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Integrating omics data for personalized medicine in treating psoriasis 整合组学数据用于个体化治疗牛皮癣
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-27 DOI: 10.1007/s00044-024-03355-4
Manish Ramchandani, Amit Kumar Goyal

Psoriasis is a chronic, multifactorial skin disorder characterized by the hyperproliferation of keratinocytes and persistent inflammation. It is driven by a complex interplay of genetic, immunological, and environmental factors. The heterogeneous nature of this disease presents significant challenges for effective diagnosis and treatment. Recent advancements in omics technologies such as genomics, transcriptomics, proteomics, and metabolomics have revolutionized our ability to understand the molecular basis of psoriasis. These technologies offer novel insights into disease mechanisms, identifying potential biomarkers for early diagnosis, disease progression, and therapeutic response. Further, longitudinal studies utilizing real-world patient data and advanced computational models will enable dynamic disease monitoring, offering prospects for predictive diagnostics and earlier intervention. As personalized treatment plans become more sophisticated, the evolution of omics-guided therapeutic strategies could revolutionize the standard of care in psoriasis, fostering a transition from reactive to preventative approaches. This review aims to elucidate the critical role of omics approaches in unraveling the intricate biological pathways involved in psoriasis and exploring how specific omics data serve as powerful tools for classifying patients and tailoring treatment options based on individual molecular profiles. Further, longitudinal studies utilizing real-world patient data and advanced computational models will enable dynamic disease monitoring, offering prospects for predictive diagnostics and earlier intervention. As personalized treatment plans become more sophisticated, the evolution of omics-guided therapeutic strategies could revolutionize the standard of care in psoriasis, fostering a transition from reactive to preventative approaches. Addressing current challenges in data integration and clinical applicability will be pivotal in advancing towards this future, with the potential to significantly improve patient outcomes and quality of life.

牛皮癣是一种慢性、多因素的皮肤疾病,其特征是角化细胞过度增生和持续炎症。它是由遗传、免疫和环境因素的复杂相互作用驱动的。这种疾病的异质性对有效的诊断和治疗提出了重大挑战。基因组学、转录组学、蛋白质组学和代谢组学等组学技术的最新进展彻底改变了我们了解牛皮癣分子基础的能力。这些技术为疾病机制提供了新的见解,确定了早期诊断、疾病进展和治疗反应的潜在生物标志物。此外,利用真实世界患者数据和先进计算模型的纵向研究将实现动态疾病监测,为预测性诊断和早期干预提供前景。随着个性化治疗计划变得越来越复杂,以组学为指导的治疗策略的发展可能会彻底改变牛皮癣的治疗标准,促进从反应性方法到预防性方法的转变。本综述旨在阐明组学方法在揭示银屑病复杂生物学途径中的关键作用,并探索特定组学数据如何作为分类患者和基于个体分子谱定制治疗方案的强大工具。此外,利用真实世界患者数据和先进计算模型的纵向研究将实现动态疾病监测,为预测性诊断和早期干预提供前景。随着个性化治疗计划变得越来越复杂,以组学为指导的治疗策略的发展可能会彻底改变牛皮癣的治疗标准,促进从反应性方法到预防性方法的转变。解决当前在数据整合和临床适用性方面的挑战将是迈向未来的关键,有可能显著改善患者的预后和生活质量。
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引用次数: 0
Synthesis and biological assessment of triazolo-quinazoline carbothioamide derivatives for p38 MAP kinase inhibition: in-silico and in-vitro approaches 三唑-喹唑啉碳硫酰胺衍生物对p38 MAP激酶抑制的合成和生物学评价:硅内和体外方法
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-27 DOI: 10.1007/s00044-024-03348-3
CH Keerthi, Ramesh Kola, Divya Pingili, Archana Awasthi, DSNBK Prasanth, Chamakuri Kantlam

A series of 4-Alkyl-5-oxo-N-(pyridin-3-yl)-4,5-dihydro [1,2,3] triazolo[1,5-a] quinazoline-3-carbothioamide compounds (8a-8k) were synthesized as p38 MAP kinase inhibitors, which could potentially be used as anticancer agents. The synthesized compounds were assessed for their effectiveness in inhibiting cancer using the MCF-7 cancer cell line. The results showed that compound 8a had the highest potency, with an IC50 value of 39.76 ± 0.25 µM. Compound 8f and 8d exhibited noteworthy activity, with IC50 values of 40.43 ± 2.04 µM and 42.15 ± 2.15 µM, respectively. Compound 8a was found to effectively bind with the active site of p38α MAP kinase, with the PDB ID 1W7H. The docking score was found to be −8.8 kcal/mol. The ADME experiments, following Lipinski’s rule of five and Ergan’s egg graph, showed that all the synthesized compounds had excellent oral bioavailability and acceptable stomach absorption. Compound 8a stood out as the most potent drug in the series, exhibiting considerable docking affinity, ADME profile, and p38 MAP kinase inhibitory action. The findings indicated that compound 8a has promising p38 kinase inhibition and can be a possible therapeutic drug for further investigation.

合成了一系列4-烷基-5-氧- n-(吡啶-3-基)-4,5-二氢[1,2,3]三唑[1,5- A]喹唑啉-3-碳硫酰胺化合物(8a-8k)作为p38 MAP激酶抑制剂,具有潜在的抗癌作用。利用MCF-7癌细胞系对合成的化合物进行了抑癌效果评估。结果表明,化合物8a的效价最高,IC50值为39.76±0.25µM。化合物8f和8d的IC50值分别为40.43±2.04µM和42.15±2.15µM。发现化合物8a与p38α MAP激酶活性位点有效结合,PDB ID为1W7H。对接评分为−8.8 kcal/mol。ADME实验采用Lipinski 's rule of five和Ergan 's egg图,结果表明所有合成的化合物具有良好的口服生物利用度和可接受的胃吸收。化合物8a是该系列中最有效的药物,具有相当大的对接亲和力、ADME谱和p38 MAP激酶抑制作用。研究结果表明,化合物8a具有良好的p38激酶抑制作用,可能成为进一步研究的治疗药物。
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引用次数: 0
Design, synthesis, stereochemical characterization, in vitro α-glucosidase, and α-amylase inhibition and in silico studies of novel pyrazole-hydrazide hydrazones 新型吡唑-肼腙的设计、合成、立体化学表征、α-葡萄糖苷酶和α-淀粉酶的体外抑制和硅研究
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-25 DOI: 10.1007/s00044-024-03335-8
Issam Ameziane El Hassani, Salma Mortada, Njabulo J. Gumede, Hamza Assila, Ali Alsalme, Afaf Oulmidi, My El Abbes Faouzi, Khalid Karrouchi, M’hammed Ansar

In this work, a novel series of fifteen pyrazole-linked hydrazide-hydrazone derivatives (4a-o) were designed, synthesized, characterized, and evaluated for their antihyperglycemic activity against α-amylase and α-glucosidase. In vitro results revealed that all synthesized compounds (4a-o) showed good to excellent antihyperglycemic activity with IC50 in the range of 30.58 ± 0.56–290.70 ± 2.77 μM for α-glucosidase and in the range of 29.08 ± 0.56–160.70 ± 0.80 μM, as compared to the standard inhibitor acarbose (IC50(α-glucosidase) = 98.12 ± 2.10 µM and IC50(α-amylase) = 126.50 ± 2.01 µM). Among the series, compound 4m with hydroxy group in para position at phenyl ring was also found as the most potent inhibitor of α-amylase and α-glucosidase with IC50 values of 29.08 ± 0.86 and 30.58 ± 0.56 μM, respectively, indicating their better potency than the standard acarbose. In silico molecular docking and molecular dynamic simulations further confirmed the binding modes and binding affinities of compound 4m and acarbose. The Structure-Activity Relationship (SAR) analysis of the effects of some functional groups in the co-structure of 4m were confirmed by IFD and MDS for both α-amylase and α-glucosidase inhibitor recognition.

在这项工作中,设计、合成了一系列新的15种吡唑连接的肼腙衍生物(4a-o),并对其抗α-淀粉酶和α-葡萄糖苷酶的高血糖活性进行了表征和评价。体外实验结果表明,与标准抑制剂阿卡波糖(α-葡萄糖苷酶IC50 = 98.12±2.10µM, α-淀粉酶IC50 = 126.50±2.01µM)相比,合成的化合物(4a-o)对α-葡萄糖苷酶的IC50范围为30.58±0.56 ~ 290.70±2.77 μM, IC50范围为29.08±0.56 ~ 160.70±0.80 μM)均表现出较好的降糖活性。其中,苯环羟基对位化合物4m对α-淀粉酶和α-葡萄糖苷酶的抑制作用最强,IC50值分别为29.08±0.86 μM和30.58±0.56 μM,其抑制作用优于标准阿卡波糖。硅分子对接和分子动力学模拟进一步证实了化合物4m与阿卡波糖的结合模式和结合亲和力。IFD和MDS证实了4m共结构中部分官能团对α-淀粉酶和α-葡萄糖苷酶抑制剂识别的构效关系(SAR)分析。
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引用次数: 0
α-Glucosidase inhibitory activities of aromatic compounds from the rhizomes of Alpinia galanga 高良姜根茎芳香族化合物α-葡萄糖苷酶抑制活性研究
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-23 DOI: 10.1007/s00044-024-03357-2
Yueh-Hung Cheng, Po-Chun Chen, Zakhele M. Dlamini, Jia-Wei Li, Bongani S. Dlamini, Yu-Kuo Chen, Chi-I Chang

Inhibition of α-glucosidase is a widely recognized approach for managing hyperglycemia, particularly postprandial glucose spikes. In this study, the α-glucosidase inhibitory activity and interaction mechanisms of aromatic compounds isolated from the rhizomes of Alpinia galanga were investigated using the p-nitrophenol-α-D-glucopyranoside (pNPG) bioassay and molecular docking. The isolated aromatic compounds (14) showed significant α-glucosidase inhibitory activity with IC50 values between 25 and 104 µM compared to the positive control acarbose (IC50 = 1236.42 ± 1.30 µM). The experimental data showed that the most potent inhibitor of α-glucosidase (E)-p-coumaryl alcohol-γ-O-methyl ether (3) inhibited the enzyme via a mixed-type mechanism, with an IC50 value of 25.00 ± 1.01 µM. Molecular docking indicated that compound 3 decreased the catalytic efficiency of α-glucosidase by competitively binding to the active pocket, thereby blocking the substrate. The binding activity is mainly mediated by hydrogen bonds and hydrophobic interactions. The results suggest that these aromatic compounds from A. galanga could serve as potential therapeutic agents for the control of postprandial hyperglycemia and the treatment of type 2 diabetes.

抑制α-葡萄糖苷酶是一种被广泛认可的治疗高血糖的方法,特别是餐后血糖峰值。本研究采用对硝基酚-α- d -葡萄糖苷(pNPG)生物测定和分子对接的方法,对高良姜根茎中分离的芳香族化合物的α-葡萄糖苷酶抑制活性及其相互作用机制进行了研究。与阳性对照阿卡波糖(IC50 = 1236.42±1.30µM)相比,分离得到的芳香族化合物(1 ~ 4)具有明显的α-葡萄糖苷酶抑制活性,IC50值在25 ~ 104µM之间。实验结果表明,α-葡萄糖苷酶抑制剂(E)-对香豆醇-γ- o -甲基醚(3)的抑制作用为混合型,IC50值为25.00±1.01µM。分子对接表明,化合物3通过竞争性结合活性口袋,阻断底物,从而降低α-葡萄糖苷酶的催化效率。结合活性主要由氢键和疏水相互作用介导。结果提示,高良姜中这些芳香族化合物可作为控制餐后高血糖和治疗2型糖尿病的潜在药物。
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引用次数: 0
A fragment-based screen for inhibitors of Escherichia coli N5-CAIR mutase 基于片段的大肠杆菌 N5-CAIR 突变酶抑制剂筛选
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-23 DOI: 10.1007/s00044-024-03356-3
Marcella F. Sharma, Steven M. Firestine

Although purine biosynthesis is a primary metabolic pathway, there are fundamental differences between how purines are synthesized in microbes versus humans. In humans, the purine intermediate, 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) is directly synthesized from 5-aminoimidazole ribonucleotide (AIR) and carbon dioxide by the enzyme AIR carboxylase. In bacteria, yeast and fungi, CAIR is synthesized from AIR via an intermediate N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) by the enzyme N5-CAIR mutase. The difference in pathways between humans and microbes indicate that N5-CAIR mutase is a potential antimicrobial drug target. To identify inhibitors of E. coli N5-CAIR mutase, a fragment-based screening campaign was conducted using a thermal shift assay and a library of 4,500 fragments. Twenty-eight fragments were initially identified that displayed dose-dependent binding to N5-CAIR mutase with Kd values ranging from 9–309 µM. Of the 28, 14 were obtained from commercial sources for retesting; however, only 5 showed dose-dependent binding to N5-CAIR mutase. The five fragments were assessed for their ability to inhibit enzyme activity. Four out of the 5 showed inhibition with Ki values of 4.8 to 159 µM. All fragments contained nitrogen heterocycles with 3 out of the 4 containing 5-membered heterocycles like those found in the substrate of the enzyme. The identified fragments show similarities to compounds identified from studies on B. anthracis N5-CAIR mutase and human AIR carboxylase suggesting a common pharmacophore.

虽然嘌呤的生物合成是一种主要的代谢途径,但微生物与人类合成嘌呤的方式存在根本差异。在人体中,嘌呤中间体4-羧基-5-氨基咪唑核糖核苷酸(CAIR)是由5-氨基咪唑核糖核苷酸(AIR)和二氧化碳通过AIR羧化酶直接合成的。在细菌、酵母和真菌中,CAIR是由AIR经中间的n5 -羧基氨基咪唑核糖核苷酸(N5-CAIR)由N5-CAIR突变酶合成的。人类和微生物途径的差异表明N5-CAIR突变酶是一个潜在的抗菌药物靶点。为了鉴定大肠杆菌N5-CAIR突变酶的抑制剂,使用热移法和4500个片段文库进行了基于片段的筛选活动。初步鉴定出28个片段显示与N5-CAIR突变酶的剂量依赖性结合,Kd值为9-309µM。在28个样本中,有14个来自商业来源进行复检;然而,只有5个与N5-CAIR突变酶表现出剂量依赖性结合。对这五个片段进行了酶活性抑制能力的评估。其中4个具有抑制作用,Ki值为4.8 ~ 159µM。所有片段都含有氮杂环,其中4个片段中有3个含有5元杂环,与酶底物中发现的杂环相似。鉴定的片段与炭疽芽孢杆菌N5-CAIR突变酶和人AIR羧化酶研究中鉴定的化合物相似,表明它们是共同的药效团。
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引用次数: 0
Oligonucleotides: evolution and innovation 寡核苷酸:演变与创新
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-21 DOI: 10.1007/s00044-024-03352-7
Amani A. Mohammed, Danah AlShaer, Othman Al Musaimi

Oligonucleotides, comprising single or double strands of RNA or DNA, are vital chemical compounds used in various laboratory and clinical applications. They represent a significant class of therapeutics with a rapidly expanding range of uses. Between 1998 and 2023, 19 oligonucleotides have received approval from the U.S. Food and Drug Administration (FDA). Their synthesis methods have undergone significant evolution over time. This review examines several oligonucleotide synthesis techniques, including phosphodiester, phosphotriester, and phosphoramidite approaches. It begins with a discussion of an early synthesis method involving a phosphoryl chloride intermediate, which proved unstable and prone to hydrolysis. The review then transitions to the solid-phase synthesis method, which uses polymer resins as a solid support, emphasizing its advantages over both phosphotriester and phosphoramidite techniques. This is followed by an exploration of recent advancements in oligonucleotide enzymatic synthesis, concluding with a discussion on modifications to bases, sugars, and backbones designed to improve their properties and therapeutic potential.

由单链或双链RNA或DNA组成的寡核苷酸是用于各种实验室和临床应用的重要化合物。它们代表了一类重要的治疗药物,其使用范围正在迅速扩大。1998年至2023年间,有19种寡核苷酸获得了美国食品和药物管理局(FDA)的批准。随着时间的推移,它们的合成方法经历了重大的演变。本文综述了几种寡核苷酸合成技术,包括磷酸二酯、磷酸三酯和磷酸酰胺方法。它首先讨论了一种早期的合成方法,涉及一种磷酸酰氯中间体,它被证明是不稳定的,容易水解。然后,回顾过渡到固相合成方法,该方法使用聚合物树脂作为固体载体,强调其优于磷酸三酯和磷酸酰胺技术。随后探讨了寡核苷酸酶合成的最新进展,最后讨论了对碱基、糖和骨架的修饰,以改善其性质和治疗潜力。
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引用次数: 0
A guide for asymmetric synthesis of morphine alkaloids 吗啡生物碱的不对称合成指南
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-21 DOI: 10.1007/s00044-024-03350-9
Hui Zhao, Yunfei Cheng

A collection of structurally related natural compounds derived from Papaver somniferum, the opium poppy, are known as the morphine alkaloids. Many generations of synthetic chemists have been drawn to the synthesis of morphine and its derivatives owing to their extraordinarily complex molecular architecture and exceptional biological activity. This overview highlights recent advance in the asymmetric synthesis of morphine alkaloids, focusing on various strategies for introducing and controlling chirality, which will hasten the feasibility of commercial production of morphinan.

从罂粟中提取的一系列结构相关的天然化合物被称为吗啡生物碱。由于吗啡及其衍生物异常复杂的分子结构和特殊的生物活性,许多代的合成化学家都被吸引到吗啡及其衍生物的合成中。本文综述了吗啡生物碱不对称合成的最新进展,重点介绍了引入和控制手性的各种策略,这将加快吗啡inan商业化生产的可行性。
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引用次数: 0
Design, synthesis and antitumor activity evaluation of benzimidazole derivatives with potent HDAC inhibitory activity 具有强HDAC抑制活性的苯并咪唑衍生物的设计、合成及抗肿瘤活性评价
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-21 DOI: 10.1007/s00044-024-03349-2
Jiantao Ping, Hongrui Chu, Yisheng Zhao, Chen Chen

This study aims to design and synthesize novel benzimidazole histone deacetylase (HDAC) inhibitors to explore their potential applications in the treatment of cancer and other related diseases. By comparing the structures of our reported benzimidazole HDAC inhibitors, we designed a series of compounds accordingly. We then used experimentally verified their inhibitory activity against HDAC enzymes. The results showed that several of the newly synthesized compounds showed good HDAC inhibition and anti-proliferative activity. Therefore, we conclude that these novel HDAC inhibitors have potential as drug candidates for the treatment of cancer.

本研究旨在设计合成新型苯并咪唑类组蛋白去乙酰化酶(HDAC)抑制剂,探索其在癌症等相关疾病治疗中的应用潜力。通过比较我们所报道的苯并咪唑类HDAC抑制剂的结构,我们相应地设计了一系列化合物。然后用实验验证了它们对HDAC酶的抑制活性。结果表明,新合成的几种化合物具有良好的抑制HDAC和抗增殖活性。因此,我们得出结论,这些新的HDAC抑制剂有潜力作为治疗癌症的候选药物。
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引用次数: 0
Phytochemical constituents isolated from Silene popovii Schischk 牡丹的植物化学成分分离
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-20 DOI: 10.1007/s00044-024-03345-6
Ugiloy Yu. Yusupova, Khayrulla M. Bobakulov, Alisher R. Khurramov, Vladimir N. Syrov, Feruza R. Egamova, Anas Karuth, Durbek A. Usmanov, Mohiuddin Quadir, Bakhtiyor Rasulev

In this work, with the aim to find new and biologically active natural compounds, the chemical content of the apolar and polar extracts (aerial part) of Silene popovii has been investigated. The obtained extracts of Silene popovii Schischk were purified by column chromatography (CC), and four compounds were isolated: one of them is a new saponin compound—silepovin (1), as well as three known secondary metabolites, 2-deoxy-α-ecdysone (2), cauloside A (3) and 20-hydroxyecdysone 22-benzoate (4). The structural elucidation of isolated compounds was performed using the 1D and 2D NMR spectroscopy analyses and LC-MS analysis, and all four structures were confirmed. For the new compound 1, an in vivo study of anti-inflammatory activity was conducted. The in vivo analysis has shown significant anti-inflammatory effects.

为了寻找新的具有生物活性的天然化合物,研究了水杨花极性和极性提取物(气相部分)的化学成分。通过柱层析(CC)纯化得到4个化合物,其中1个为新皂苷类化合物silepovin(1), 3个已知次生代谢产物2-脱氧-α-蜕皮酮(2)、cauloside a(3)和20-羟基蜕皮酮22-苯甲酸酯(4)。通过1D和2D NMR分析和LC-MS分析对分离得到的化合物进行了结构鉴定,证实了这4个化合物的结构。对新化合物1进行了体内抗炎活性研究。体内分析显示有明显的抗炎作用。
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引用次数: 0
Thiophene ring-opening reactions. Part VII: synthesis and antitumor, anti-inflammatory, and antioxidant properties of 1,3,4‒thiadiazoline‒6-sulfanylthiopyran-4(1H)-one hybrids 噻吩开环反应。第七部分:1,3,4 -噻二唑啉- 6-巯基硫代吡喃-4(1H)- 1杂合体的合成及其抗肿瘤、抗炎和抗氧化性能
IF 2.6 4区 医学 Q3 CHEMISTRY, MEDICINAL Pub Date : 2024-11-18 DOI: 10.1007/s00044-024-03343-8
Shaima K. Alsawaleha, Jalal A. Zahra, Mustafa M. El-Abadelah, Violet Kasabri, Salim S. Sabri, Monther A. Khanfar

The reaction of N′’(aryl)benzothiohydrazides with 2-chloro-6-((substituted)amino)-3-nitro-4-oxo-4H-thieno[2,3-b]thiopyran-5-carboxylate (13-15) under basic conditions (NEt3) in acetonitrile proceeds via thiophene ring-opening processes and yields, upon addition of iodomethane, the respective 1,3,4-thiadiazoline-6-sulfanylthiopyran-4(1H)-one hybrids. The new compounds were characterized by HRMS and NMR spectral data and confirmed by single-crystal X-ray crystallography. The cytotoxicity affinities for compounds 10-17 were evaluated in cross-correlations with their anti-inflammation and radical scavenging capacities. Compound 13 exhibited the highest cytotoxic properties, with IC50 values ranging from 160 nM in mammary T47D to less than 20.35 µM in colorectal CACO2 among 12 diverse cancer monolayers. Compound 17c significantly reduced lung and mammary cancer cell viability, with anti-tumorigenesis IC50 values of less than 10 µM. These new compounds have the potential to be further optimized into novel selective cytotoxic treatments.

N ' '(芳基)苯并噻唑肼与2-氯-6-(取代)氨基)-3-硝基-4-氧-4- h -噻吩[2,3-b]硫代吡喃-5-羧酸盐(13-15)在乙腈碱性条件下通过噻吩开环过程进行反应,在加入碘甲烷后,分别得到1,3,4-噻二唑-6-磺胺基硫代吡喃-4(1H)- 1杂化物。用HRMS和NMR谱数据对新化合物进行了表征,并用单晶x射线晶体学对其进行了确证。化合物10-17的细胞毒性亲和性与抗炎能力和自由基清除能力相互关联。化合物13表现出最高的细胞毒性,在12种不同的肿瘤单层中,其IC50值从乳腺T47D的160 nM到结直肠CACO2的20.35µM以下。化合物17c显著降低肺癌和乳腺癌细胞活力,抗肿瘤IC50值小于10µM。这些新化合物有可能进一步优化为新的选择性细胞毒治疗方法。
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引用次数: 0
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