Bioorganic & Medicinal Chemistry最新文献_第3页

Photodynamic therapy: An emerging therapeutic modality in dentistry 光动力疗法：一种新兴的牙科治疗模式。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-19 DOI: 10.1016/j.bmc.2024.117962

Nandita Suresh , Betsy Joseph , Pradeesh Sathyan , Vishnupriya K. Sweety , Tuomas Waltimo , Sukumaran Anil

Photodynamic Therapy (PDT) is a rapidly evolving, non-invasive treatment modality with considerable promise in dental pharmacotherapeutics. This review article comprehensively examines PDT, beginning with its principles and then delving into its diverse applications in dentistry, including periodontal disease, endodontics, oral cancer, dental implants, and dental caries. Each area presents the latest research and discusses the potential benefits and challenges. The unique advantages of PDT are highlighted, such as selective targeting, broad-spectrum antimicrobial effect, lack of resistance development, and its synergistic effect with other treatments. However, challenges such as photosensitizer delivery, light penetration, oxygen availability, and the need to standardize protocols are also acknowledged. The review further explores future perspectives of PDT in dentistry, including advancements in photosensitizer design, overcoming hypoxic limitations, personalized protocols, integration with other therapies, and standardization and regulation. The potential of advanced technologies, such as nanotechnology and synthetic biology, to improve PDT outcomes is also discussed. The review concludes that while PDT has shown immense potential to revolutionize dental pharmacotherapeutics, further high-quality research is needed to translate this potential into everyday dental practice. The promising future of PDT in dentistry suggests a more effective and less invasive treatment option for a range of dental conditions.

光动力疗法（PDT）是一种发展迅速的非侵入性治疗方式，在牙科药物治疗中大有可为。这篇综述文章全面探讨了光动力疗法，首先介绍了其原理，然后深入探讨了它在牙科中的各种应用，包括牙周病、牙髓病、口腔癌、牙种植体和龋齿。每个领域都介绍了最新的研究成果，并讨论了潜在的益处和挑战。其中强调了光敏剂的独特优势，如选择性靶向、广谱抗菌作用、不产生抗药性以及与其他治疗方法的协同作用。然而，光敏剂输送、光穿透、氧气供应以及标准化方案的必要性等挑战也得到了认可。综述进一步探讨了光动力疗法在牙科中的未来前景，包括光敏剂设计的进步、克服缺氧限制、个性化方案、与其他疗法的整合以及标准化和监管。此外，还讨论了先进技术（如纳米技术和合成生物学）在改善 PDT 治疗效果方面的潜力。综述的结论是，虽然光动力疗法在牙科药物治疗方面显示出巨大的变革潜力，但要将这种潜力转化为日常的牙科实践，还需要进一步的高质量研究。PDT在牙科领域的发展前景广阔，为一系列牙科疾病提供了更有效、创伤更小的治疗方案。

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引用次数: 0

Design, synthesis and biological evaluation of novel oxazole derivatives as potential hypoglycemic agents 作为潜在降糖药的新型噁唑衍生物的设计、合成和生物学评价。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-18 DOI: 10.1016/j.bmc.2024.117961

Ruifeng Wang , Ke Chen , Shuihua Liu , Ruyue Ren , Hongbao Hou , Qingxuan Zeng , Yi Zhang , Yunfeng Liu

A series of 2,4-disubstituted-oxazole derivatives have been designed and synthesized based on compound 3a, a promising lead compound developed in our lab. Among these derivatives, the optimized compound 5k exhibited potent hypoglycemic activity, increasing glucose consumption by 60 % in HepG2 cells compared to the solvent control, and its activity was higher than that of metformin. Further investigation indicated that compound 5k exhibited negligible cytotoxic effects at a concentration of 25 μM in HepG2 and 3T3-L1 cells and showed moderate inhibitory activity against various subtypes of human cytochrome P450 subtypes. An oral glucose tolerance test confirmed that 5k is an effective hypoglycemic agent. Additionally, mechanistic studies suggested that 5k may exert its hypoglycemic activity through the activation of the AMPK pathway.

以我们实验室开发的前景看好的先导化合物 3a 为基础，设计并合成了一系列 2,4-二取代噁唑衍生物。在这些衍生物中，优化后的化合物 5k 表现出了强效的降血糖活性，与溶剂对照相比，它能使 HepG2 细胞的葡萄糖消耗量增加 60%，其活性高于二甲双胍。进一步的研究表明，当浓度为 25 μM 时，化合物 5k 在 HepG2 和 3T3-L1 细胞中的细胞毒性作用可忽略不计，并且对人类细胞色素 P450 的各种亚型具有中等程度的抑制活性。口服葡萄糖耐量试验证实 5k 是一种有效的降血糖药。此外，机理研究表明，5k 可能通过激活 AMPK 途径发挥降血糖活性。

引用次数: 0

Discovery of cyanoguanidine derivatives as biased μ-opioid receptor agonists 发现氰基胍衍生物作为有偏倚的μ-阿片受体激动剂。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-16 DOI: 10.1016/j.bmc.2024.117943

Liang-han Zhu , Hui-huan Mao , Mingchao He , Zhi-ying Cui , Qi-hua Zhu , Hong-feng Gu , Yun-gen Xu

Opioid agonists, including morphine and its derivatives, have historically been utilized in conventional pain relief therapies. However, the morphine-like side effects associated with these compounds have constrained their broader application in clinical environments. Fortunately, novel compounds that selectively activate μ-opioid receptors (MOR) without activating the β-arrestin2 pathway, such as PZM21 and TRV130, demonstrate the potential to mitigate side effects while maintaining analgesic efficacy. In this study, we structurally modified PZM21 to get a series of compounds with a 2-cyanoguanidine scaffold, the majority of which display significant analgesic effects. Notably, Compound I-11 exhibited an analgesic effect comparable to that of morphine and selectively activates μ-opioid receptors while avoiding the activation of the β-arrestin2 pathway. Our work not only introduces a novel biased μ-opioid receptor agonist but also serves as a valuable reference for the further optimization of PZM21.

包括吗啡及其衍生物在内的阿片类受体激动剂历来被用于传统的止痛疗法。然而，与这些化合物相关的吗啡样副作用限制了它们在临床环境中的广泛应用。幸运的是，选择性激活μ-阿片受体（MOR）而不激活β-阿司匹林2通路的新型化合物，如PZM21和TRV130，展示了在保持镇痛疗效的同时减轻副作用的潜力。在这项研究中，我们对 PZM21 进行了结构修饰，得到了一系列具有 2-氰基胍支架的化合物，其中大多数化合物都具有显著的镇痛效果。值得注意的是，化合物 I-11 显示出与吗啡相当的镇痛效果，并能选择性地激活μ-阿片受体，同时避免激活β-arrestin2 通路。我们的研究不仅推出了一种新型偏性μ-阿片受体激动剂，还为进一步优化PZM21提供了有价值的参考。

引用次数: 0

Synthesis and biological evaluation of novel isobenzofuran-1(3H)-one derivatives as antidepressant agents 作为抗抑郁剂的新型异苯并呋喃-1(3H)-酮衍生物的合成和生物学评价。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-16 DOI: 10.1016/j.bmc.2024.117941

Liu Tao , Chuanjie Yao , Sijie Wang , Yuying Ye , Zhengchao Tu , Xiaojian Jiang , Lipeng Xu , Luchen Shan , Zheng Liu , Pei Yu

A series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as antidepressants. Firstly, the serotonin reuptake inhibition of these compounds was tested in vitro, and most of them exhibited activity. Particularly, compounds 9d, 10a, and 10c demonstrated superior inhibitory effects and possibly avoided addiction via the μ-opioid receptor and CCK-B receptor. Secondly, the antidepressant effect of compound 10a was evaluated using chronic restraint stress (CRS)-induced mice. The results showed that compound 10a significantly improved CRS-induced depression-like behavior by increasing the neurotransmitters 5-HT in the cortex and THP2 expression in the hippocampus. Thirdly, compound 10a was further investigated and found to enhance CRS-induced hippocampal neuron damage recovery and elevate the expression of synaptic-associated proteins such as BDNF, TrkB, PSD95, and Spinophilin in CRS-induced mice. These findings suggested that novel isobenzofuran-1(3H)-one derivative showed efficacy in treating depression, with compound 10a emerging as a potential lead compound warranting further investigation.

研究人员设计并合成了一系列新型异苯并呋喃-1(3H)-酮衍生物作为抗抑郁药物。首先，对这些化合物的血清素再摄取抑制作用进行了体外测试，结果表明大多数化合物都具有活性。特别是化合物 9d、10a 和 10c 表现出了卓越的抑制作用，并可能避免了通过μ-阿片受体和 CCK-B 受体上瘾。其次，利用慢性束缚应激（CRS）诱导的小鼠评估了化合物 10a 的抗抑郁作用。结果表明，化合物 10a 通过增加大脑皮层中神经递质 5-HT 和海马中 THP2 的表达，明显改善了 CRS 诱导的抑郁样行为。第三，进一步研究发现，化合物 10a 能增强 CRS 诱导的海马神经元损伤恢复，并提高 CRS 诱导的小鼠突触相关蛋白（如 BDNF、TrkB、PSD95 和 Spinophilin）的表达。这些研究结果表明，新型异苯并呋喃-1(3H)-酮衍生物具有治疗抑郁症的疗效，其中化合物 10a 是一种潜在的先导化合物，值得进一步研究。

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引用次数: 0

Design, synthesis and biological evaluation of 4,6-diarylquinoxaline-based KDM4D inhibitors 基于 4,6-二芳基喹喔啉的 KDM4D 抑制剂的设计、合成和生物学评价。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-16 DOI: 10.1016/j.bmc.2024.117945

Dongxuan Ni , Xuechun Chen , Hairong Wang , Tianze Shen , Xiaoli Li , Bin Liang , Ruihan Zhang , Rong Liu , Weilie Xiao

Histone lysine demethylase 4D (KDM4D) is a critical player in the regulation of tumorigenesis, emerging as a potential target for developing anti-tumor agents. In this study, a series of KDM4D inhibitors containing the 4,6-diarylquinoxaline scaffold were prepared based on the previously discovered hit compound QD-1. Among these inhibitors, 33a was the most potent compound, with an IC₅₀ value of 0.62 μM. In an in vitro assay, 33a showed a superior ability to inhibit the viability of liver cancer Huh-7 cells with IC₅₀ = 5.23 μM. 33a exhibits significant effects in inhibiting cell cycle progression and proliferation of liver cancer cells, as well as suppressing cell migration. This work provided a promising scaffold for developing KDM4D inhibitors, as well as a lead compound for the development of anti-tumor drugs targeting KDM4D.

组蛋白赖氨酸去甲基化酶 4D (KDM4D)是调控肿瘤发生的关键角色，是开发抗肿瘤药物的潜在靶点。本研究以之前发现的热门化合物 QD-1 为基础，制备了一系列含有 4,6-二芳基喹喔啉支架的 KDM4D 抑制剂。在这些抑制剂中，33a 是最有效的化合物，其 IC50 值为 0.62 μM。在体外实验中，33a 显示出抑制肝癌 Huh-7 细胞活力的卓越能力，IC50 = 5.23 μM。33a 在抑制肝癌细胞的细胞周期进展和增殖以及抑制细胞迁移方面表现出明显的效果。这项工作为开发 KDM4D 抑制剂提供了一个前景广阔的支架，也为开发针对 KDM4D 的抗肿瘤药物提供了一个先导化合物。

引用次数: 0

Novel benzenesulfonamide-aroylhydrazone conjugates as carbonic anhydrase inhibitors that induce MAPK/ERK-mediated cell cycle arrest and mitochondrial-associated apoptosis in MCF-7 breast cancer cells 新型苯磺酰胺-芳酰基腙结合物作为碳酸酐酶抑制剂，可诱导 MCF-7 乳腺癌细胞发生由 MAPK/ERK 介导的细胞周期停滞和线粒体相关性凋亡。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-15 DOI: 10.1016/j.bmc.2024.117958

Beata Żołnowska , Jarosław Sławiński , Jarosław Chojnacki , Andrea Petreni , Claudiu T. Supuran , Anna Kawiak

A series of novel 4-alkylthio-2-chloro-5-[(2-arylmethylidene)hydrazinecarbonyl]benzenesulfonamide derivatives 3–22 were synthesized and evaluated for their inhibitory activity against human carbonic anhydrase isozymes hCA I, hCA II, hCA IX, and hCA XII. These compounds showed varying degrees of activity against the studied isoenzymes. However, the importance of substituent choice in designing potent carbonic anhydrase inhibitors is highlighted by the strong inhibition profiles of compounds 3 and 10 against hCA IX and the low average K_I values for compounds 9 and 10 (134 nM and 77 nM, respectively). All the synthesized compounds were evaluated for their antiproliferative activity toward HeLa, HCT-116, and MCF-7 cell lines. Compounds 9 and 19 exhibited significant activity, particularly against the MCF-7 cell line (IC₅₀ values of 4 μM and 6 μM, respectively). Notably, compound 9 demonstrated a high selectivity index (SI = 8.2) for MCF-7 cells. The antiproliferative effects of compounds 9 and 19 were linked to the induction of cell cycle arrest and apoptosis via the mitochondrial pathway and involved the activation of the MAPK/ERK signaling pathway. Inhibition of MAPK/ERK activity reduced the compounds’ ability to induce cell cycle arrest and apoptosis, indicating the critical role of this pathway. These findings suggest that compounds 9 and 19 are promising candidates for further development as specific and potent anticancer agents targeting the MAPK/ERK pathway.

合成了一系列新型 4-烷硫基-2-氯-5-[(2-芳基亚甲基)肼羰基]苯磺酰胺衍生物 3-22，并评估了它们对人碳酸酐酶同工酶 hCA I、hCA II、hCA IX 和 hCA XII 的抑制活性。这些化合物对所研究的同工酶表现出不同程度的活性。然而，化合物 3 和 10 对 hCA IX 具有很强的抑制作用，而化合物 9 和 10 的平均 KI 值很低（分别为 134 nM 和 77 nM），这突出表明了选择取代基对设计强效碳酸酐酶抑制剂的重要性。评估了所有合成化合物对 HeLa、HCT-116 和 MCF-7 细胞系的抗增殖活性。化合物 9 和 19 表现出了显著的活性，尤其是对 MCF-7 细胞系（IC50 值分别为 4 μM 和 6 μM）。值得注意的是，化合物 9 对 MCF-7 细胞具有很高的选择性指数（SI = 8.2）。化合物 9 和 19 的抗增殖作用与通过线粒体途径诱导细胞周期停滞和细胞凋亡有关，并涉及 MAPK/ERK 信号途径的激活。抑制 MAPK/ERK 的活性会降低化合物诱导细胞周期停滞和细胞凋亡的能力，这表明了该途径的关键作用。这些研究结果表明，化合物 9 和 19 有希望进一步发展成为针对 MAPK/ERK 通路的特异性强效抗癌剂。

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引用次数: 0

Novel bibenzyl compound 8Ae induces apoptosis and inhibits glycolysis by detaching hexokinase 2 from mitochondria in A549 cells 新型双苄化合物 8Ae 可通过从线粒体分离己糖激酶 2 来诱导 A549 细胞凋亡并抑制糖酵解。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-12 DOI: 10.1016/j.bmc.2024.117955

Li Guan , Yanxin Xia , Pengfei Song , Huiru Zhao , Shengjie Zhang , Wanzhen Su , Aiyun Li , Weize Li

In this paper, we investigated the anticancer effect and the mechanism of our newly synthesized bibenzyl 8Ae against human lung cancer A549 cells. Compound 8Ae could induce apoptosis by inhibiting the glycolysis in A549 cells. Hexokinase 2 (HK2), the first key enzyme in glycolysis process, was significantly down-regulated by 8Ae. Besides, compound 8Ae induced HK2 dissociated from mitochondria to cytosol, which could be induced by inhibiting the phosphorylation of Akt. In addition, 8Ae could induce mitochondrial-mediated apoptosis, and mitochondrial membrane potential (MMP) was decreased. After 8Ae treatment, the Bax/Bcl-2 ratio was increased and cytochrome c (Cyt c) was release from mitochondria to cytosol. Molecular docking indicated that 8Ae have an interaction with HK2 by extending into acitve pockets of the protein to form stable hydrogen bonds. Additionally, 8Ae had significantly improved pharmacokinetic properties through the prediction, comparison, and analysis of the ADMET properties of 8Ae and moscatilin (MST). Taken together, 8Ae might inhibit glycolysis by stimulating the shedding of HK2 from mitochondria and promoting mitochondria-regulated apoptosis to inhibit the proliferation of A549 cells. This article provides a research basis for bibenzyl compounds as new small molecule drugs for lung cancer.

本文研究了新合成的联苄 8Ae 对人类肺癌 A549 细胞的抗癌作用及其机制。化合物 8Ae 可通过抑制 A549 细胞的糖酵解作用诱导细胞凋亡。糖酵解过程中的第一个关键酶六磷酸酶2（HK2）被8Ae显著下调，而且化合物8Ae能诱导HK2从线粒体分离到细胞质，这可能是通过抑制Akt的磷酸化而诱导的。此外，8Ae 还能诱导线粒体介导的细胞凋亡，线粒体膜电位（MMP）降低。经 8Ae 处理后，Bax/Bcl-2 比率升高，细胞色素 c（Cyt c）从线粒体释放到细胞膜。分子对接表明，8Ae 与 HK2 有相互作用，能延伸到蛋白质的活性袋中形成稳定的氢键。此外，通过预测、比较和分析 8Ae 和莫斯卡替林（MST）的 ADMET 特性，8Ae 的药代动力学特性得到了显著改善。综上所述，8Ae可能通过刺激线粒体中HK2的脱落和促进线粒体调控的细胞凋亡来抑制糖酵解，从而抑制A549细胞的增殖。本文为双苄基化合物作为治疗肺癌的小分子新药提供了研究基础。

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引用次数: 0

Synthesis and evaluation of novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors for overcoming MDR in cancer 合成和评估新型四氢异喹啉-苯并[h]色烯-4-酮共轭物作为 ABCB1/CYP1B1 双重抑制剂用于克服癌症的 MDR

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-11 DOI: 10.1016/j.bmc.2024.117944

Jinyun Dong , YuLong Li , Zhiyuan Jin , Zumei Wu , Maohua Cai , Guangzhao Pan , Wenchong Ye , Wen Zhou , Zheshen Li , Sichao Tian , Zhe-Sheng Chen , Jiang-Jiang Qin

The emergence of multidrug resistance (MDR) in malignant tumors is one of the major threats encountered currently by many chemotherapeutic agents. Among the various mechanisms involved in drug resistance, P-glycoprotein (P-gp, ABCB1), a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells, and the metabolic enzyme CYP1B1 are widely considered to be two critical targets for overcoming MDR. Unfortunately, no MDR modulator has been approved by the FDA to date. In this study, based on pharmacophore hybridization, bioisosteric and fragment-growing strategies, we designed and synthesized 11 novel tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates as dual ABCB1/CYP1B1 inhibitors. Among them, the preferred compound A10 exhibited the best MDR reversal activity (IC₅₀ = 0.25 μM, RF = 44.4) in SW620/AD300 cells, being comparable to one of the most potent third-generation P-gp inhibitors WK-X-34. In parallel, this dual ABCB1/CYP1B1 inhibitory effect drives compound A10 exhibiting prominent drug resistance reversal activity to doxorubicin (IC₅₀ = 4.7 μM, RF = 13.7) in ABCB1/CYP1B1-overexpressing DOX-SW620/AD300-1B1 resistant cells, which is more potent than that of the CYP1B1 inhibitor ANF. Furthermore, although compound A2 possessed moderate ABCB1/CYP1B1 inhibitory activity, it showed considerable antiproliferative activity towards drug-resistant SW620/AD300 and MKN45-DDP-R cells, which may be partly related to the increase of PUMA expression to promote the apoptosis of the drug-resistant MKN45-DDP-R cells as confirmed by proteomics and western blot assay. These results indicated that the tetrahydroisoquinoline-benzo[h]chromen-4-one conjugates may provide a fundamental scaffold reference for further discovery of MDR reversal agents.

恶性肿瘤中出现的多药耐药性（MDR）是许多化疗药物目前面临的主要威胁之一。在导致耐药性的各种机制中，P-糖蛋白（P-gp，ABCB1）和代谢酶 CYP1B1 被广泛认为是克服 MDR 的两个关键靶点，P-糖蛋白（P-gp，ABCB1）是 ABC 转运体家族的成员，能显著增加各种抗癌药物从肿瘤细胞中的外流。遗憾的是，迄今为止还没有一种 MDR 调节剂获得 FDA 批准。在本研究中，我们基于药效杂交、生物异构和片段生长策略，设计并合成了 11 种新型四氢异喹啉-苯并[h]色烯-4-酮共轭物，作为 ABCB1/CYP1B1 双重抑制剂。其中，首选化合物 A10 在 SW620/AD300 细胞中表现出最佳的 MDR 逆转活性（IC50 = 0.25 μM，RF = 44.4），可与最有效的第三代 Pp 抑制剂之一 WK-X-34 相媲美。与此同时，这种 ABCB1/CYP1B1 双重抑制作用促使化合物 A10 在 ABCB1/CYP1B1 表达缺失的 DOX-SW620/AD300-1B1 耐药细胞中对多柔比星具有显著的耐药逆转活性（IC50 = 4.7 μM，RF = 13.7），比 CYP1B1 抑制剂 ANF 更强。此外，虽然化合物 A2 具有中等的 ABCB1/CYP1B1 抑制活性，但它对耐药的 SW620/AD300 和 MKN45-DDP-R 细胞却具有相当强的抗增殖活性，这可能与蛋白质组学和 Western 印迹检测证实的 PUMA 表达增加促进耐药的 MKN45-DDP-R 细胞凋亡有部分关系。这些结果表明，四氢异喹啉-苯并[h]色烯-4-酮共轭物可为进一步发现 MDR 逆转剂提供基本的支架参考。

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引用次数: 0

Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CLpro 结构引导设计和光化学合成对 SARS-CoV-2 3CLpro 有更好药效的新型氨基甲酰（二硫代丙氧）硫酸盐。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-11 DOI: 10.1016/j.bmc.2024.117940

De-Hang Yin , Jie Xin , Shizhao Chen , Shuai-Shuai Li , Zi-Ying Li , Jin-Xi Meng , Yue-Chi Lin , Bing-Qian Yin , Cheng Zhao , Jia Li , Hang Gao , Jun Tian , Wen-Chao Gao

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CL^pro of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CL^pro; however, its structure lacks bonding site with active pockets of 3CL^pro and its highly symmetric structure doesn’t match well with the irregular cavity of the active center, limiting its therapeutic applications. To enhance their affinity for the 3CL^pro target, in this study, two kinds of disulfiram derivatives, designed based on the reevaluation and optimization of disulfiram, have been synthesized through photoredox chemistry, and the novel carbamo(dithioperoxo)thioates 4g-m were found to display 5–17 folds potency against SARS-CoV-2 3CL^pro compared to the parent disulfiram, with resulting half-maximal inhibitory concentration (IC₅₀) values ranging from 0.14–0.47 μM. Carbamo(dithioperoxo)thioates 4i containing a 4-hydroxy piperidine and a 4-trifluoromethyl phenyl ring, was identified as the most potent inhibitor to both 3CL^pro (IC₅₀ = 0.14 μM) and PL^pro (IC₅₀ = 0.04 μM). Furthermore, molecular dynamics simulations, binding free energy analysis and mass analysis were performed and provided insights on the stability, conformational behavior, and interactions of 4g with 3CL^pro. The green synthetic methodology, the privileged carbamo(dithioperoxo)thioate scaffold, and the molecular mechanisms presented might serve as a useful system for the further discovery of highly potent inhibitors targeting SARS-CoV-2 3CL^pro.

由SARS-CoV-2病毒引起的COVID-19大流行引发了2019年至2022年旷日持久的全球大流行，对人类健康构成了重大威胁。SARS-CoV-2 的非结构蛋白之一 3CLpro 被认为是开发病毒抑制剂的有效靶点。据报道，双硫仑是 3CLpro 的共价抑制剂，但其结构缺乏与 3CLpro 活性袋的结合位点，而且其高度对称的结构与活性中心的不规则空腔不太匹配，限制了其治疗应用。为了提高其对3CLpro靶点的亲和力，本研究在对双硫仑进行重新评估和优化的基础上，通过光氧化化学反应合成了两种双硫仑衍生物，并发现新型硫代氨甲酰氨基甲烷4g-m与母体双硫仑相比，对SARS-CoV-2 3CLpro的效力提高了5-17倍，其半最大抑制浓度（IC50）值在0.14-0.47 μM之间。含有一个 4-羟基哌啶和一个 4-三氟甲基苯基环的硫代氨基甲酸碳酰胺 4i 被确定为对 3CLpro （IC50 = 0.14 μM）和 PLpro （IC50 = 0.04 μM）最有效的抑制剂。此外，还进行了分子动力学模拟、结合自由能分析和质量分析，并对 4g 的稳定性、构象行为以及与 3CLpro 的相互作用进行了深入研究。所提出的绿色合成方法、特殊的氨基甲酰（二硫代丙氧）硫酸盐支架和分子机制可作为进一步发现针对 SARS-CoV-2 3CLpro 的高效抑制剂的有用系统。

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引用次数: 0

Synthesis, pharmacological evaluation, and modeling of novel quaternary ammonium salts derived from β-carboline containing an imidazole moiety as angiogenesis inhibitors 由含有咪唑分子的 β-咔啉衍生的新型季铵盐作为血管生成抑制剂的合成、药理评估和模型制作

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2024-10-09 DOI: 10.1016/j.bmc.2024.117946

Shuang Chen, Xiaofei Chen, Dongping Qiu, Jiahao Wei, Jie Zhang, Liang Guo

In this study, a series of novel β-carboline condensed imidazolium derivatives (7a-7y) were designed and synthesized by incorporating imidazolium salt structures into β-carboline. The cytotoxicity of compounds 7a-7y was evaluated in various cancer cell lines, including lung cancer (A549), gastric cancer (BGC-823), mouse colon cancer (CT-26), liver cancer (Bel-7402), and breast cancer (MCF-7), using the MTT assay. Most compounds exhibited significant activity against one or more of the cancer cell lines. Notably, compounds 7 g, 7o, 7r, 7 s, 7u, 7v, 7x, and 7w showed the highest cytotoxic activity (IC₅₀ < 2 μM) in the tested tumor cell lines. Compound 7x demonstrated cytotoxic activities of 1.3 ± 0.3 μM (for BGC-823), 2.4 ± 0.4 μM (against A549), 7.8 ± 0.9 μM (for Bel-7402), and 9.8 ± 1.4 μM (against CT-26). The chick chorioallantoic membrane assay revealed significant anti-angiogenic potential of compound 7x. Molecular imprinting studies suggested the anti-angiogenic effect of compound 7x might be attributed to inhibition of VEGFR2 kinase. Molecular docking and molecular dynamics further indicate that its activity may be primarily associated with the potential inhibition of VEGFR2. Our research outcomes have provided valuable lead compounds for the development of novel antitumor drugs and have offered beneficial insights for subsequent drug design and optimization.

本研究通过在β-咔啉中加入咪唑盐结构，设计并合成了一系列新型β-咔啉缩合咪唑鎓衍生物（7a-7y）。利用 MTT 试验评估了化合物 7a-7y 在各种癌细胞系（包括肺癌（A549）、胃癌（BGC-823）、小鼠结肠癌（CT-26）、肝癌（Bel-7402）和乳腺癌（MCF-7））中的细胞毒性。大多数化合物对一种或多种癌细胞株都有明显的活性。值得注意的是，化合物 7 g、7o、7r、7 s、7u、7v、7x 和 7w 在测试的肿瘤细胞系中显示出最高的细胞毒性活性（IC50 < 2 μM）。化合物 7x 的细胞毒性活性为 1.3 ± 0.3 μM（针对 BGC-823）、2.4 ± 0.4 μM（针对 A549）、7.8 ± 0.9 μM（针对 Bel-7402）和 9.8 ± 1.4 μM（针对 CT-26）。小鸡绒毛膜试验显示化合物 7x 具有显著的抗血管生成潜力。分子印迹研究表明，化合物 7x 的抗血管生成作用可能归因于对 VEGFR2 激酶的抑制。分子对接和分子动力学进一步表明，其活性可能主要与潜在的 VEGFR2 抑制作用有关。我们的研究成果为新型抗肿瘤药物的开发提供了有价值的先导化合物，并为后续的药物设计和优化提供了有益的启示。

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引用次数: 0