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Synthesis of a new series of 4-pyrazolylquinolinones with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors† 作为表皮生长因子受体/BRAFV600E 双重抑制剂合成具有凋亡抗增殖作用的 4-吡唑喹啉酮新系列
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-24 DOI: 10.1039/D4MD00230J
Lamya H. Al-Wahaibi, Bahaa G. M. Youssif, Hesham A. Abou-Zied, Stefan Bräse, Alan B. Brown, Hendawy N. Tawfeek and Essmat M. El-Sheref

The current study focuses on developing a single molecule that acts as an antiproliferative agent with dual or multi-targeted action, reducing drug resistance and adverse effects. A new series of 4-pyrazolylquinolin-2-ones (5a–j) with apoptotic antiproliferative effects as dual EGFR/BRAFV600E inhibitors were designed and synthesized. Compounds 5a–j were investigated for their cell viability effect against a normal cell line (MCF-10A). Results showed that none of the compounds were cytotoxic, and all 5a–j demonstrated more than 90% cell viability at 50 μM concentration. Using erlotinib as a reference, the MTT assay investigated the antiproliferative impact of targets 5a–j against four human cancer cell lines. Compounds 5e, 5f, 5h, 5i, and 5j were the most potent antiproliferative agents with GI50 values of 42, 26, 29, 34, and 37 nM, making compounds 5f and 5h more potent than erlotinib (GI50 = 33 nM). Moreover, compounds 5e, 5f, 5h, 5i, and 5j were further investigated as dual EGFR/BRAFV600E inhibitors, and results revealed that compounds 5f, 5h, and 5i are potent antiproliferative agents that act as dual EGFR/BRAFV600E inhibitors. Cell cycle analysis and apoptosis detection revealed that compound 5h displaying cell cycle arrest at the G1 transition could induce apoptosis with a high necrosis percentage. Docking studies revealed that compound 5f exhibited a strong affinity for EGFR and BRAFV600E, with high docking scores of −8.55 kcal mol−1 and −8.22 kcal mol−1, respectively. Furthermore, the ADME analysis of compounds 5a–j highlighted the diversity in their pharmacokinetic properties, emphasizing the importance of experimental validation.

目前的研究重点是开发具有双重或多靶点作用的单分子抗增殖剂,减少耐药性和不良反应。研究人员设计并合成了一系列新的具有凋亡抗增殖作用的 4-吡唑基喹啉-2-酮(5a-j),作为表皮生长因子受体/BRAFV600E 双重抑制剂。研究了 5a-j 化合物对正常细胞系(MCF-10A)的细胞活力影响。结果表明,所有化合物都没有细胞毒性,所有 5a-j 在 50 μM 浓度下的细胞存活率均超过 90%。以厄洛替尼为参照物,MTT 试验研究了靶标 5a-j 对四种人类癌细胞株的抗增殖作用。化合物 5e、5f、5h、5i 和 5j 是最有效的抗增殖剂,其 GI50 值分别为 42、26、29、34 和 37 nM,其中化合物 5f 和 5h 比厄洛替尼(GI50 = 33 nM)更有效。此外,化合物 5e、5f、5h、5i 和 5j 作为 EGFR/BRAFV600E 双重抑制剂进行了进一步研究,结果显示化合物 5f、5h 和 5i 是作为 EGFR/BRAFV600E 双重抑制剂的强效抗增殖剂。细胞周期分析和细胞凋亡检测显示,化合物 5h 在 G1 过渡期出现细胞周期停滞,可诱导细胞凋亡,且坏死率较高。对接研究显示,化合物 5f 与表皮生长因子受体和 BRAFV600E 具有很强的亲和力,对接得分分别高达 -8.55 kcal mol-1 和 -8.22 kcal mol-1。此外,对化合物 5a-j 的 ADME 分析凸显了其药代动力学特性的多样性,强调了实验验证的重要性。
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引用次数: 0
Design, synthesis, and structure–activity relationship studies of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as necroptosis inhibitors† 作为坏死抑制剂的 6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑衍生物的设计、合成和结构-活性关系研究
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-21 DOI: 10.1039/D4MD00265B
Zechen Jin, Yang Dai, Yinchun Ji, Xia Peng, Wenhu Duan, Jing Ai and Hefeng Zhang

The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26 displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivo pharmacokinetic studies were performed to determine the oral exposure of compound 26. Finally, molecular docking elucidated that compound 26 could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26 represented a promising lead compound for future necroptosis inhibitor development.

开发坏死抑制剂已成为有效缓解与坏死相关的炎症性疾病、神经退行性疾病和癌症的一种有前途的策略。本文报道了一系列 6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑衍生物作为强效的坏死抑制剂。代表性化合物 26 在人和小鼠细胞实验中均显示出强效的抗坏死活性,并对受体相互作用蛋白激酶 1 (RIPK1) 具有强效的抑制活性。研究人员进行了体内药代动力学研究,以确定化合物 26 的口服暴露量。最后,分子对接阐明了化合物 26 能有效地与 RIPK1 的异构口袋结合,成为 III 型抑制剂。综上所述,我们的研究结果表明,化合物 26 是未来开发坏死抑制剂的一种很有前景的先导化合物。
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引用次数: 0
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
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。
{"title":"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†","authors":"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","doi":"10.1039/D4MD00280F","DOIUrl":"10.1039/D4MD00280F","url":null,"abstract":"<p >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 <strong>2d</strong>, <strong>2f</strong>, <strong>2j</strong>, <strong>2k</strong>, and <strong>2n</strong> had potent IC<small><sub>50</sub></small> values of 65, 24, 150, 170, and 18 nM against c-MET, respectively. Additionally, they had potent IC<small><sub>50</sub></small> values of 310, 35, 290, 320, and 24 nM against VEGFR-2, respectively. Regarding cytotoxicity, compounds <strong>2d</strong>, <strong>2f</strong>, <strong>2j</strong>, <strong>2k</strong> and <strong>2n</strong> exhibited potent cytotoxicity against MCF-7 with IC<small><sub>50</sub></small> values in the range 0.76–21.5 μM, and they showed promising cytotoxic activity against PC-3 with IC<small><sub>50</sub></small> values in the range 1.85–3.42 μM compared to cabozantinib (IC<small><sub>50</sub></small> = 1.06 μM against MCF-7 and 2.01 μM against PC-3). Regarding cell death, compound <strong>2n</strong> 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 G<small><sub>2</sub></small>/M phase, affecting the expression of apoptosis-related genes P53, Bax, caspases 3 and 9 and the anti-apoptotic gene, Bcl-2. <em>In vivo</em> study illustrated the anticancer activity of compound <strong>2n</strong> by reduction of tumor mass and volume, and the tumor inhibition ratio reached 56.1% with an improvement of hematological parameters. Accordingly, compound <strong>2n</strong> can be further developed as a selective target-oriented chemotherapeutic against breast cancer.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":null,"pages":null},"PeriodicalIF":3.597,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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
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
Leveraging bounded datapoints to classify molecular potency improvements† 利用有界数据点对分子效力改进进行分类
IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-05-31 DOI: 10.1039/D4MD00325J
Zachary Fralish, Paul Skaluba and Daniel Reker

Molecular machine learning algorithms are becoming increasingly powerful at predicting the potency of potential drug candidates to guide molecular discovery, lead series prioritization, and structural optimization. However, a substantial amount of inhibition data is bounded and inaccessible to traditional regression algorithms. Here, we develop a novel molecular pairing approach to process this data. This creates a new classification task of predicting which one of two paired molecules is more potent. This novel classification task can be accurately solved by various, established molecular machine learning algorithms, including XGBoost and Chemprop. Across 230 ChEMBL IC50 datasets, both tree-based and neural network-based “DeltaClassifiers” show improvements over traditional regression approaches in correctly classifying molecular potency improvements. The Chemprop-based deep DeltaClassifier outperformed all here evaluated regression approaches for paired molecules with shared and with distinct scaffolds, highlighting the promise of this approach for molecular optimization and scaffold-hopping.

分子机器学习算法在预测潜在候选药物的药效以指导分子发现、先导系列优先排序和结构优化方面正变得越来越强大。然而,大量的抑制数据是有边界的,传统回归算法无法获取。在此,我们开发了一种新的分子配对方法来处理这些数据。这就产生了一个新的分类任务,即预测两个配对分子中哪一个更有效。包括 XGBoost 和 Chemprop 在内的各种成熟的分子机器学习算法都能准确地解决这项新的分类任务。在 230 个 ChEMBL IC50 数据集中,基于树的 "DeltaClassifiers "和基于神经网络的 "DeltaClassifiers "在正确分类分子效价改进方面都比传统回归方法有所提高。对于具有共享支架和不同支架的配对分子,基于 Chemprop 的深度 DeltaClassifier 的表现优于所有在此评估的回归方法,这凸显了这种方法在分子优化和支架跳转方面的前景。
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引用次数: 0
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MedChemComm
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