Electrochemical synthesis of quinazolinone via I2-catalyzed tandem oxidation in aqueous solution

The development of protocols for synthesizing quinazolinones using biocompatible catalysts in aqueous medium will help to resolve the difficulties of using green and sustainable chemistry for their synthesis. Herein, using I₂ in coordination with electrochemical synthesis induced a C–H oxidation reaction which is reported when using water as the environmentally friendly solvent to access a broad range of quinazolinones at room temperature. The reaction mechanism strongly showed that I₂ cooperates electrochemically promoted the oxidation of alcohols, then effectively cyclizing amides to various quinazolinones.

The development of protocols for synthesizing quinazolinones using biocompatible catalysts in aqueous medium will help to resolve the difficulties of using green and sustainable chemistry for their synthesis.

The N-heterocycles are key core structures that form the basis of many pharmaceutical, agrochemical and natural products.¹ Among them, quinazolinones are an important motif in several biologically relevant pharmacophores,² such as methaqualone which is famous for its effective sedative and hypnotic effects, luotonin A which is a quinazolinone alkaloid with anti-inflammatory effects, and erlotinib which is an anti-tumour agent, and all these compounds contain a quinazoline bond in their backbone (Fig. 1).³Open in a separate windowFig. 1Bioactive compounds containing quinazolinone skeleton.Due to their advantageous structures quinazolinones have been widely explored in numerous syntheses.⁴ The classical method involves condensation of aldehydes and o-aminobenzamides to give aminal intermediates, which then undergo oxidation to yield the final quinazolinone product.⁵ Another strategy is to use more benign and readily available alcohols as starting materials.⁶ The reaction takes place through a two-step oxidation pathway, where the alcohols are first oxidized to aldehydes, followed by coupling with o-aminobenzamides. The catalyst needs to demonstrate high activity and selectivity as the reaction involves dehydrogenation of both the C–H and N–H bonds in one pot. In 2018, Sarma and co-workers⁷ demonstrated that a magnetically recoverable iron oxide-carbon dot nanocomposite was an effective catalyst for cyclooxidative tandem synthesis of quinazolinones in aqueous medium using alcohols as starting materials. Furthermore, annulation reactions of o-aminoaryl acids may be the most employed strategies, which include the condensation of o-aminoaryl acids with amides, nitriles, or acid derivatives plus a nitrogen source.⁸ Moreover, the synthesis of quinazolinone involving transition metal catalysed reactions of o-haloarylamides with nitriles, or amines⁹ and reaction of o-halogenated aryl acid with amides¹⁰ have been explored (Scheme 1).Open in a separate windowScheme 1Methods for the synthesis of quinazolinones.Although the above approaches solved a lot of practical problems, there are still some limitations such as long reaction time, high temperature and by-products. Hence, development of greener, atom economic, synthetic approaches for the preparation of quinazolinones from inexpensive and easily available starting materials under relatively mild conditions is desirable. On one hand, electrochemical-induced direct functionalization has gained significant attention from the synthetic chemistry community due to it being environmentally friendly, and requiring mild conditions, and low-energy irradiation.¹¹ With electrons as the oxidizing/reducing agent, organic electrosynthesis could offer appropriate alternatives to traditional oxidation or reduction reactions. For example, Zhao and co-workers¹² reported an efficient electrochemical-induced C–H methylthiolation of electron-rich aromatics via a three-component cross-coupling strategy. On the other hand, the non-metallic oxidant, iodine, catalysed C–H oxidation has attracted great interest in recent times due to its low toxicity and because it is inexpensive compared with transition metal catalysts.¹³ Therefore, the combination of electrochemical catalysis and non-metallic oxidant iodine is a very feasible means of organic synthesis and does not require use of the historical large doses of iodine. In this research the possibility of combining the two in a one-pot reaction was explored, thus avoiding the isolation of either aldehyde or amine intermediates leading to quinazolinones formed from alcohols as starting materials.Furthermore, water as a reaction medium is generally considered as an inexpensive, safe, and environmentally benign alternative to organic solvents.¹⁴ Recently, Muthaiah and co-workers¹⁵ demonstrated a catalyst system for the dehydrogenative oxidation of alcohols to carbonyl compounds and dehydrogenative lactonization of diols in water catalyzed by a water-soluble bifunctional iridium complex. In continuation of our work to develop new organic transformations,^16,11f herein, it is demonstrated that I₂ is an efficient catalyst for a novel, one-pot electrochemical-induced tandem reaction in aqueous solution.The investigation was initially begun by selecting o-aminobenzamide 1a and benzyl alcohol 2a as the model substrate to optimize the reaction conditions shown in 17 It was also observed that the reduction in current also leads to a reduction in yield (

A pilot study of thiamin and folic acid in hemodialysis patients with cognitive impairment

ObjectiveThis study aimed to explore the effectiveness of thiamin and folic acid supplementation on the improvement of the cognitive function in patients with maintenance hemodialysis.MethodIn the present study, we randomly assigned patients undergoing hemodialysis who had the Montreal Cognitive Assessment (MoCA) score lower than 26 to treatment group (n = 25, thiamin 90 mg/day combined with folic acid 30 mg/day) or control group (n = 25, nonintervention). All subjects were followed up for 96 weeks. The primary outcome was the improvement of the MoCA score. The secondary outcomes included homocysteine level, survival and safety.ResultsPatients in treatment group had an increase of the MoCA score from 21.95 ± 3.81 at baseline to 25.68 ± 1.96 at week 96 (p < 0.001, primary outcome), as compared with the MoCA score from 20.69 ± 3.40 to 19.62 ± 3.58 in control group. Thiamin combined with folic acid treatment also resulted in lower level of serum homocysteine in treatment group compare with control group at week 96 (p < 0.05, secondary outcome). 3 patients and 9 patients died during follow-up period in treatment and control group respectively (p = 0.048). The proportion of adverse events in treatment group was significantly lower than that in control group.ConclusionHemodialysis patients with cognitive impairment treated with thiamin and folic acid had a significant improvement in MoCA score.     

DCZ0014, a novel compound in the therapy of diffuse large B-cell lymphoma via the B cell receptor signaling pathway

Diffuse large B cell lymphoma (DLBCL) is a clinical and genetically heterogeneous lymphoid malignancy. Although R-CHOP (rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone) treatment can improve the survival rate of patients with DLBCL, more than 30% of patients exhibit treatment failure, relapse, or refractory disease. Therefore, novel drugs or targeted therapies are needed to improve the survival of patients with DLBCL. The compound DCZ0014 is a novel chemical similar to berberine. In this study, we found that DCZ0014 significantly inhibited the proliferation and activity of DLBCL cells, and induced cell apoptosis. Following treatment with DCZ0014, DLBCL cells accumulated in G0/G1-phase of the cell cycle and showed decreased mitochondrial membrane potential. Additionally, DCZ0014 inhibited DNA synthesis, enhanced DNA damage in DLBCL cells, as well as inhibited Lyn/Syk in B cell receptor signaling pathway. Further experiments demonstrated that DCZ0014 did not significantly affect peripheral blood mononuclear cells. Tumor xenograft model showed that DCZ0014 not only inhibited tumor growth but also extended the survival time of mice. Thus, DCZ0014 showed potential for clinical application in the treatment of patients with DLBCL.     

海拔4 300m居住高原不同时间血生化的改变

目的:探讨居住海拔4300m高原不同时间青年肝功能、肾功能、血脂、血浆蛋白及血清酶的变化。方法:对进驻高原3个月(n=174)、6个月(n=73)及一年(n=88)的男性汉族青年检测其血清总胆红素(STB)、直接胆红素(SDB)、总蛋白(TP)、白蛋白(ALB)、尿素氮(BUN)、肌酐(Cr)、尿酸(UA)、甘油三脂(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、丙氨酸氨基转换酶(ALT)、门冬氨酸氨基转换酶(AST)、γ-谷氨酰转移酶(γ-GT)、碱性磷酸酶(ALP)。结果:居住3个月较6个月及1年STB、SDB、BLA、TC、TG、LDL-C、γ-GT增高,差别有显著性(P<0.05或0.01),3个月较1年AST、ALT、BUN增高,差别非常有显著性(P<0.01);居住6个月较1年TP增高,差别有显著性(P<0.05);其余均无统计学意义(P>0.05)。结论:进驻高原初期引起肝功能、肾功能等多项指标异常,脏器损伤较居住半年以上严重。     

Signaling via Src family kinases is required for normal internalization of the receptor c-Kit.

Stem cell factor (SCF) exerts its biological effects by binding to a specific receptor, the tyrosine kinase c-Kit, which is expressed on the cell surface. Although normal cellular trafficking of growth factor receptors may play a critical role in the modulation of receptor function, the mechanisms that regulate the distribution of c-Kit on the cell surface and the internalization of c-Kit have not been fully defined. We investigated whether signal transduction via Src family kinases is required for normal c-Kit trafficking. Treatment of the SCF-responsive human hematopoietic cell line MO7e with the inhibitor of Src family kinases PP1 blocked SCF-induced capping of c-Kit and internalization of c-Kit. c-Kit was able to associate with clathrin in the presence of PP1, suggesting that entry of c-Kit into clathrin-coated pits occurs independently of Src family kinases. SCF-induced internalization of c-Kit was also diminished in the D33-3 lymphoid cell line in which expression of Lyn kinase was disrupted by homologous recombination. These results indicate that Src family kinases play a role in ligand-induced trafficking of c-Kit.     

颅中窝内侧肿瘤的显微外科治疗

目的　报告 2 7例颅中窝内侧肿瘤的显微外科治疗。方法　分析 2 7例病例影像学特点、手术方法、手术结果及术后并发症等。结果　肿瘤全切除 12例 ,次全切除 9例 ,部分切除 6例。手术死亡 2例 ,术后颅神经功能障碍加重 5例 ,术后颅神经症状同术前 5例 ,其余病例临床症状及体征均有不同程度好转。结论　经额—颧—颞入路切除颅中窝内侧肿瘤是适宜的。     

老年性白内障血、房水、晶体核中抗氧化酶和抗氧化物研究

目的：了解抗氧化酶和抗氧化物之间的关系及其在老年性白内障形成中的作用。方法：随机取符合条件的老年性白内障４４例（４４眼）,男２３例,妇女１例,平均年龄６７．７岁。用黄嘌呤氧化酶法测定超氧化物歧化酶（Ｓｕｐｅｒｏｘｉｄｅ ｄｉｓｍｕｔａｓｅ,ＳＯＤ）、丙二醛（Ｍａｌｏｎｄｉａｌｄｅｈｙｄｅ ＭＤＡ）用巴比妥酸反应比色法测定,谷胱甘肽过氧化物酶（Ｇｌｕｔａｔｈｉｏｎｅ－Ｐｅｒｏｘｉｄｅ,ＧＳＨ－ＰＸ）     

人免疫球蛋白和重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗中毒性表皮坏死松解症的对比研究

目的:评价静脉注射人免疫球蛋白（IVIG）及重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白（rhTNFR：Fc）治疗中毒性表皮坏死松解症（TEN）的疗效。方法:收集2013—2019年武汉市第一医院使用IVIG及rhTNFR：Fc治疗的TEN患者资料。IVIG组11例,男3例,女8例,年龄25 ~ 72岁,中位TEN疾病严重...     

尿动力学检查术前对BPH患者TVP术后疗效的评价作用

目的：探讨尿动力学检查在术前对前列腺增生（BPH）患者行经尿道前列腺电汽化术（TVP）术后疗效的评价作用。方法：对800例拟行TVP的BPH患者术前行尿动力学检查、国际前列腺症状（IPSS）评分,并于术后随访1年,观察最大尿流率,IPSS评分。结果：800例BPH患者术前最大尿流率均〈15ml／s,IPSS评分平均〉29分。根据术前最大尿道压力、最大尿道压力与充盈时膀胱最大压力的关系、膀胱顺应性及是否存在尿道外括约肌与膀胱逼尿肌压力不协调等指标共分为四组。术后1年最大尿流率平均分别为18．3ml／s、17．9ml／s、9．2ml／s和8．2ml,s,IPSS评分平均分别为12分、11分、23分和26分。其中各组术后最大尿流率〉15ml／s,分别占89．8％、85．5％,29,2％和22．5％。Ⅰ组、Ⅱ组术后各项指标与Ⅲ组,Ⅳ组比较差异均有统计学意义（P〈0．05）。结论：尿动力学榆查对BPH患者行TVP术的疗效有良好的评价作用,可为BPH患者采用何种治疗方法提供重要依据。     

环氧乙烷对一次使用性卫生巾消毒效果的试验观察

在温度为41～45℃、相对湿度为60％条件下,以400mg／L环氧乙烷作用6h对枯草杆菌黑色变种芽胞的杀灭率可达100％;但以800mg／L环氧乙烷,作用10h才能使HBsAg转阴。对载物车各层物品的消毒效果无明显差别;温度较高则消毒效果较好。消毒后的卫生巾在室温下放3～5d,环氧乙烷残留量≤66．8mg／kg。