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Design, synthesis, and anticancer assessment of structural analogues of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an imidazo[1,2-a]quinoxaline-based non-covalent EGFR inhibitor† (E)-1-((3,4,5-三甲氧基亚苄基)氨基)-4-(3,4,5-三甲氧基苯基)咪唑并[1,2-a]喹喔啉-2-甲腈(6b)结构类似物的设计、合成和抗癌评估--一种基于咪唑并[1,2-a]喹喔啉的非共价表皮生长因子受体抑制剂
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-20 DOI: 10.1039/D4MD00237G
Manvendra Kumar, Kiran T. Patil, Pritam Maity, Joydeep Chatterjee, Tashvinder Singh, Gaurav Joshi, Sandeep Singh and Raj Kumar

In our quest to find improved anticancer therapeutics, we expedite the lead optimization of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an EGFR inhibitor previously discovered in our laboratory through an in-house screening program. The lead optimization was rationally initiated considering the catalytic site of EGFR. We synthesized twenty-nine new analogues of 6b and assessed their anticancer activities. SAR studies highlighted the role of important groups in controlling anticancer activities. Among all, 5a and 5l were found to exhibit improved EGFR inhibition with anticancer asset potential. In silico studies corroborated with in vitro EGFR inhibitory results. The deeper analysis of 5a and 5l revealed that these synthetics could alter the MMP (ΔΨm) and significantly reduce the ROS levels in lung cancer cells. This is a vital prerequisite for better plausible EGFR inhibitors devoid of cardiotoxicity. qPCR analysis further revealed that the investigational compounds 5a and 5l were able to downregulate the expression of key oncogenes, viz., KRAS, MAP2K, and EGFR. The downregulation of these genes suggests that the investigational compounds could interact and inhibit key players in the signalling cascade along with the EGFR, which may lead to the inhibition of the growth and prognosis of cancer cells via a holistic approach.

为了寻找更好的抗癌疗法,我们加快了(E)-1-((3,4,5-三甲氧基亚苄基)氨基)-4-(3,4,5-三甲氧基苯基)咪唑并[1,2-a]喹喔啉-2-甲腈(6b)的先导优化,这是我们实验室之前通过内部筛选计划发现的一种表皮生长因子受体抑制剂。考虑到表皮生长因子受体的催化位点,我们对先导化合物进行了合理的优化。我们合成了 29 种新的 6b 类似物,并评估了它们的抗癌活性。SAR 研究强调了重要基团在控制抗癌活性中的作用。在所有类似物中,5a 和 5l 具有更好的表皮生长因子受体抑制作用和抗癌潜力。硅学研究与体外表皮生长因子受体抑制结果相吻合。对 5a 和 5l 的深入分析显示,这些合成物可以改变肺癌细胞中的 MMP(ΔΨm),并显著降低 ROS 水平。qPCR 分析进一步显示,研究化合物 5a 和 5l 能够下调关键癌基因(即 KRAS、MAP2K 和表皮生长因子受体)的表达。这些基因的下调表明,这些研究化合物可以与表皮生长因子受体相互作用并抑制信号级联中的关键角色,从而通过整体方法抑制癌细胞的生长和预后。
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引用次数: 0
Extension of multi-site analogue series with potent compounds using a bidirectional transformer-based chemical language model 利用基于双向转换器的化学语言模型,扩展多位点类似物系列的强效化合物
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-17 DOI: 10.1039/D4MD00423J
Hengwei Chen, Atsushi Yoshimori and Jürgen Bajorath

Generating potent compounds for evolving analogue series (AS) is a key challenge in medicinal chemistry. The versatility of chemical language models (CLMs) makes it possible to formulate this challenge as an off-the-beaten-path prediction task. In this work, we have devised a coding and tokenization scheme for evolving AS with multiple substitution sites (multi-site AS) and implemented a bidirectional transformer to predict new potent analogues for such series. Scientific foundations of this approach are discussed and, as a benchmark, the transformer model is compared to a recurrent neural network (RNN) for the prediction of analogues of AS with single substitution sites. Furthermore, the transformer is shown to successfully predict potent analogues with varying R-group combinations for multi-site AS having activity against many different targets. Prediction of R-group combinations for extending AS with potent compounds represents a novel approach for compound optimization.

为不断演化的类似物系列(AS)生成强效化合物是药物化学领域的一项关键挑战。化学语言模型(CLM)的多功能性使我们有可能将这一挑战制定为非主流预测任务。在这项工作中,我们为具有多个取代位点(多位点 AS)的 AS 演化设计了一种编码和标记化方案,并实施了一种双向转换器来预测此类系列的新的强效类似物。我们讨论了这种方法的科学基础,并将转换器模型与预测单取代位点 AS 类似物的递归神经网络(RNN)进行了比较。此外,研究还表明转化器能成功预测具有不同 R 组组合的强效类似物,这些类似物是针对许多不同靶点具有活性的多位点 AS。预测 R 基团组合以扩展 AS 的强效化合物是化合物优化的一种新方法。
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引用次数: 0
A comprehensive framework for managing metabolic dysfunction-associated steatotic liver disease: analyzing novel risk factors and advances in nanotechnology-based treatments and diagnosis 管理代谢功能障碍相关脂肪性肝病的综合框架:分析新的风险因素以及基于纳米技术的治疗和诊断进展
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-13 DOI: 10.1039/D4MD00420E
Lucia M. Chávez-López, Gabriela I. Carballo-López, Karina del Carmen Lugo-Ibarra and Ana B. Castro-Ceseña

Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.

代谢功能障碍相关性脂肪性肝病(MASLD)是一项日益严峻的全球性健康挑战,需要采用创新方法进行有效管理。本综述探讨了新的风险因素,包括重金属等环境污染物,并强调了受性别和性差异影响,根据患者个体情况定制个性化药物的复杂性。传统的 MASLD 治疗方法(如降糖和降脂药物)效果不一,突出表明有必要进行更大规模的长期研究,以确定其安全性和有效性。包括抗氧化剂、干细胞和抗血小板在内的替代疗法虽然前景广阔,但需要进行广泛的临床试验来验证。本综述强调了个性化医疗的重要性,即考虑个体差异和特定因素,如性别和性,以优化治疗反应。从代谢相关性脂肪肝(MAFLD)到MASLD术语的转变强调了该疾病的代谢成分,与多重打击理论相一致,并突出了全面风险因素管理的必要性。我们的愿景主张采用综合方法治疗 MASLD,包括广泛的风险因素分析和开发更安全、更有效的治疗方法。初级预防和宣传活动对于解决 MASLD 发病率不断上升的问题至关重要。未来的研究必须优先考虑更大规模的长期研究和个性化医疗原则,以确保有效利用新兴疗法和技术。本综述强调了在平衡纳米技术的益处和挑战的基础上不断探索和创新的必要性,以防治 MASLD 并全面改善患者的预后。
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引用次数: 0
Discovery of new 1,3-diphenylurea appended aryl pyridine derivatives as apoptosis inducers through c-MET and VEGFR-2 inhibition: design, synthesis, in vivo and in silico studies† 通过抑制 c-MET 和 VEGFR-2 发现作为细胞凋亡诱导剂的新型 1,3-二苯基脲附加芳基吡啶衍生物:设计、合成、体内和硅学研究
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-12 DOI: 10.1039/D4MD00280F
Heba A. Elsebaie, Mohamed S. Nafie, Haytham O. Tawfik, Amany Belal, Mohammed M. Ghoneim, Ahmad J. Obaidullah, Salwa Shaaban, Abdelmoneim A. Ayed, Mohamed El-Naggar, Ahmed B. M. Mehany and Moataz A. Shaldam

Interest has been generated in VEGFR-2 and c-MET as potential receptors for the treatment of different malignancies. Using aryl pyridine derivatives with 1,3-diphenylurea attached, a number of promising dual VEGFR-2 and c-MET inhibitors were developed and synthesized. Regarding the molecular target, compounds 2d, 2f, 2j, 2k, and 2n had potent IC50 values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC50 values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds 2d, 2f, 2j, 2k and 2n exhibited potent cytotoxicity against MCF-7 with IC50 values in the range 0.76–21.5 μM, and they showed promising cytotoxic activity against PC-3 with IC50 values in the range 1.85–3.42 μM compared to cabozantinib (IC50 = 1.06 μM against MCF-7 and 2.01 μM against PC-3). Regarding cell death, compound 2n caused cell death in MCF-7 cells by 87.34-fold; it induced total apoptosis by 33.19% (8.04% for late apoptosis, 25.15% for early apoptosis), stopping their growth in the G2/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. In vivo study illustrated the anticancer activity of compound 2n by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound 2n can be further developed as a selective target-oriented chemotherapeutic against breast cancer.

VEGFR-2 和 c-MET 作为治疗不同恶性肿瘤的潜在受体,引起了人们的兴趣。利用芳基吡啶衍生物与 1,3-二苯基脲的连接,开发并合成了一些有前景的 VEGFR-2 和 c-MET 双重抑制剂。在分子靶标方面,化合物 2d、2f、2j、2k 和 2n 对 c-MET 的有效 IC50 值分别为 65、24、150、170 和 18 nM。此外,它们对 VEGFR-2 的有效 IC50 值分别为 310、35、290、320 和 24 nM。在细胞毒性方面,化合物 2d、2f、2j、2k 和 2n 对 MCF-7 具有强效细胞毒性,IC50 值在 0.76-21.5 μM 之间;与卡博赞替尼(对 MCF-7 的 IC50 = 1.06 μM 和对 PC-3 的 IC50 = 2.01 μM)相比,它们对 PC-3 的 IC50 值在 1.85-3.42 μM 之间,显示出良好的细胞毒性活性。在细胞死亡方面,化合物 2n 可使 MCF-7 细胞死亡 87.34 倍;诱导 33.19% 的细胞凋亡(晚期凋亡为 8.04%,早期凋亡为 25.15%),使细胞在 G2/M 期停止生长,影响细胞凋亡相关基因 P53、Bax、caspases 3 和 9 以及抗凋亡基因 Bcl-2 的表达。体内研究表明,化合物 2n 具有抗癌活性,能减少肿瘤的体积和质量,肿瘤抑制率达到 56.1%,并能改善血液学指标。因此,化合物 2n 可进一步开发为针对乳腺癌的选择性靶向化疗药物。
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引用次数: 0
N-Sulfonylphenoxazines as neuronal calcium ion channel blockers† 作为神经元钙离子通道阻滞剂的 N-磺酰吩噁嗪类化合物
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-12 DOI: 10.1039/D4MD00336E
Matthieu Schmit, Md. Mahadhi Hasan, Yashad Dongol, Fernanda C. Cardoso, Michael J. Kuiper, Richard J. Lewis, Peter J. Duggan and Kellie L. Tuck

Neuropathic pain is a type of chronic pain, usually caused by nerve damage, that responds poorly to traditional pain therapies. The N-type calcium channel (CaV2.2) is a well-validated pharmacological target to treat this condition. In order to further improve the inhibition of the N-type calcium channel relative to previously described inhibitors, and also address their problematic instability in blood plasma, the development of N-sulfonylphenoxazines as new calcium channel inhibitors was pursued. A series of N-sulfonylphenoxazines bearing ammonium side chains were synthesised and tested for their ability to inhibit both CaV2.2 and CaV3.2 (T-type) neuronal ion channels. Compounds with low micromolar activity in CaV2.2 were identified, equivalent to the most effective reported for this class of bioactive, and calculations based on their physical and chemical characteristics suggest that the best performing compounds have a high likelihood of being able to penetrate the blood–brain barrier. Representative N-sulfonylphenoxazines were tested for their stability in rat plasma and were found to be much more resilient than the previously reported N-acyl analogues. These compounds were also found to be relatively stable in an in vitro liver microsome metabolism model, the first time that this has been investigated for this class of compound. Finally, molecular modelling of the CaV2.2 channel was used to gain an understanding of the mode of action of these inhibitors at a molecular level. They appear to bind in a part of the channel, in and above its selectivity filter, in a way that hinders its ability to undergo the conformational changes required to open and allow calcium ions to pass through.

神经病理性疼痛是一种慢性疼痛,通常由神经损伤引起,对传统的疼痛疗法反应不佳。N 型钙通道(CaV2.2)是治疗这种病症的公认药理靶点。为了进一步提高 N 型钙通道抑制剂的疗效,并解决其在血浆中不稳定的问题,研究人员开发了 N-磺酰基吩噁嗪类新的钙通道抑制剂。我们合成了一系列带有铵侧链的 N-磺酰吩噁嗪,并测试了它们抑制 CaV2.2 和 CaV3.2(T 型)神经元离子通道的能力。根据这些化合物的物理和化学特性进行的计算表明,性能最好的化合物很有可能能够穿透血脑屏障。对具有代表性的 N-磺酰基吩噁嗪在大鼠血浆中的稳定性进行了测试,结果发现它们比之前报道的 N-酰基类似物更有弹性。研究还发现,这些化合物在体外肝微粒体代谢模型中相对稳定,这是首次对这一类化合物进行研究。最后,通过对 CaV2.2 通道进行分子建模,从分子水平上了解了这些抑制剂的作用模式。这些抑制剂似乎与通道的一部分结合,位于其选择性过滤器内部和上方,阻碍通道发生打开所需的构象变化,使钙离子无法通过。
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引用次数: 0
Correction: Highly potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors as broad-spectrum anti-rhinoviral agents 更正:作为广谱抗鼻病毒药物的高效力和选择性磷脂酰肌醇 4- 激酶 IIIβ 抑制剂
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-12 DOI: 10.1039/D4MD90022G
Avinash G. Vishakantegowda, Dasom Hwang, Prashant Chakrasali, Eunhye Jung, Joo-Youn Lee, Jin Soo Shin and Young-Sik Jung

Correction for ‘Highly potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors as broad-spectrum anti-rhinoviral agents’ by Avinash G. Vishakantegowda et al., RSC Med. Chem., 2024, 15, 704–719, https://doi.org/10.1039/D3MD00630A.

对 Avinash G. Vishakantegowda 等人发表的 "作为广谱抗鼻病毒药物的高效力和选择性磷脂酰肌醇 4- 激酶 IIIβ 抑制剂 "的更正。Vishakantegowda 等人,RSC Med.Chem.,2024,15,704-719,https://doi.org/10.1039/D3MD00630A。
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引用次数: 0
A method for estimation of plasma protein binding using diffusion ordered NMR spectroscopy (DOSY)† 利用扩散有序核磁共振光谱(DOSY)估算血浆蛋白结合力的方法
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-11 DOI: 10.1039/D4MD00244J
Rachel Taylor, Thomas Swift, David Wilkinson and Kamyar Afarinkia

The plasma protein binding (PPB) of a drug plays a key role in both its pharmacokinetic and pharmacodynamic properties. During lead optimisation, medium and high throughput methods for the early determination of PPB can provide important information about potential PKPD profile within a chemotype or between different chemotype series. Diffusion ordered spectroscopy (DOSY) is an NMR spectroscopic technique that measures the diffusion of a molecule through the magnetic field gradient, according to its molecular size/weight. Here, we describe the use of DOSY for a rapid and straightforward method to evaluate the PPB of drug molecules, using their binding to bovine serum albumin (BSA) as a model.

药物的血浆蛋白结合力(PPB)对其药代动力学和药效学特性起着关键作用。在先导药物优化过程中,用于早期测定 PPB 的中高通量方法可提供有关一种化学型内或不同化学型系列之间潜在 PKPD 特征的重要信息。扩散有序光谱(DOSY)是一种核磁共振光谱技术,可根据分子大小/重量测量分子在磁场梯度中的扩散情况。在这里,我们以药物分子与牛血清白蛋白(BSA)的结合为模型,介绍了如何利用 DOSY 快速、直接地评估药物分子的 PPB。
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引用次数: 0
New pyrazole–pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking, in silico studies and investigation of their anti-inflammatory potential by evaluation of TNF-α, IL-6, PGE-2 and NO in LPS-induced RAW264.7 macrophages† 作为选择性 COX-2 抑制剂的新型吡唑哒嗪杂化物:设计、合成、分子对接、硅学研究,以及通过评估 TNF-α、IL-6、PGE-2 和 NO 在 LPS 诱导的 RAW264.7 巨噬细胞中的作用来研究其抗炎潜力
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-05 DOI: 10.1039/D4MD00135D
Eman O. Osman, Nadia A. Khalil, Alaa Magdy and Yara El-Dash

Hybrid-based design has gained significant interest in the development of novel active substances with anti-inflammatory properties. In this study, two series of new pyrazole–pyridazine-based hybrids, 5a–f and 6a–f, were designed and synthesized. Molecules containing pyrazole and pyridazine pharmacophores in a single molecule, each with a unique mechanism of action and different pharmacological characteristics, are believed to exert higher biological activity. The cell viability of all compounds was evaluated using MTT assay in LPS-induced RAW264.7 macrophages. In vitro COX-1 and COX-2 inhibition assays were performed for the investigation of the anti-inflammatory activity of target compounds. Trimethoxy derivatives 5f and 6f were the most active candidates, demonstrating higher COX-2 inhibitory action than celecoxib, with IC50 values of 1.50 and 1.15 μM, respectively. Bromo derivative 6e demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds 5f, 6e, and 6f to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds 5f and 6f demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives 5f and 6f showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.

在开发具有抗炎特性的新型活性物质的过程中,基于杂化的设计受到了极大的关注。本研究设计并合成了两个系列的新型吡唑-哒嗪基杂交化合物 5a-f 和 6a-f。单个分子中含有吡唑和哒嗪药效团,每个药效团都具有独特的作用机制和不同的药理特征,相信能发挥更高的生物活性。在 LPS 诱导的 RAW264.7 巨噬细胞中,使用 MTT 法评估了所有化合物的细胞活力。为了研究目标化合物的抗炎活性,还进行了体外 COX-1 和 COX-2 抑制试验。三甲氧基衍生物 5f 和 6f 是最有活性的候选化合物,其 COX-2 抑制作用高于塞来昔布,IC50 值分别为 1.50 和 1.15 μM。溴衍生物 6e 的 COX-2 抑制活性与塞来昔布相当。此外,还评估了化合物 5f、6e 和 6f 在 LPS 刺激下抑制 RAW264.7 巨噬细胞中特定促炎细胞因子和介质(包括一氧化氮(NO)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)和前列腺素-E2(PGE-2))生成的能力。化合物 5f 和 6f 的活性最强。此外,根据分子建模研究,与参考配体相比,衍生物 5f 和 6f 与 COX-2 活性位点的结合亲和力相当可观。此外,还计算了最有效化合物的 ADME 参数、理化特征、药代动力学特征和 l。
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引用次数: 0
Copper selective 8-aminoquinoline based tetradentate chelators as anticancer agents 作为抗癌剂的铜选择性 8-氨基喹啉基四价螯合剂
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-04 DOI: 10.1039/D4MD00171K
Yingzhen Guan, Michel Nguyen, Anne Robert, Yan Liu and Bernard Meunier

Cancer cell proliferation and metastasis are known to be dependent on angiogenesis which is regulated by several parameters including copper availability. Tetradentate monoquinoline (TDMQ) ligands constitute a series of chelators tailored to regulate copper homeostasis due to their specificity for copper(II) with respect to Cu(I) or other biometals like iron or zinc. One of these chelators, TDMQ20 efficiently inhibits both proliferation and migration of several human cancer cell lines, better than the reference drug 5-fluorouracil, and with higher selectivity indexes with respect to non-cancer human cells. The biological activity of TDMQ20 may be driven by the coordination chemistry of copper, and the ability of this chelator to restore copper homeostasis and its subsequent redox properties. The anticancer mechanism of action of TDMQ20 involves intracellular production of reactive oxygen species, drastic mitochondrial damages and induction of tumor cell apoptosis. These data support the selection of TDMQ20 as drug-candidate against several human cancers.

众所周知,癌细胞的增殖和转移依赖于血管生成,而血管生成受包括铜供应在内的多种参数的调节。四价单喹啉(TDMQ)配体构成了一系列专门用于调节铜平衡的螯合剂,因为它们对铜(II)具有特异性,而对铜(I)或铁或锌等其他生物金属则没有特异性。其中一种螯合剂 TDMQ20 能有效抑制几种人类癌细胞株的增殖和迁移,其效果优于参考药物 5-氟尿嘧啶,而且对非癌细胞具有更高的选择性。TDMQ20 的生物活性可能是由铜的配位化学性质、这种螯合剂恢复铜平衡的能力及其随后的氧化还原特性所驱动的。TDMQ20 的抗癌作用机制涉及细胞内活性氧的产生、线粒体的剧烈损伤和诱导肿瘤细胞凋亡。这些数据支持选择 TDMQ20 作为治疗多种人类癌症的候选药物。
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引用次数: 0
Phosphonodiamidate prodrugs of phosphoantigens (ProPAgens) exhibit potent Vγ9/Vδ2 T cell activation and eradication of cancer cells† 磷酸抗原的膦酰二胺原药(ProPAgens)具有强效的 Vγ9/Vδ2 T 细胞活化和消灭癌细胞的作用
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-03 DOI: 10.1039/D4MD00208C
Qin Xu, Maria Sharif, Edward James, Jack O. Dismorr, James H. R. Tucker, Benjamin E. Willcox and Youcef Mehellou

The phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) is an established activator of Vγ9/Vδ2 T cells and stimulates downstream effector functions including cytotoxicity and cytokine production. In order to improve its drug-like properties, we herein report the design, synthesis, serum stability, in vitro metabolism, and biological evaluation of a new class of symmetrical phosphonodiamidate prodrugs of methylene and difluoromethylene monophosphonate derivatives of HMBPP. These prodrugs, termed phosphonodiamidate ProPAgens, were synthesized in good yields, exhibited excellent serum stability (>7 h), and their in vitro metabolism was shown to be initiated by carboxypeptidase Y. These phosphonodiamidate ProPAgens triggered potent activation of Vγ9/Vδ2 T cells, which translated into efficient Vγ9/Vδ2 T cell-mediated eradication of bladder cancer cells in vitro. Together, these findings showcase the potential of these phosphonodiamidate ProPAgens as Vγ9/Vδ2 T cell modulators that could be further developed as novel cancer immunotherapeutic agents.

磷酸抗原(E)-4-羟基-3-甲基-丁-2-烯基焦磷酸(HMBPP)是一种成熟的 Vγ9/Vδ2 T 细胞激活剂,可刺激下游效应器功能,包括细胞毒性和细胞因子的产生。为了改善其药物样特性,我们在此报告了 HMBPP 亚甲基和二氟亚基单膦酸盐衍生物的一类新型对称膦酰二胺原药的设计、合成、血清稳定性、体外代谢和生物学评价。这些原药被称为膦酰二胺原药(phosphonodiamidate ProPAgens),合成产量高,血清稳定性极佳(7 小时),体外代谢由羧肽酶 Y 启动。这些发现共同展示了这些膦酰二胺ProPAgens作为Vγ9/Vδ2 T细胞调节剂的潜力,可进一步开发为新型癌症免疫治疗剂。
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引用次数: 0
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