4-(4-Nitro-phen-yl)morpholine.

Aromatic π-π stacking inter-actions stabilize the crystal structure of the title compound, C(10)H(12)N(2)O(3), the perpendic-ular distance between parallel planes being 3.7721 (8) Å. The morpholine ring adopts a chair comformation.

[Clinical observation on deep needling at Xiaguan (ST 7) with round sharp needle combined with plum-blossom needle for trigeminal neuralgia of wind and heat].

OBJECTIVE: To compare the clinical therapeutic effect between deep needling at Xiaguan (ST 7) with round sharp needle combined with plum-blossom needle and conventional acupuncture in patients with trigeminal neuralgia (TN) of wind and heat, and explore its mechanism. METHODS: A total of 60 patients with TN of wind and heat were randomized into an observation group (30 cases) and a control group (30 cases). In the observation group, deep needling with round sharp needle was applied at Xiaguan (ST 7), and tapping with plum-blossom needle was applied at Yangbai (GB 14), Quanliao (SI 18), Dicang (ST 4), Sibai (ST 2), etc. of affected side. In the control group, conventional acupuncture was applied at the same acupoints selected in the observation group. The treatment was given once a day, 5 times a week for 4 weeks in the both groups. Before and after treatment, the scores of short-form McGill pain questionnaire (SF-MPQ), TCM syndrome, patient global impression of change (PGIC) and comprehensive symptom were observed, the serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vasoactive intestinal peptide (VIP) and ß-endorphin (ß-EP) were detected, and the adverse reaction was observed in the both groups. RESULTS: After treatment, the scores of PRI, PPI, VAS, TCM syndrome, PGIC and comprehensive symptom and the serum levels of IL-6, TNF-α and VIP were decreased compared before treatment in the both groups (P<0.05), and the variations of above indexes in the observation group were larger than those in the control group (P<0.05). After treatment, the serum levels of ß-EP were increased compared before treatment in the both groups (P<0.05), and the variation of that in the observation group was larger than the control group (P<0.05). No severe adverse reaction was observed in the both groups. CONCLUSION: Deep needling at Xiaguan (ST 7) with round sharp needle combined with plum-blossom needle can effectively treat the trigeminal neuralgia of wind and heat and relieve pain, its therapeutic effect is superior to conventional acupuncture. The mechanism may be related to the regulation of serum IL-6, TNF-α, VIP and ß-EP.

Synthesis and enhanced ethanol sensing characteristics of alpha-Fe2O3/SnO2 core-shell nanorods.

Alpha-Fe(2)O(3)/SnO(2) core-shell nanorods are synthesized via a three-step process. X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses reveal that their diameters and lengths are respectively in the ranges 35-120 nm and 0.35-1.2 microm, and the thickness of the shell composed of 3.5 nm SnO(2) nanoparticles is about 10 nm. The core-shell nanostructures exhibit a dramatic improvement in ethanol sensing characteristics compared to pure alpha-Fe(2)O(3) nanorods. The sensor response is up to 19.6 under 10 ppm ethanol exposure at 220 degrees C. Both the response time and the recovery time of the core-shell structures are less than 30 s. Based on the space-charge layer model and semiconductor heterojunction theory, the small thickness of the SnO(2) shell and the formation of heterojunctions contribute to the enhanced ethanol sensing characteristics. Our results demonstrate that one-dimensional metal oxide core-shell nanostructures whose shell thickness is smaller than the Debye length are very promising materials for fabricating gas sensors with good performances.

Src kinase inhibitor PP2 regulates the biological characteristics of A549 cells via the PI3K/Akt signaling pathway.

Lung cancer is one of the most prevalent types of cancer worldwide, with a poor prognosis for patients and a concomitant financial burden on society. There are a number of different pathological subtypes, with non-small cell lung cancer (NSCLC) being the primary subtype. Although anticancer therapy has led to a marked improvement in the survival rate of patients in recent years, the survival rate remains poor. Potential reasons for this include a lack of early diagnosis and drug resistance, which is considered to be associated with mutations in components of signaling pathways, tumor suppressors and epidermal growth factor receptor, and certain other complex mechanisms to a certain extent. It is therefore imperative to develop novel therapies. In the present study, the pyrazolopyrimidine compound PP2 was used to inhibit Src family protein tyrosine kinases in A549 cells. It was demonstrated that PP2 was able to suppress cell viability, migration and invasion, and promote apoptosis via regulating the phosphoinositide 3-kinase/protein kinase B/B-cell lymphoma 2/caspase-3 signaling pathway. PP2 may therefore be useful in anti-NSCLC therapy in the future.

Drug Discovery against Psoriasis: Identification of a New Potent FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor, 1-(4-((1H-Pyrazolo[3,4-d]pyrimidin-4-yl)oxy)-3-fluorophenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea, That Showed Potent Activity in a Psoriatic Animal Model.

Psoriasis is a chronic T-cell-mediated autoimmune disease, and FMS-like tyrosine kinase 3 (FLT3) has been considered as a potential molecular target for the treatment of psoriasis. In this investigation, structural optimization was performed on a lead compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (1), which showed a moderate inhibitory activity againt FLT3. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis led to the discovery of a number of potent FLT3 inhibitors. One of the most active compounds, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (18b), was then chosen for in-depth antipsoriasis studies because this compound displayed the highest potency in a preliminary antipsoriasis test. Compound 18b exhibited significant antipsoriatic effects in the K14-VEGF transgenic mouse model of psoriasis, and no recurrence was found 15 days later after the last administration. Detailed mechanisms of action of compound 18b were also investigated. Collectively, compound 18b could be a potential drug candidate for psoriasis treatment.

Structure-activity relationship studies of pyrazolo[3,4-d]pyrimidine derivatives leading to the discovery of a novel multikinase inhibitor that potently inhibits FLT3 and VEGFR2 and evaluation of its activity against acute myeloid leukemia in vitro and in vivo.

We describe the structural optimization of a hit compound, 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)-3-(3-methoxyphenyl)urea (1), which exhibits inhibitory activity but low potency against FLT3 and VEGFR2. A series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized, and structure-activity relationship analysis using cell- and transgenic-zebrafish-based assays led to the discovery of a number of compounds that exhibited both high potency against FLT3-driven human acute myeloid leukemia (AML) MV4-11 cells and a considerable antiangiogenic effect in transgenic-zebrafish-based assays. The compound 1-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (33), which exhibited the highest activity in preliminary in vivo anti-AML assays, was chosen for further anti-AML studies. The results demonstrated that compound 33 is a multikinase inhibitor that potently inhibits FLT3 and VEGFR2. In an MV4-11 xenograft mouse model, a once-daily dose of compound 33 at 10 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analyses were performed to determine the mechanism of action of compound 33.

Structural optimization and structure-activity relationships of N2-(4-(4-Methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine derivatives, a new class of reversible kinase inhibitors targeting both EGFR-activating and resistance mutations.

This paper describe the structural optimization of a hit compound, N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.

Discovery of the novel potent and selective FLT3 inhibitor 1-{5-[7-(3- morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea and its anti-acute myeloid leukemia (AML) activities in vitro and in vivo.

Structure-activity relationship (SAR) studies of 2-(quinazolin-4-ylthio)thiazole derivatives, which are for optimizing the in vitro and in vivo antiacute myeloid leukemia (AML) activity of a previously identified FLT3 inhibitor 2-(6,7-dimethoxyquinazolin-4-ylthio)thiazole (1), are described. SAR studies centering around the head (thiazole) and tails (6- and 7-positions) of the quinazoline moiety of 1 led to the discovery of a series of compounds that exhibited significantly increased potency against FLT3-driven AML MV4-11 cells. Preliminary in vivo assays were carried out on three highly active compounds, whose results showed that 1-{5-[7-(3-morpholinopropoxy)quinazolin-4-ylthio]-[1,3,4]thiadiazol-2-yl}-3-p-tolylurea (20c) had the highest in vivo activity. Further in vitro and in vivo anti-AML studies were then performed on 20c; in an MV4-11 xenograft mouse model, a once-daily dose of 20c at 100 mg/kg for 18 days led to complete tumor regression without obvious toxicity. Western blot and immunohistochemical analysis were carried out to illustrate the mechanism of action of 20c.