来氟米特异构体的合成研究

以5-甲基异噁唑-4-甲酸(1)为起始原料,经酰氯化得5-甲基-4-异噁唑甲酰氯(2),2与三氟甲基苯胺(3)缩合反应,得来氟米特异构体(4),最后经氢氧化钠水解,得水解产物5,纯度98%,收率为74%~85%。所合成的化合物经熔点和质谱分析确证,为来氟米特质量控制提供依据。     

5-甲基-4-异噁唑甲酰氯的合成研究

以乙酰乙酸乙酯为起始原料,经与原甲酸三乙酯缩合,与盐酸羟胺环合,再经酯水解和酰氯化得标题化合物,４步总收率在３０％以上,产品含量在９９％以上。     

新型高效杀虫剂氟虫腈制备新工艺

2,6-二氯-4-三氟甲基苯胺是合成氟虫腈的关键中间体。对以4-三氟甲基苯胺、硫酰氯、氯仿等为原料合成该中间体进行了研究。结果表明,最佳合成工艺条件为4-三氟甲基苯胺∶硫酰氯=1∶3.5(摩尔比),反应时间为4h,产品收率为84.3%。     

来氟米特的合成工艺研究

以乙酰乙酸乙酯为原料,与原甲酸三乙酯、乙酸酐反应生成乙氧基衍生物,再与盐酸羟胺反应生成5-甲基-4-异噁唑甲酸甲酯,经水解、氯代后与对氟三甲基苯胺生成产物来氟米特,五步总收率29.2%。产品质量稳定,并成功的实现中试化生产。     

来氟米特3-甲基异构体的制备及结构确证

来氟米特3-甲基异构体（2）是一个有毒副作用的杂质,需定量分析。提供了一种制备来氟米特3-甲基异构体的方法,纯度99．5％,结构经IR、NMR、MS等光谱确证,可以作为控制来氟米特质量的杂质标准品。     

4-氯-2-三氟甲基苯胺的合成

以邻三氟甲基苯胺为起始原料,二水氯化铜为催化剂,盐酸-双氧水为氯化剂,合成4-氯-2-三氟甲基苯胺。研究了催化剂、盐酸用量和温度对反应的影响。通过设计一组正交实验,得到了较优反应条件。当原料、催化剂、盐酸的摩尔比为1：1：10,滴加双氧水的温度为0℃时,实验结果最好,转化率达95％,目标产物的选择性80％以上。     

杀菌剂氟菌唑的合成及表征

以2-三氟甲基-4-氯苯胺和正丙氧基乙酸为原料,经缩合、取代和缩合3步反应合成杀菌剂氟菌唑.反应工艺选择了固体光气工艺,使N-(2-三氟甲基-4-氯苯基)正丙氧基乙酰胺(3)的收率达到97%,质量分数达98.4%;在N-(4-氯-2-三氟甲基苯基)正丙氧基氯异腈(2)的工艺中选择固体光气作为氯代试剂及采用三乙胺作为亲核性催化剂,使氟菌唑的质量分数达98%,收率达83%以上.氟菌唑结构经红外、核磁氢谱、质谱和元素分析确证.     

5—甲基—4—异恶唑甲酰氯的合成研究

以乙酰乙酸乙酯为起始原料,经与原甲酸二乙酯缩合,与盐酸羟胺环合,再经酯水解和氯化得标题化合物,4步总收率在30%以上,产品含量在99%以上。     

2-甲基-4-三氟甲基噻唑-5-甲酰氯的制备

以固体光气为氯化试剂,二氯乙烷为反应溶剂,2-甲基-4-三氟甲基噻唑-5-甲酸与固体光气发生氯化反应,得到2-甲基-4-三氟甲基噻唑-5-甲酰氯。反应中通过调节滴加固体光气二氯乙烷溶液的时间,来控制反应速度,使固体光气得到充分利用;通过热回流的方式,热解离固体光气,避免了解聚剂的引入;以蒸馏的方式回收了反应溶剂,实现了溶剂套用5次以上,收率大于99%,产品含量大于99%,副产盐酸,三废量少,已完成中试。     

活性酯法合成来氟米特

2-氯-4,6-二甲氧基-1,3,5-三嗪和N-甲基吗啉反应得到氯化4-(4,6-二 甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉,其与5-甲基异(噁)唑-4-甲酸反应制备2-(5-甲基异(噁)唑-4-甲酰氧基)-4,6-二甲氧基-1,3,5-三嗪,所得化合物与4-三氟甲基苯胺反应合成标题化合物,总收率约72％(以...     

奥卡西平及其中间体的新合成方法

介绍了一种新的合成奥卡西平(OCBZ)及其中间体的方法:以5H-二苯并[b,f]氮杂卓-5-甲酰氯为原料,通过加成溴化、氨解、水解得到OCBZ,总收率可达62左右,OCBZ的摩尔分数大于99.0。考察了影响氨解反应的因素,优化条件为n(NH3)/n(10,11-二溴-5H-二苯并[b,f]氮杂卓-5-甲酰氯)=5,反应温度约20℃,反应时间约35h,10-溴-5H-二苯并[b,f]氮杂卓-5-甲酰胺收率大于98,摩尔分数大于98.0。结果表明,温度高时氨解反应主要易生成副产物10,11-二溴-5H-二苯并[b,f]氮杂卓。主要产物及副产物的结构均用元素分析和MS进行了确证。该文报道工作的新颖性,已为浙江省科技信息研究院2008年1月8日出具的第200833B210143号《科技查新报告》所证实。该工作已进行1t/a规模的中试,结果为:平均收率约61,产品摩尔分数大于99.1。     

Fibrinolysis: A Primordial System Linked to the Immune Response

The fibrinolytic system provides an essential means to remove fibrin deposits and blood clots. The actual protease responsible for this is plasmin, formed from its precursor, plasminogen. Fibrin is heralded as it most renowned substrate but for many years plasmin has been known to cleave many other substrates, and to also activate other proteolytic systems. Recent clinical studies have shown that the promotion of plasmin can lead to an immunosuppressed phenotype, in part via its ability to modulate cytokine expression. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allows plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, a multitude of pathogens can also express their own plasminogen activators, or contain surface proteins that provide binding sites host plasminogen. Plasmin formed under these circumstances also empowers these pathogens to modulate host immune defense mechanisms. Phylogenetic studies have revealed that the plasminogen activating system predates the appearance of fibrin, indicating that plasmin did not evolve as a fibrinolytic protease but perhaps has its roots as an immune modifying protease. While its fibrin removing capacity became apparent in lower vertebrates these primitive under-appreciated immune modifying functions still remain and are now becoming more recognised.     

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review

Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body’s own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016–2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.     

BTN3A: A Promising Immune Checkpoint for Cancer Prognosis and Treatment

Butyrophilin-3A (BTN3A) subfamily members are a group of immunoglobulins present on the surface of different cell types, including innate and cancer cells. Due to their high similarity with the B7 family members, different studies have been conducted and revealed the involvement of BTN3A molecules in modulating T cell activity within the tumor microenvironment (TME). However, a great part of this research focused on γδ T cells and how BTN3A contributes to their functions. In this review, we will depict the roles and various aspects of BTN3A molecules in distinct tumor microenvironments and review how BTN3A receptors modulate diverse immune effector functions including those of CD4+ (Th1), cytotoxic CD8+ T cells, and NK cells. We will also highlight the potential of BTN3A molecules as therapeutic targets for effective immunotherapy and successful cancer control, which could represent a bright future for patient treatment.     

Regulator of G Protein Signalling 4 (RGS4) as a Novel Target for the Treatment of Sensorineural Hearing Loss

We and others have previously identified signalling pathways associated with the adenosine A₁ receptor (A₁R) as important regulators of cellular responses to injury in the cochlea. We have shown that the “post-exposure” treatment with adenosine A₁R agonists confers partial protection against acoustic trauma and other forms of sensorineural hearing loss (SNHL). The aim of this study was to determine if increasing A₁R responsiveness to endogenous adenosine would have the same otoprotective effect. This was achieved by pharmacological targeting of the Regulator of G protein Signalling 4 (RGS4). RGS proteins inhibit signal transduction pathways initiated by G protein-coupled receptors (GPCR) by enhancing GPCR deactivation and receptor desensitisation. A molecular complex between RGS4 and neurabin, an intracellular scaffolding protein expressed in neural and cochlear tissues, is the key negative regulator of A₁R activity in the brain. In this study, Wistar rats (6–8 weeks) were exposed to traumatic noise (110 dBSPL, 8–16 kHz) for 2 h and a small molecule RGS4 inhibitor CCG-4986 was delivered intratympanically in a Poloxamer-407 gel formulation for sustained drug release 24 or 48 h after noise exposure. Intratympanic administration of CCG-4986 48 h after noise exposure attenuated noise-induced permanent auditory threshold shifts by up to 19 dB, whilst the earlier drug administration (24 h) led to even better preservation of auditory thresholds (up to 32 dB). Significant improvement of auditory thresholds and suprathreshold responses was linked to improved survival of sensorineural tissues and afferent synapses in the cochlea. Our studies thus demonstrate that intratympanic administration of CCG-4986 can rescue cochlear injury and hearing loss induced by acoustic overexposure. This research represents a novel paradigm for the treatment of various forms of SNHL based on regulation of GPCR.     

The Immune Response in Adipocytes and Their Susceptibility to Infection: A Possible Relationship with Infectobesity

The current obesity pandemic has been expanding in both developing and developed countries. This suggests that the factors contributing to this condition need to be reconsidered since some new factors are arising as etiological causes of this disease. Moreover, recent clinical and experimental findings have shown an association between the progress of obesity and some infections, and the functions of adipose tissues, which involve cell metabolism and adipokine release, among others. Furthermore, it has recently been reported that adipocytes could either be reservoirs for these pathogens or play an active role in this process. In addition, there is abundant evidence indicating that during obesity, the immune system is exacerbated, suggesting an increased susceptibility of the patient to the development of several forms of illness or death. Thus, there could be a relationship between infection as a trigger for an increase in adipose cells and the impact on the metabolism that contributes to the development of obesity. In this review, we describe the findings concerning the role of adipose tissue as a mediator in the immune response as well as the possible role of adipocytes as infection targets, with both roles constituting a possible cause of obesity.     

Immune Checkpoints Inhibitors and SRS/SBRT Synergy in Metastatic Non-Small-Cell Lung Cancer and Melanoma: A Systematic Review

Background: Several immunotherapy (IT) agents are FDA approved for treatment of melanoma and non-small-cell lung cancer (NSCLC). The addition of stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT) to immunotherapy looks promising. A systematic review was conducted to evaluate the possible synergistic effects of immune checkpoints inhibitors (ICIs) and stereotactic radiation therapy in melanoma and NSCLC. Materials and methods: Pubmed databases from January 2010 to December 2020 were reviewed to identify English language studies reporting control of local and abscopal effect of the combination of ICI-SBRT/SRS in metastatic NSCLC and melanoma cancer. The inclusion criteria were followed according to PICO criteria. Results: Thirty-nine articles were included of the 2141 initial results. The reported rates for local control were 16.5–100% and 40–94% in brain and extracerebral metastases, respectively. Distant/abscopal response rates were 1–45% in extracerebral metastases. Abscopal effect could not be evaluated in brain metastases because it was not reported in studies. Treatments were well tolerated with few grade 4 toxicities and no grade 5. Conclusions: The combined treatment of ICI-SBRT/SRS achieves high local control and non-negligible abscopal response in patients with extracerebral metastases, with its benefit in cerebral metastases being more controversial. Clinical trials are needed to better characterize the potential synergism.     

新型含氰侧基氯取代聚芳醚醚酮酮/芳醚醚酮酮的合成及性能研究

在无水AlCl3及N-甲基吡咯烷酮(NMP)/1,2-二氯乙烷(DCE)复合溶剂的存在下,用2,6-二苯氧基苯甲腈(DPOBN)与对苯二甲酰氯(TPC)及2,5-二氯对苯二甲酰氯(DCC)进行三元低温共缩聚反应,合成了一系列新型含氰侧基氯取代的聚芳醚醚酮酮/芳醚醚酮酮.用IR、DSC、TG、WAXD等方法对其结构和性能进行了表征.结果表明,所合成的聚合物均为非晶态聚合物,其玻璃化转变温度(Tg)为180～229℃、热分解5%的温度(Td)为445～498℃,具有突出的耐高温性能.     

Diabetic Nephropathy and COVID-19: The Potential Role of Immune Actors

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.