Design and synthesis of a biotinylated probe of COX-2 inhibitor nimesulide analog JCC76

JCC76 is a derivative of cyclooxygenase-2(COX-2) selective inhibitor nimesulide and exhibits potent anti-breast cancer activity. It selectively induces apoptosis of Her2 positive breast cancer cells. However, the specific molecular targets of JCC76 still remain unclear, which significantly withdraw the further drug development of JCC76. To identify the molecular targets of JCC76, a six carbon linker and biotin conjugated JCC76 probe was designed and synthesized. The anti-proliferation activity of the probe and its analogs was evaluated.     

尼美舒利联合甲硝唑对牙周炎患者血清IL-10、TNF-α和MMP-8水平的影响

目的:研究尼美舒利联合甲硝唑对牙周炎患者血清白细胞介素-10(IL-10)、肿瘤坏死因子(TNF-α)、基质金属蛋白酶-8(MMP-8)水平的影响。方法:收集2014年3月至2015年3月我院收治的90例牙周炎患者,按照抽签法分为实验组和对照组,每组各45例。两组均采用牙结石以及牙菌斑除去、根面平整、冲洗牙周袋等常规治疗。对照组在此基础上采用甲硝唑治疗,0.9%生理盐水进行冲洗。实验组在对照组基础上采用尼美舒利治疗,每次2片,每天2次。观察和比较两组的治疗疗效,牙周情况,治疗前后血清IL-10、TNF-α、MMP-8水平的变化及不良反应的发生情况。结果:治疗后,实验组总有效率显著高于对照组(P0.05);GI、PD、PLI、AL显著低于对照组(P0.05);血清IL-10水平显著高于对照组(P0.05),血清TNF-α、MMP-8水平显著低于对照组(P0.05);两组不良反应总发生率比较差异无统计学意义(P0.05)。结论:尼美舒利联合甲硝唑治疗牙周炎可显著提高其临床疗效,消除或缓解临床症状,可能与其提高血清IL-10水平,降低TNF-α、MMP-8水平,抑制炎症反应,保持牙内环境稳定有关。     

1,2,3-Triazole-nimesulide hybrid: Their design,synthesis and evaluation as potential anticancer agents

A new hybrid template has been designed by integrating the structural features of nimesulide and the 1,2,3-triazole moiety in a single molecular entity at the same time eliminating the problematic nitro group of nimesulide. The template has been used for the generation of a library of molecules as potential anticancer agents. A mild and greener CuAAC approach has been used to synthesize these compounds via the reaction of 4-azido derivative of nimesulide and terminal alkynes in water. Three of these compounds showed promising growth inhibition (IC₅₀ ～6–10 μM) of A549, HepG2, HeLa and DU145 cancer cell lines but no significant effects on HEK293 cell line. They also inhibited PDE4B in vitro (60–70% at 10 μM) that was supported by the docking studies (PLP score 87–94) in silico.     

Comparison of the effect of tromethamine and polyvinylpyrrolidone on dissolution properties and analgesic effect of nimesulide

The solubilizing and absorption enhancer properties towards nimesulide (ND) of tromethamine (Tris) and polyvinylpyrrolidone (PVP) have been investigated. Solid binary systems were prepared at various drug-polymer ratios by mixing or coprecipitation, characterized by differential scanning calorimetry, X-ray diffractometry, and Fourier transform infrared spectroscopy, and tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on concentration of the hydrophilic carrier in coprecipitates. Tris was more effective than PVP, despite the amorphizing power of PVP as revealed by solid state analyses. Complete drug amorphiztion was attained at 1∶3 (wt/wt) drug: PVP, 25% (wt/wt) ND in PVP. According to thermal behavior of ND and Tris, ND-Tris systems present a eutectic behavior. The eutectic composition was 30% ND-70% Tris at ∼129°C. Amorphous ND-PVP and eutectic ND-Tris mixtures showed an improvement of 5.55 and 6.6 times of drug dissolution efficiency, respectively. In vivo experiments in mice demonstrated that administration of 60 mg/kg of drug coprecipitated with PVP or Tris resulted, respectively, in a 50% and 94% reduction of acetic acid-induced writhings in comparison with pure drug, which, instead, was statistically ineffective as compared with the control group. Moreover, the eutectic mixture of ND-Tris demonstrated antiwrithing potency 1.88 times higher than amorphous ND-PVP coprecipitate. Thus, the solubilizing power, dissolution-enhancing effect, and analgesic effect enhancer ability toward the drug make Tris particularly suitable for developing a reduced-dose, fast-release solid oral dosage form of nimesulide. Published: August 10, 2007     

Nimesulide inhibits lipopolysaccharide-induced production of superoxide anions and nitric oxide and iNOS expression in alveolar macrophages

The study was designed to investigate the effect of nimesulide on lipopolysaccharide (LPS)-induced proinflammatory oxidants production by rat alveolar macrophages (AMs). Effects of LPS and nimesulide on antioxidant defense and the expression of inducible nitric oxide synthase (iNOS) were also studied. It was found that nimesulide could scavenge superoxide anions (O2*-), nitric oxide (NO*) and total oxidant burden induced by LPS in AMs in vitro. Approximately 850 nmoles of nimesulide had activity equivalent to one IU of superoxide dismutase (SOD). Further, to confirm the in vitro observation, Male Wistar rats were orally administered with nimesulide (9 mg/kg b. wt. twice daily) for one week followed by intratracheal instillation of 2 microg LPS to stimulate lung inflammation. AMs from bronchoalveolar lavage fluid were collected 18 h after instillation of LPS. Nimesulide pretreatment could inhibit O2*-, NO() and lipid peroxidation in AMs. Nimesulide also suppressed LPS-induced iNOS expression in AMs in vivo and in vitro. Nimesulide could also normalize LPS-induced changes in the levels of superoxide dismutase (SOD), glutathione reductase (GR) and reduced glutathione (GSH) in AMs. Inhibition in production of oxidants in LPS-challenged AMs by nimesulide could be one of the pathways for its anti-inflammatory action.     

尼美舒利的临床应用及其不良反应

尼美舒利具有强大的抗炎、镇痛和解热作用。临床主要用于急慢性疼痛、关节炎、月经痛、癌症疼痛和解热。其作用机理主要是通过选择性抑制COX-2而抑制前列腺素的合成。尼美舒利的不良反应与其他NSAIDs相似,但对胃肠道副作用较少。本文总结了尼美舒利的主要临床应用及不良反应。     

Rapid and simple high-performance liquid chromatographic determination of nimesulide in human plasma

A high-performance liquid chromatographic method for the quantitation of nimesulide in human plasma is presented. The method is based on protein precipitation with methanol and reversed-phase chromatography with spectrophotometric detection at 404 nm. The separation was performed on a Nucleosil 120-5 C₁₈, 50×4-mm I.D. column and the mobile phase consisted of acetonitrile–methanol–15 mM potassium dihydrogenphosphate buffer, pH 7.3 (30:5:65, v/v). Only 250 μl of plasma are used for sample preparation and no internal standard is necessary. The limit of quantitation is 80 ng/ml and the calibration curve is linear up to 10 000 ng/ml. More than 20 samples can be analysed within 1 h. Within-day and between-day precision expressed by relative standard deviation is less than 5% and inaccuracy does not exceed 8%. The assay was used for pharmacokinetic studies.     

Copper conjugates of nimesulide Schiff bases targeting VEGF, COX and Bcl-2 in pancreatic cancer cells

Copper conjugates of Schiff base derivatives of nimesulide (1), a well-known cyclooxygenase-2 (COX-2) inhibitor, were synthesized, structurally characterized and evaluated for their COX selectivity indices and cytotoxicities on pancreatic tumor, BxPC-3 (COX-2 positive) and MiaPaCa (COX-2 negative) cell lines. Copper conjugates exhibit distorted square planar geometries as revealed by the single crystal X-ray structure determination of Cu(L1)(2) and show significant growth inhibition in both cell lines (IC50 values 3-26 microM for COX-2 positive and 5-9 microM for COX-2 negative cell line) than the parent nimesulide (35 microM for COX-2 positive and >100 microM for COX-2 negative cell line). The mechanistic pathway for the biological activity involves inhibition of vascular endothelial growth factor (VEGF) and COX inhibition, as well as down regulation of antiapoptotic Bcl-2 and Bcl-(XL) proteins.     

Novel 1-alkynyl substituted 1,2-dihydroquinoline derivatives from nimesulide (and their 2-oxo analogues): a new strategy to identify inhibitors of PDE4B

A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized are presented.     

Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potential PDE4B inhibitors against cancer cells

A new class of 1,2,3-triazol derivatives derived from nimesulide was designed as potential inhibitors of PDE4B. Synthesis of these compounds was carried out via a multi-step sequence consisting of copper-catalyzed azide–alkyne cycloaddition (CuAAC) as a key step in aqueous media. The required azide was prepared via the reaction of aryl amine (obtained from nimesulide) with α-chloroacetyl chloride followed by displacing the α-chloro group by an azide. Some of the synthesized compounds showed encouraging PDE4B inhibitory properties in vitro that is >50% inhibition at 30 μM that were supported by the docking studies of these compounds at the active site of PDE4B enzyme (dock scores ～ ?28.6 for a representative compound). Two of these PDE4 inhibitors showed promising cytotoxic properties against HCT-15 human colon cancer cells in vitro with IC₅₀ ～ 21–22 μg/mL.