一种阿糖腺苷合成的新方法

阿糖腺苷是一种有效的抗疱疹及带状疱疹病毒药物,也是抗脱氧核糖核酸(DNA)病毒药单磷酸阿糖腺苷以及治疗B-细胞慢性淋巴细胞白血病(B-CLL)特效药氟达拉滨等下游产品合成的主要原料。开发阿糖腺苷的合成方法具有广阔的市场前景。以廉价的腺苷作为原料,经8位溴代、羟基磺酰化、羟基乙酰化、一锅两步完成构型翻转和脱肼等五步反应合成阿糖腺苷是一种新的有效的化学合成法。反应步骤中大多使用自来水作为绿色溶剂,具有工艺简单、安全性高、三废排放少以及经济性高的优势,在工业生产中极具发展潜力。     

抗艾滋病药物司他呋啶合成方法的研究

司他呋啶(2′,3′-双脱氢-3′-脱氧胸苷,d4T)是抑制HIV逆转录酶的抗病毒药物.对多年来有关d4T的合成方法进行了综述.合成d4T主要有两大合成路线,一条是以β-胸苷为原料,另一条是以5-甲基尿苷为原料,对各条路线的优缺点进行了评述.     

慢性粒细胞白血病树突状细胞对T细胞增殖作用的研究

目的　体外诱导慢性粒细胞白血病 (CML)患者外周血单个核细胞 (PBMCs)为树突状细胞 (DCs) ,并对其形态、表型及对T细胞刺激增殖作用进行研究。方法　利用GM CSF、IL 4、TNF α体外定向诱导生成树突状细胞 ,对所诱生的细胞进行细胞表型及形态检测 ,用D FISH方法检测所诱生DCs的白血病源性 ,应用MTT法检测所诱生的DCs刺激T细胞增殖的能力。结果　CML患者PBMCs在体外可诱导生成bcr/abl融合基因阳性的DCs(CMLDCs)。CMLDCs对自体T细胞有明显刺激增殖作用 ,而CML细胞无此作用。CMLDCs刺激同一异体T细胞增殖能力弱于正常DCs,但当培养体系中加入 30 0U/ml干扰素 α(IFN α)时可使其刺激能力接近正常DCs。结论　CMLDCs具有刺激自体及异体T细胞增殖的能力 ,但对异体T细胞的刺激作用弱于正常DCs,IFN α可提高CMLDCs刺激T细胞增殖能力     

白血病治疗药物伊马替尼的合成研究进展

伊马替尼是世界首个获得批准的肿瘤发生相关信号传导抑制剂,临床上主要用于治疗慢性粒细胞白血病和急性淋巴细胞白血病,且有新的适应症被不断发现。文章介绍了伊马替尼的化学合成方法,对国内外主要合成工艺进行了分析,研究了国内外的发展趋势。并设计出一条原料廉价,操作简便的合成路线,探讨了该工艺路线的可行性。     

奥希替尼合成路线图解

奥希替尼是一种抗肺癌新药,用于治疗表皮生长因子受体(EGFR)突变,且对表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)产生耐药性的非小细胞肺癌患者,是目前唯一的治疗EGFR T790M突变阳性的转移性非小细胞肺癌的药物。文章综述了奥希替尼及其中间体的合成,以期为奥希替尼及其中间体的合成研究及生产提供参考依据。     

含Schiff碱结构的2-芳胺基嘧啶衍生物的合成及体外抗肿瘤活性研究

以邻甲基苯胺、3-乙酰基吡啶、N,N二甲基甲酰胺二甲基缩醛为起始原料,经硝化、加成、环合、还原、缩合等6步反应合成目标化合物。以伊马替尼为阳性对照药,采用台盼蓝排染法,以慢性粒细胞白血病K562细胞为测试细胞株,对目标化合物进行体外抗白血病活性评价。所合成的18个化合物结构经1HNMR和MS确证。初步药理实验结果表明,目标化合物对K562细胞有一定的抗肿瘤活性,但低于阳性对照药伊马替尼和先导化合物。酰胺键结构对保持活性有重要的影响,是药物与受体的重要结合位点。     

外泌体在白血病免疫调节中的作用

外泌体是活细胞分泌至胞外的一种微囊泡结构,携带有亲本细胞来源的核酸、蛋白质和脂质等生物大分子信息,是细胞间的通讯载体。外泌体与肿瘤细胞的免疫逃逸、增殖、迁移与血管生成等恶性生物学行为有关,促使白血病细胞对化疗药物产生耐药以及诱导T细胞凋亡。外泌体促进免疫系统激活,是一种潜在的白血病免疫治疗疫苗。另外,外泌体是发现白血病诊断和治疗生物标记物的一个窗口。本文就外泌体的生物学特性及其在白血病免疫调节中的作用作一综述。     

阿糖胞苷衍生物的合成与应用研究进展

阿糖胞苷是重要的细胞周期特异性药物,主要用于急性白血病的治疗。该文总结了近年来阿糖胞苷衍生物在合成和应用方面的研究进展,为阿糖胞苷衍生物的进一步研究开发提供了参考。     

吡唑衍生物的合成与细胞毒性研究

设计合成了七个吡唑类化合物,通过1H NMR和质谱分析对所合成的化合物进行了结构表征,并且用四甲基偶氮唑蓝(MTT)染色法测试了它们对Bel-7402(人肝癌细胞)、KB(口腔表皮样癌细胞)、HL-60(白血病细胞)和BGC-823(胃腺癌细胞)四类癌细胞株的细胞毒性,测试结果表明,4f对Bel-7402和BGC-823细胞株有较高的细胞毒性。     

一种抗人T淋巴细胞免疫球蛋白淋巴细胞毒效价检测方法的建立

目的 建立基于人白血病T细胞株Jurkat的抗人T淋巴细胞免疫球蛋白(anti-human T lymphocyte immunoglobulin,ALG)淋巴细胞毒效价定量检测方法,并进行验证。方法 采用人Jurkat细胞作为靶细胞,抗人T细胞兔免疫球蛋白(商品名：Grafalon)作为待检样品,建立其淋巴细胞毒效价定量检测方法。优化反应体系,考察细胞培养密度、细胞代次对待检样品效价的影响,并对方法的精密度进行验证。结果 优化的反应体系组成为50μL待检样品+50μL补体(1∶5稀释)+50μL细胞(5×10⁶个/mL);细胞传代密度为2×10⁵个/mL传代培养72 h或3×10⁵个/mL传代培养48 h用于效价测定最佳;当细胞生长状态较好且一致时,从P10到P25代次的细胞效价测定结果较一致。采用该方法板内重复测定待检样品效价,变异系数(CV)为6.32%,重复性良好;不同代次Jurkat细胞测定待检样品效价6次,CV为4.15%,中间精密度良好。结论 建立了一种便捷、精确的测定ALG淋巴细胞毒效价的定量检测方法,为...     

两步酶法合成阿糖鸟苷

The chemical synthesis of Guanine arabinoside （ara-G） is extremely complex, time-consuming, and seriously polluted. A two-step enzymatic synthesis process was developed to acquire ara-G easily. 2,6-Diaminopurine arabinoside （ara-DA） was first synthesized with purine nucleoside phosphorylase and pyrimidine nucleoside phosphorylase produced by Enterobacter aerogenes DGW-07. The conversion yield of ara-DA could reach above 90% when the reaction liquid contained 30 mmol·L^-1 uracil arabinoside as arabinose donor, 10 mmol·L^- 1 2,6-diaminopurine as arabinose acceptor in pH 7.0 20 mmol·L^-1 phosphate buffer, and reacted at 60℃ for 48h. Then, ara-DA was effectively transformed into ara-G with adenylate deaminase produced by Aspergillus oryzae DAW-01. The total process had no complex separation and purification.     

Effects of dietary n−3 polyunsaturated fatty acids on T-Cell membrane composition and function

Dietary n−3 PUFA have been shown to attenuate T-cell-mediated inflammation, in part, by suppressing T-cell activation and proliferation. n−3 PUFA have also been shown to promote apoptosis, another important mechanism for the prevention of chronic inflammation by maintaining T-cell homeostasis through the contraction of populations of activated T cells. Recent studies have specifically examined Fas death receptor-mediated activation-induced cell death (AICD), since it is the form of apoptosis associated with peripheral T-cell deletion involved in immunological tolerance and T-cell homeostasis. Data from our laboratory indicate that n−3 PUFA promote AICD in T helper 1 polarized cells, which are the mediators of chronic inflammation. Since Fas and components of the deathinducing signaling complex are recruited to plasma membrane microdomains (rafts), the effect of dietary n−3 PUFA on raft composition and resident protein localization has been the focus of recent investigations. Indeed, there is now compelling evidence that dietary n−3 PUFA are capable of modifying the composition of T-cell membrane microdomains (rafts). Because the lipids found in membrane microdomains actively participate in signal transduction pathways, these results support the hypothesis that dietary n−3 PUFA influence signaling complexes and modulate T-cell cytokinetics in vivo by altering T-cell raft composition.     

CD40/APC-specific antibodies with three T-cell epitopes loaded in the constant domains induce CD4+ T-cell responses

CD4+ T lymphocytes play a central role in the orchestration and maintenance of the adaptive immune response. Targeting of antigen to antigen presenting cells (APCs) increases peptide loading of major histocompatibility complex (MHC) class II molecules and CD4+ T-cell activation. APCs have been targeted by APC-specific recombinant antibodies (rAbs) with single T-cell epitopes integrated in the constant region of the heavy chain (C(H)). However, the strategy may be improved if several T-cell epitopes could be delivered simultaneously by one rAb. We here demonstrate that a single rAb can be loaded with multiple identical or different T-cell epitopes, integrated as loops between β-strands in C(H) domains. One epitope was inserted in C(H)1, while two were placed in C(H)2 of IgG. T-cell proliferation assays showed that all three peptides were excised from loops and presented on MHC class II to T-cells. Induction of T-cell activation by each epitope in the multi-peptide rAb was as good, or even better, than that elicited by corresponding single-peptide rAbs. Furthermore, following DNA vaccination of mice with plasmids that encode CD40-specific rAbs loaded with either one or three peptides, T-cell responses were induced. Thus, integration of multiple epitopes in C(H) region loops of APC-specific rAbs is feasible and may be utilized in design of multi-vaccines.     

Role of Histone Deacetylases in T-Cell Development and Function

Histone deacetylases (HDACs) are a group of enzymes called “epigenetic erasers”. They remove the acetyl group from histones changing the condensation state of chromatin, leading to epigenetic modification of gene expression and various downstream effects. Eighteen HDACs have been identified and grouped into four classes. The role of HDACs in T-cells has been extensively studied, and it has been proven that many of them are important players in T-cell development and function. In this review, we present the current state of knowledge on the role of HDACs in the early stages of T-cell development but also in the functioning of mature lymphocytes on the periphery, including activation, cytokine production, and metabolism regulation.     

Epigenetics of Cutaneous T-Cell Lymphomas

Epigenetic modifications rarely occur in isolation (as single “epigenetic modifications”). They usually appear together and form a network to control the epigenetic system. Cutaneous malignancies are usually affected by epigenetic changes. However, there is limited knowledge regarding the epigenetic changes associated with cutaneous lymphomas. In this review, we focused on cutaneous T-cell lymphomas such as mycosis fungoides, Sézary syndrome, and anaplastic large cell lymphoma. With regard to epigenetic changes, we summarize the detailed chemical modifications categorized into DNA methylation and histone acetylation and methylation. We also summarize the epigenetic modifications and characteristics of the drug for cutaneous T-cell lymphoma (CTCL). Furthermore, we discuss current research on epigenetic-targeted therapy against cutaneous T-cell lymphomas. Although the current method of treatment with histone deacetylase inhibitors does not exhibit sufficient therapeutic benefits in all cases of CTCL, epigenetic-targeted combination therapy might overcome this limitation for patients with CTCL.     

Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy

The advent of T-cell-based immunotherapy has remarkably transformed cancer patient treatment. Despite their success, the currently approved immunotherapeutic protocols still encounter limitations, cause toxicity, and give disparate patient outcomes. Thus, a deeper understanding of the molecular mechanisms of T-cell activation and inhibition is much needed to rationally expand targets and possibilities to improve immunotherapies. Protein ubiquitination downstream of immune signaling pathways is essential to fine-tune virtually all immune responses, in particular, the positive and negative regulation of T-cell activation. Numerous studies have demonstrated that deregulation of ubiquitin-dependent pathways can significantly alter T-cell activation and enhance antitumor responses. Consequently, researchers in academia and industry are actively developing technologies to selectively exploit ubiquitin-related enzymes for cancer therapeutics. In this review, we discuss the molecular and functional roles of ubiquitination in key T-cell activation and checkpoint inhibitory pathways to highlight the vast possibilities that targeting ubiquitination offers for advancing T-cell-based immunotherapies.     

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.     

The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

The interaction of the T-cell receptor (TCR) with a peptide in the major histocompatibility complex (pMHC) plays a central role in the adaptive immunity of higher chordates. Due to the high specificity and sensitivity of this process, the immune system quickly recognizes and efficiently responds to the appearance of foreign and altered self-antigens. This is important for ensuring anti-infectious and antitumor immunity, in addition to maintaining self-tolerance. The most common parameter used for assessing the specificity of TCR-pMHC interaction is affinity. This thermodynamic characteristic is widely used not only in various theoretical aspects, but also in practice, for example, in the engineering of various T-cell products with a chimeric (CAR-T) or artificial (TCR-engineered T-cell) antigen receptor. However, increasing data reveal the fact that, in addition to the thermodynamic component, the specificity of antigen recognition is based on the kinetics and mechanics of the process, having even greater influence on the selectivity of the process and T lymphocyte activation than affinity. Therefore, the kinetic and mechanical aspects of antigen recognition should be taken into account when designing artificial antigen receptors, especially those that recognize antigens in the MHC complex. This review describes the current understanding of the nature of the TCR-pMHC interaction, in addition to the thermodynamic, kinetic, and mechanical principles underlying the specificity and high sensitivity of this interaction.