflammatory activities was performed in vivo using acid-induced writhing and carrageenin-induced hind paw oedema models in mice. Derivatives with activity levels more potent compared with reference drugs ketorolac and diclofenac sodium were identified. Preliminary SAR was performed based on the screening results. [ABSTRACT FROM AUTHOR]

The carbon skeleton of the Stemona alkaloids stemokerrin and cochinchistemonine was assembled from three building blocks (a piperidine, a furan, and a tetronate). Key steps linking the fragments included a Stille cross-coupling (piperidine/furan) and an aldol-type addition of a tetronate. The furan served as a latent 1,4-difunctional compound which was converted into a γ-ketolactone by a type II photooxygenation. Attempts to construct the C12–C13 double bond of stemokerrin by a late-stage oxidation or by an elimination remained unsuccessful. The non-natural products dihydrostemokerrin and furostemokerrin were obtained instead. [ABSTRACT FROM AUTHOR]

IntroductionInsomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients.Methods and analysisIn this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality.Ethics and disseminationEthics approval was obtained through the 'Committee on Clinical Investigations' at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals.Trial registration numberThis trial has been registered at clinicaltrials.gov on 17 September 2019 (NCT04092894).

Therapeutic targeting of epigenetic modulators offers a novel approach to the treatment of multiple diseases. The cellular consequences of chemical compounds that target epigenetic regulators (epi-drugs) are complex. Epi-drugs affect global cellular phenotypes and cause local changes to gene expression due to alteration of a gene chromatin environment. Despite increasing use in the clinic, the mechanisms responsible for cellular changes are unclear. Specifically, to what degree the effects are a result of cell-wide changes or disease related locus specific effects is unknown. Here we developed a platform to systematically and simultaneously investigate the sensitivity of epi-drugs at hundreds of genomic locations by combining DNA barcoding, unique split-pool encoding, and single cell expression measurements. Internal controls are used to isolate locus specific effects separately from any global consequences these drugs have. Using this platform we discovered wide-spread loci specific sensitivities to epi-drugs for three distinct epi-drugs that target histone deacetylase, DNA methylation and bromodomain proteins. By leveraging ENCODE data on chromatin modification, we identified features of chromatin environments that are most likely to be affected by epi-drugs. The measurements of loci specific epi-drugs sensitivities will pave the way to the development of targeted therapy for personalized medicine.

Transcriptional and epigenetic alterations occur early in Huntington's disease (HD), and treatment with epigenetic modulators is beneficial in several HD animal models. The drug JQ1, which inhibits histone acetyl-lysine reader bromodomains, has shown promise for multiple cancers and neurodegenerative disease. We tested whether JQ1 could improve behavioral phenotypes in the R6/2 mouse model of HD and modulate HD-associated changes in transcription and epigenomics. R6/2 and non-transgenic (NT) mice were treated with JQ1 daily from 5 to 11 weeks of age and behavioral phenotypes evaluated over this period. Following the trial, cortex and striatum were isolated and subjected to mRNA-seq and ChIP-seq for the histone marks H3K4me3 and H3K27ac. Initially, JQ1 enhanced motor performance in NT mice. In R6/2 mice, however, JQ1 had no effect on rotarod or grip strength but exacerbated weight loss and worsened performance on the pole test. JQ1-induced gene expression changes in NT mice were distinct from those in R6/2 and primarily involved protein translation and bioenergetics pathways. Dysregulation of HD-related pathways in striatum was exacerbated by JQ1 in R6/2 mice, but not in NTs, and JQ1 caused a corresponding increase in the formation of a mutant huntingtin protein-dependent high molecular weight species associated with pathogenesis. This study suggests that drugs predicted to be beneficial based on their mode of action and effects in wild-type or in other neurodegenerative disease models may have an altered impact in the HD context. These observations have important implications in the development of epigenetic modulators as therapies for HD.