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Discovery of cloxiquine derivatives as potent HDAC inhibitors for the treatment of melanoma via activating PPARγ 发现通过激活 PPARγ 治疗黑色素瘤的强效 HDAC 抑制剂氯喹衍生物
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-04 DOI: 10.1016/j.ejmech.2024.117029
Limin Yang , Ran Ding , Xiaojie Tong , Tong Shen , Shuting Jia , Xiqing Yan , Chong Zhang , Liqiang Wu
The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor γ (PPARγ) agonists has displayed significant anticancer efficacy. Based on these results, a series of cloxiquine derivatives were prepared as potent HDAC inhibitors for the treatment of melanoma. Among these compounds, CS4 exhibited excellent inhibitory effects on HDAC1 (IC50 = 38 nM) and HDAC6 (IC50 = 12 nM), and had good antiproliferative effects against A375 and SK-MEL-5 melanoma cells (IC50 values, 1.20 and 0.93 μM, respectively). Mechanism research indicated that CS4 inhibited SK-MEL-5 cell growth by promoting α-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with BG11 activated PPARγ and blocked glycolysis in SK-MEL-5 cells, which mediated partial antimelanoma effects of CS4. In addition, CS4 also induced cell cycle arrest at G2, suppressed migration and facilitated apoptosis of SK-MEL-5 cells. More importantly, compound CS4 demonstrated significant in vivo anticancer effect compared with SAHA, and exhibited neglectable toxicity. Consequently, CS4 is the potent HDAC inhibitor, which may be developed as the candidate antimelanoma drug.
组蛋白去乙酰化酶(HDAC)抑制剂与过氧化物酶体增殖激活受体γ(PPARγ)激动剂联合治疗显示出显著的抗癌疗效。基于这些结果,研究人员制备了一系列氯喹衍生物,作为治疗黑色素瘤的强效 HDAC 抑制剂。在这些化合物中,CS4 对 HDAC1(IC50 = 38 nM)和 HDAC6(IC50 = 12 nM)有很好的抑制作用,对 A375 和 SK-MEL-5 黑色素瘤细胞有很好的抗增殖作用(IC50 值分别为 1.20 和 0.93 μM)。机理研究表明,CS4通过促进α-微管蛋白和组蛋白3(H3)乙酰化来抑制SK-MEL-5细胞的生长。在代谢水平上,BG11 能激活 PPARγ 并阻断 SK-MEL-5 细胞的糖酵解,从而介导 CS4 的部分抗黑色素瘤作用。此外,CS4 还能诱导细胞周期停滞在 G2 阶段,抑制迁移并促进 SK-MEL-5 细胞凋亡。更重要的是,与 SAHA 相比,化合物 CS4 在体内具有显著的抗癌效果,而且毒性可忽略不计。因此,CS4 是一种有效的 HDAC 抑制剂,可作为抗黑色素瘤的候选药物进行开发。
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引用次数: 0
Development of hybrid aptamers-engineered PROTACs for degrading VEGF165 in both tumor- and vascular endothelial cells 开发可在肿瘤细胞和血管内皮细胞中降解 VEGF165 的混合适配体工程化 PROTACs
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.ejmech.2024.117027
Ziting Feng , Duoli Xie , Fang Qiu , Jie Huang , Zhuqian Wang , Chao Liang
Tumors and angiogenesis are connected through a complex interplay. VEGF165, generated from both tumor and vascular endothelial cells, serves as a mutual benefit for both cell types. Therapeutic approaches modulating VEGF165 have been proposed as promising antitumor therapies. PROTACs are bifunctional molecules that exploit the intracellular ubiquitin-proteasome system to degrade specific proteins. To date, there are no targeted PROTACs designed to degrade VEGF165 in both tumor and vascular endothelial cells. The aptamer AS1411 is notable for its ability to selectively recognize and enter both tumor and vascular endothelial cells by targeting the cell surface nucleolin (NCL). Moreover, AS1411 has also been repurposed as an intracellular recruiter of E3 ligase MDM2 via leveraging NCL as a molecular bridge. In this study, we conjugated AS1411 with a VEGF165-specific aptamer V7t1, creating hybrid aptamers-engineered PROTACs. The PROTACs demonstrate remarkable selectivity for both tumor and vascular endothelial cells and facilitate the ubiquitination and proteasomal degradation of VEGF165. The PROTACs inhibit the growth of tumor cells and also impede angiogenesis, without causing toxicity to normal tissues. The hybrid aptamers-engineered PROTACs provide an avenue for disrupting the tumor-angiogenesis interplay through modulation of VEGF165 in both tumor and vascular endothelial cells.
肿瘤和血管生成通过复杂的相互作用联系在一起。由肿瘤细胞和血管内皮细胞产生的 VEGF165 对两种细胞类型都有好处。调控 VEGF165 的治疗方法被认为是有前景的抗肿瘤疗法。PROTACs 是一种双功能分子,可利用细胞内泛素-蛋白酶体系统降解特定蛋白质。迄今为止,还没有设计出同时降解肿瘤细胞和血管内皮细胞中 VEGF165 的靶向 PROTACs。适配体 AS1411 的显著特点是能通过靶向细胞表面的核素蛋白(NCL),选择性地识别并进入肿瘤细胞和血管内皮细胞。此外,AS1411 还通过利用 NCL 作为分子桥,被重新用作 E3 连接酶 MDM2 的细胞内招募剂。在本研究中,我们将 AS1411 与 VEGF165 特异性拟合物 V7t1 共轭,创造出混合拟合物工程化的 PROTACs。PROTACs 对肿瘤细胞和血管内皮细胞都具有显著的选择性,能促进 VEGF165 的泛素化和蛋白酶体降解。PROTACs 可抑制肿瘤细胞的生长,阻碍血管生成,但不会对正常组织造成毒性。这种由混合适配体设计的 PROTACs 为通过调节肿瘤细胞和血管内皮细胞中的 VEGF165 来破坏肿瘤与血管生成之间的相互作用提供了一条途径。
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引用次数: 0
Recent report on indoles as a privileged anti-viral scaffold in drug discovery 关于吲哚作为药物研发中的抗病毒支架的最新报告
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117017
Asmita Singh , Charu Bhutani , Pankaj Khanna , Sangeeta Talwar , Sandeep Kumar Singh , Leena Khanna
In recent years, viral infections such as COVID-19, Zika virus, Nipah virus, Ebola, Influenza, Monkeypox, and Dengue have substantially impacted global health. These outbreaks have led to heightened global health initiatives and collaborative efforts to address and mitigate these significant threats effectively. Thus, developing antiviral treatments and research in this field has become highly important. Heterocycles, particularly indole motifs, have been a valuable resource in drug discovery, as they can be used as treatments or inspire the synthesis of new potent candidates. Indole-containing drugs, such as enfuvirtide (T-20), arbidol, and delavirdine, have demonstrated significant efficacy in treating viral diseases. This review aims to comprehensively assess the latest research and developments in novel indoles as potential scaffolds for antiviral activity. We have compiled detailed information about indoles as potential antivirals by conducting a thorough literature survey from the past ten years. The review includes discussions on synthetic protocols, inhibitory concentrations, SAR study, and computational study. This review shall identify new antiviral indoles that may help to combat new viral threats in the future.
近年来,COVID-19、寨卡病毒、尼帕病毒、埃博拉病毒、流感、猴痘和登革热等病毒感染严重影响了全球健康。这些疫情的爆发促使人们加强全球卫生倡议和合作努力,以有效地应对和减轻这些重大威胁。因此,开发抗病毒治疗方法和在这一领域开展研究已变得非常重要。杂环化合物,尤其是吲哚基团,一直是药物发现领域的宝贵资源,因为它们可以用作治疗药物或激发新的强效候选药物的合成。含吲哚的药物,如恩夫韦肽(T-20)、阿比多和德尔维利定,在治疗病毒性疾病方面具有显著疗效。本综述旨在全面评估新型吲哚作为抗病毒活性潜在支架的最新研究和发展。我们通过对过去十年的文献进行全面调查,汇编了有关吲哚作为潜在抗病毒药物的详细信息。综述包括对合成方案、抑制浓度、SAR 研究和计算研究的讨论。这篇综述将发现新的抗病毒吲哚,它们可能有助于对抗未来新的病毒威胁。
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引用次数: 0
Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential 微管蛋白/HDAC 双靶点抑制剂:从设计策略、SARs 和治疗潜力中获得的启示
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117022
Zhen Zhang , Rui Su , Junao Liu , Keyu Chen , Chengjun Wu , Pinghua Sun , Tiemin Sun
Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties. At present, tubulin/HDAC dual-target inhibitors have been obtained in three main ways: uncleavable linked pharmacophores, cleavable linked pharmacophores, and modification of single-target drugs. Their therapeutic efficacy has been verified in vivo and in vitro assays. In this article, we reviewed the research progress of tubulin/HDAC dual inhibitors from design strategies, SARs, and biological activities, which may provide help for the discovery of novel tubulin/HDAC dual inhibitors.
微管是真核细胞中的细胞骨架之一,能维持多种细胞功能的正常运行。此外,微管受 HDAC6 和 SIRT2 的乙酰化调节,而乙酰化会影响微管的动力学。鉴于微管蛋白和 HDAC 抑制剂在许多癌症的治疗中发挥着协同作用,开发微管蛋白/HDAC 双靶点抑制剂有利于解决耐药性、剂量毒性和不可预测的药代动力学特性等多重限制。目前,获得微管蛋白/HDAC 双靶点抑制剂的途径主要有三种:不可逆连接药基、可裂解连接药基以及对单靶点药物进行修饰。它们的疗效已在体内和体外实验中得到验证。本文从设计策略、SARs和生物活性等方面综述了微管蛋白/HDAC双重抑制剂的研究进展,以期为新型微管蛋白/HDAC双重抑制剂的发现提供帮助。
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引用次数: 0
Advance on the effects of algal carotenoids on inflammatory signaling pathways 藻类类胡萝卜素对炎症信号通路影响的研究进展
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117020
Yudi Wang , Xinrong Geng , Song Qin , Tuanjie Che , Libo Yan , Biao Yuan , Wenjun Li
The development of inflammation has an indispensable importance in the self-protection of the human body. However, over-inflammation may damage human health, and inflammatory pathways and inflammasomes have a significant impact on the onset of inflammation. Therefore, how to constrain the development of inflammation through inflammatory pathways or inflammasomes becomes a hot research issue. Carotenoids are a natural pigment and an active substance in algae, with anti-inflammatory and antioxidant effects. Many studies have shown that carotenoids have inhibitory effects on the inflammatory pathways and inflammasomes. In this review, we discussed the mechanism of carotenoids targeting those important inflammatory pathways and their effects on common inflammasome NLRP3 and inflammation-related diseases from the perspective of several inflammatory pathways, including p38 MAPK, IL-6/JAK/STAT3, and PI3K, with a focus on the targets and targeting effects of carotenoids on different inflammatory signaling pathways, and at last proposed possible anti-inflammatory targets.
炎症的发展对人体的自我保护具有不可或缺的重要意义。然而,过度炎症会损害人体健康,而炎症通路和炎性体对炎症的发生有重要影响。因此,如何通过炎症通路或炎症小体来制约炎症的发展成为研究热点。类胡萝卜素是一种天然色素,也是藻类中的一种活性物质,具有抗炎和抗氧化作用。许多研究表明,类胡萝卜素对炎症通路和炎症体具有抑制作用。在这篇综述中,我们从p38 MAPK、IL-6/JAK/STAT3和PI3K等几种炎症通路的角度探讨了类胡萝卜素靶向那些重要炎症通路的机制及其对常见炎症体NLRP3和炎症相关疾病的影响,重点讨论了类胡萝卜素对不同炎症信号通路的靶点和靶向作用,最后提出了可能的抗炎靶点。
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引用次数: 0
Design, synthesis, and evaluation of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine derivatives as potential glutaminyl cyclase isoenzyme inhibitors for the treatment of cancer 设计、合成和评估 4-(4-甲基-4H-1,2,4-三唑-3-基)哌啶衍生物作为治疗癌症的潜在谷氨酰胺环化酶同工酶抑制剂
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117019
Qingqing Zhou , Zhenxin Wu , Feixia Qin , Pan He , Zhuoran Wang , Fangyi Zhu , Ying Gao , Wei Xiong , Chenyang Li , Haiqiang Wu
Upregulated glutaminyl cyclase isoenzyme (isoQC) contributes to cancer development by catalyzing pE-CD47 generation and thus enhancing CD47-SIRPα binding and subsequent “don't eat me” signals. We thus consider that isoQC could represent a novel target for cancer therapy. We previously prepared a series of diphenyl conjugated imidazole derivatives (DPCIs) and evaluated their use as glutaminyl cyclase (QC) inhibitors. Here, a new series of DPCIs was rationally designed and synthesized. As anticipated, the analogues exhibited considerably improved inhibitory potency against both QC and isoQC. Crucially, these chemicals exhibited marked selectivity toward isoQC. Further assessments established that one selected compound (27) did not affect the viability of A549, H1299, PC9, or HEK293T cells or the body weight of mice. This compound did, however, reduce pE-CD47 levels in infected A549 cells (isoQC_OE and isoQC_KD) and exhibited apparent anti-cancer effects in vivo by downregulating the level of pE-CD47 via the inhibition of isoQC activity. Taken together, these findings indicated that the compounds synthesized in this study could represent potential QC/isoQC inhibitors for the treatment of cancers.
上调的谷氨酰胺酰环酶同工酶(isoQC)可催化 pE-CD47 的生成,从而增强 CD47-SIRPα 的结合和随后的 "别吃我 "信号,从而促进癌症的发展。因此,我们认为异QC可能是癌症治疗的一个新靶点。我们之前制备了一系列二苯基共轭咪唑衍生物(DPCIs),并评估了它们作为谷氨酰胺酰环化酶(QC)抑制剂的用途。在此,我们合理地设计并合成了一系列新的 DPCIs。正如预期的那样,这些类似物对 QC 和异 QC 的抑制效力都有显著提高。最重要的是,这些化学物质对异QC具有明显的选择性。进一步的评估表明,一种被选中的化合物(27)不会影响 A549、H1299、PC9 或 HEK293T 细胞的活力或小鼠的体重。不过,这种化合物确实降低了受感染的 A549 细胞(isoQC_OE 和 isoQC_KD)中 pE-CD47 的水平,并通过抑制 isoQC 活性下调 pE-CD47 的水平,在体内表现出明显的抗癌效果。综上所述,这些发现表明本研究合成的化合物可能是治疗癌症的潜在 QC/isoQC 抑制剂。
{"title":"Design, synthesis, and evaluation of 4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidine derivatives as potential glutaminyl cyclase isoenzyme inhibitors for the treatment of cancer","authors":"Qingqing Zhou ,&nbsp;Zhenxin Wu ,&nbsp;Feixia Qin ,&nbsp;Pan He ,&nbsp;Zhuoran Wang ,&nbsp;Fangyi Zhu ,&nbsp;Ying Gao ,&nbsp;Wei Xiong ,&nbsp;Chenyang Li ,&nbsp;Haiqiang Wu","doi":"10.1016/j.ejmech.2024.117019","DOIUrl":"10.1016/j.ejmech.2024.117019","url":null,"abstract":"<div><div>Upregulated glutaminyl cyclase isoenzyme (isoQC) contributes to cancer development by catalyzing pE-CD47 generation and thus enhancing CD47-SIRPα binding and subsequent “don't eat me” signals. We thus consider that isoQC could represent a novel target for cancer therapy. We previously prepared a series of diphenyl conjugated imidazole derivatives (DPCIs) and evaluated their use as glutaminyl cyclase (QC) inhibitors. Here, a new series of DPCIs was rationally designed and synthesized. As anticipated, the analogues exhibited considerably improved inhibitory potency against both QC and isoQC. Crucially, these chemicals exhibited marked selectivity toward isoQC. Further assessments established that one selected compound (<strong>27</strong>) did not affect the viability of A549, H1299, PC9, or HEK293T cells or the body weight of mice. This compound did, however, reduce pE-CD47 levels in infected A549 cells (isoQC_OE and isoQC_KD) and exhibited apparent anti-cancer effects <em>in vivo</em> by downregulating the level of pE-CD47 via the inhibition of isoQC activity. Taken together, these findings indicated that the compounds synthesized in this study could represent potential QC/isoQC inhibitors for the treatment of cancers.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117019"},"PeriodicalIF":6.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2 发现首个针对伪激酶 TRIB2 的选择性强效 PROTAC 降解剂
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-11-01 DOI: 10.1016/j.ejmech.2024.117016
Chaowei Wen , Prathibha R. Gajjala , Yihan Liu , Bingzhong Chen , Mehtab S. Bal , Payal Sutaria , Qiao Yuanyuan , Yang Zheng , Yang Zhou , Jinwei Zhang , Weixue Huang , Xiaomei Ren , Zhen Wang , Ke Ding , Arul M. Chinnaiyan , Fengtao Zhou
Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions. Among these compounds, 5k demonstrated potent TRIB2 degradation with a DC50 value of 16.84 nM (95 % CI: 13.66–20.64 nM) in prostate cancer PC3 cells. Mechanistic studies revealed that 5k directly interacted with TRIB2, selectively inducing its degradation through a CRBN-dependent ubiquitin-proteasomal pathway. Moreover, 5k outperformed the TRIB2 binder alone in inhibiting cell proliferation and inducing apoptosis, confirming that TRIB2 protein degradation could be a promising therapeutic strategy for TRIB2-associated cancers. Additionally, compound 5k also serves as an effective tool for probing TRIB2 biology.
伪激酶 TRIB2 是 CAMK Ser/Thr 蛋白激酶家族的成员,通过磷酸化无关机制调节各种细胞过程。TRIB2 的失调与促进肿瘤生长、转移和耐药性有关,因此是一个很有前景的癌症治疗靶点。在这项研究中,我们设计并合成了一系列 TRIB2 PROTAC 降解剂,方法是通过不同长度和组成的连接体将 TRIB2 结合剂 1 与 VHL 或 CRBN 配体连接。在这些化合物中,5k 对前列腺癌 PC3 细胞的 TRIB2 降解效果显著,DC50 值为 16.84 nM(95% CI:13.66 - 20.64 nM)。机理研究显示,5k 与 TRIB2 直接相互作用,通过依赖 CRBN 的泛素-蛋白酶体途径选择性地诱导其降解。此外,5k 在抑制细胞增殖和诱导细胞凋亡方面的表现优于单独的 TRIB2 结合剂,这证实了 TRIB2 蛋白降解可能是治疗 TRIB2 相关癌症的一种有前景的策略。此外,化合物 5k 还是探究 TRIB2 生物学特性的有效工具。
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引用次数: 0
A novel life for antitumor combretastatins: Recent developments of hybrids, prodrugs, combination therapies, and antibody-drug conjugates 抗肿瘤联合司他汀类药物的新生命:混合药、原药、联合疗法和抗体-药物共轭物的最新进展
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-10-31 DOI: 10.1016/j.ejmech.2024.117021
Marialuigia Fantacuzzi, Simone Carradori, Letizia Giampietro, Cristina Maccallini, Barbara De Filippis, Rosa Amoroso, Alessandra Ammazzalorso
Since their discovery from natural sources, the potent cytotoxic effects of combretastatins were widely studied for the application in antitumor therapy. However, major pharmacokinetic issues as low water solubility and chemical instability of the double bond configuration prevented their use in therapy. A lot of efforts have been directed towards the search of novel strategies, allowing a safer use of combretastatins as anticancer agents. This review analyses the recent landscape in combretastatin research, characterized by the identification of hybrids, prodrugs, and novel combination treatments. Interestingly, the potent cytotoxic agent combretastatin A4 (CA4) was recently proposed as payload in the construction of novel antibody-drug conjugates (ADCs), allowing an efficient targeting of the cytotoxic agent to specific tumors.
自从从天然资源中发现考布他汀类化合物以来,人们一直在广泛研究其强大的细胞毒性作用,以便将其应用于抗肿瘤治疗。然而,由于低水溶性和双键构型的化学不稳定性等主要的药代动力学问题,阻碍了它们在治疗中的应用。为了更安全地使用考布他汀类药物作为抗癌药物,人们一直在努力寻找新的策略。这篇综述分析了联合司他汀类药物研究的最新进展,其特点是发现了混合药物、原药和新型联合疗法。有趣的是,最近有人提出将强效细胞毒性药物考布他汀 A4(CA4)作为构建新型抗体-药物共轭物(ADCs)的有效载荷,从而使细胞毒性药物有效靶向特定肿瘤。
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引用次数: 0
Naphthoindole-2-carboxamides as a lipophilic chemotype of hetarene-anthraquinones potent against P-gp resistant tumor cells 萘吲哚-2-羧酰胺作为一种亲脂型 Hetarene-Anthraquinones 化合物,对具有 P-gp 抗性的肿瘤细胞有效
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-10-30 DOI: 10.1016/j.ejmech.2024.117013
Valeria A. Litvinova , Vladimir B. Tsvetkov , Yulia L. Volodina , Lyubov G. Dezhenkova , Alina A. Markova , Minh Tuan Nguyen , Alexander S. Tikhomirov , Andrey E. Shchekotikhin
The acquisition of multidrug resistance (MDR) to chemotherapy is a major obstacle to successful cancer treatment. Aiming to improve the potency of anthraquinone-derived antitumor compounds against MDR cancer cells, we employed a rational design approach to develop new heteroarene-fused anthraquinones. Shifting the carboxamide group in the naphtho[2,3-f]indole scaffold from the 3-position to 2 increased the lipophilicity and P-glycoprotein (P-gp) binding of the derivatives, potentially enhancing their ability to circumvent P-gp-mediated MDR. To validate the computations, we developed a scheme for heterocyclization into esters of naphtho[2,3-f]indole-2-carboxylic acid, based on the 5-endo-dig cyclization of 2-alkynyl-3-amino-1,4-dimethoxyanthraquinone under mild basic conditions using tetra-n-butylammonium fluoride (TBAF). The synthesized naphthoindole-2-carboxamides, particularly compound 1a bearing (S)-3-aminopyrrolidine in the carboxamide fragment, demonstrated the highest antiproliferative activity. Most importantly, 1a suppressed the growth of the P-gp-positive K562/4 leukemia tumor cell line (resistance index = 2.4), while its 3-isomer LCTA-2640 and Dox did not (RI = 125 and 140, respectively). Studies of intracellular uptake and distribution showed that 1a, unlike its 3-substituted isomer, effectively accumulated in resistant tumor cells, confirming the correlation between in silico and experimental data. The lead compound 1a interacts with DNA duplex and inhibits topoisomerase 1 but does not induce oxidative stress. Treatment with 1a increases the population of apoptotic cells in both K562 and K562/4 sublines, regardless of the cell cycle phase. Taken together, this work provides an interesting example of how a little modification in chemical structure can lead to striking differences in antitumor properties. In conclusion, we have identified a potent class of compounds that offer distinct advantages in combating resistant tumor cells.
对化疗产生多药耐药性(MDR)是成功治疗癌症的一大障碍。为了提高蒽醌类抗肿瘤化合物对 MDR 癌细胞的药效,我们采用合理的设计方法开发了新的杂芳烃融合蒽醌类化合物。将萘并[2,3-f]吲哚支架中的羧酰胺基团从 3 位移到 2 位,增加了衍生物的亲脂性和 P-glycoprotein (P-gp) 结合力,从而增强了它们规避 P-gp 介导的 MDR 的能力。为了验证计算结果,我们根据 2-炔基-3-氨基-1,4-二甲氧基蒽醌在温和碱性条件下使用四正丁基氟化铵 (TBAF) 进行 5-endo-dig 环化反应的结果,开发了一种杂环化为萘并[2,3-f]吲哚-2-羧酸酯的方案。合成的萘吲哚-2-羧酰胺类化合物,特别是羧酰胺片段中含有 (S)-3- 氨基吡咯烷的化合物 1a,显示出最高的抗增殖活性。最重要的是,1a 能抑制 P-gp 阳性的 K562/4 白血病肿瘤细胞系的生长(抗性指数 = 2.4),而其 3-异构体 LCTA-2640 和 Dox 则不能(抗性指数分别为 125 和 140)。对细胞内摄取和分布的研究表明,与 3-取代异构体不同,1a 能有效地在耐药性肿瘤细胞内积累,这证实了硅学数据与实验数据之间的相关性。先导化合物 1a 与 DNA 双链相互作用,抑制拓扑异构酶 1,但不会诱发氧化应激。用 1a 处理会增加 K562 和 K562/4 亚系的凋亡细胞数量,与细胞周期阶段无关。综上所述,这项工作提供了一个有趣的例子,说明化学结构上的微小变化如何导致抗肿瘤特性的显著差异。总之,我们发现了一类强效化合物,它们在抗击耐药性肿瘤细胞方面具有独特的优势。
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引用次数: 0
Design, synthesis, and in vitro and in vivo biological evaluation of dihydroartemisinin derivatives as potent anti-cancer agents with ferroptosis-inducing and apoptosis-activating properties 设计、合成二氢青蒿素衍生物并对其进行体内外生物学评价,使其成为具有铁蛋白沉降诱导和细胞凋亡激活特性的强效抗癌剂
IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL Pub Date : 2024-10-30 DOI: 10.1016/j.ejmech.2024.117018
Qian Xu , Hao Deng , Xing Huang , Guo-Qing Chen , Yin-Sheng Quan , Ya-Lan Wang , Jin-Ying Liu , Rui Yan , Wen-Zhe Nie , Qing-Kun Shen , Zhe-Shan Quan , Hong-Yan Guo
Natural products play a pivotal role in drug development, including their direct use as pharmaceuticals and their structural modification, yielding molecules with enhanced therapeutic potential. The discovery of bioactive molecules, lead compounds, and novel drugs is intrinsically linked to the structural optimization of natural products. In this study, forty-one derivatives of dihydroartemisinin (DHA) were synthesized by incorporating fragments with anti-tumour activity via molecular hybridization, and assessed for their anti-proliferative activity against human cancer cell lines (A549, Bel-7402, HCT-116, and SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to DHA. Notably, compound A3, featuring a 4-Cl phenyl carbamate moiety, demonstrated significant anti-proliferative activity against HCT-116 cells with an IC50 of 0.31 μM, making it 16-fold more potent than DHA (IC50 = 5.10 μM). The anti-proliferative mechanism did not involve cytotoxicity (SI = 54.13), indicating its superior safety profile compared to DHA (SI = 1.65).
Further mechanistic studies revealed that compound A3 inhibits HCT-116 cell proliferation by modulating the expression of PI3K/AKT/mTOR and STAT3 proteins. STAT3 downregulation represses the expression of the critical ferroptosis protein glutathione peroxidase 4 (GPX4), aggravating the accumulation of reactive oxygen species (ROS) and depletion of glutathione (GSH). This redox imbalance triggers and accelerates ferroptosis. Additionally, A3 also induces apoptosis by damaging mitochondria and influencing MAPK signaling. Compound A3 arrested cells in the G2/M phase by regulating p53 expression. In an HCT-116 xenograft mouse model, compound A3 exhibited significant anti-cancer efficacy, with a tumor growth inhibition rate of 58.7 %. Therefore, compound A3 thus has the potential to serve as a lead compound for the development of new anti-tumor drugs.
天然产品在药物开发中发挥着举足轻重的作用,包括直接用作药物和对其进行结构改造,从而产生具有更大治疗潜力的分子。生物活性分子、先导化合物和新型药物的发现与天然产物的结构优化有着内在联系。在这项研究中,通过分子杂交将具有抗肿瘤活性的片段加入到双氢青蒿素(DHA)中,合成了 41 种衍生物,并评估了它们对人类癌细胞株(A549、Bel-7402、HCT-116 和 SW620)和正常人类肝细胞(LO2)的抗增殖活性。与 DHA 相比,大多数衍生物都表现出更强的抗增殖活性。值得注意的是,化合物 A3 具有 4-Cl 苯基氨基甲酸酯分子,对 HCT-116 细胞具有显著的抗增殖活性,IC50 为 0.31 μM,比 DHA(IC50 = 5.10 μM)强 16 倍。进一步的机理研究发现,化合物 A3 通过调节 PI3K/AKT/mTOR 和 STAT3 蛋白的表达来抑制 HCT-116 细胞的增殖。STAT3 的下调抑制了关键的铁氧化蛋白谷胱甘肽过氧化物酶 4(GPX4)的表达,加剧了活性氧(ROS)的积累和谷胱甘肽(GSH)的消耗。这种氧化还原失衡引发并加速了铁凋亡。此外,A3 还会通过破坏线粒体和影响 MAPK 信号转导来诱导细胞凋亡。化合物 A3 通过调节 p53 的表达,使细胞停滞在 G2/M 阶段。在 HCT-116 异种移植小鼠模型中,化合物 A3 表现出显著的抗癌效果,肿瘤生长抑制率达 58.7%。因此,化合物 A3 有潜力成为开发新型抗肿瘤药物的先导化合物。
{"title":"Design, synthesis, and in vitro and in vivo biological evaluation of dihydroartemisinin derivatives as potent anti-cancer agents with ferroptosis-inducing and apoptosis-activating properties","authors":"Qian Xu ,&nbsp;Hao Deng ,&nbsp;Xing Huang ,&nbsp;Guo-Qing Chen ,&nbsp;Yin-Sheng Quan ,&nbsp;Ya-Lan Wang ,&nbsp;Jin-Ying Liu ,&nbsp;Rui Yan ,&nbsp;Wen-Zhe Nie ,&nbsp;Qing-Kun Shen ,&nbsp;Zhe-Shan Quan ,&nbsp;Hong-Yan Guo","doi":"10.1016/j.ejmech.2024.117018","DOIUrl":"10.1016/j.ejmech.2024.117018","url":null,"abstract":"<div><div>Natural products play a pivotal role in drug development, including their direct use as pharmaceuticals and their structural modification, yielding molecules with enhanced therapeutic potential. The discovery of bioactive molecules, lead compounds, and novel drugs is intrinsically linked to the structural optimization of natural products. In this study, forty-one derivatives of dihydroartemisinin (DHA) were synthesized by incorporating fragments with anti-tumour activity via molecular hybridization, and assessed for their anti-proliferative activity against human cancer cell lines (A549, Bel-7402, HCT-116, and SW620) and normal human liver cells (LO2). Most derivatives exhibited superior anti-proliferative activity compared to DHA. Notably, compound <strong>A3</strong>, featuring a 4-Cl phenyl carbamate moiety, demonstrated significant anti-proliferative activity against HCT-116 cells with an IC<sub>50</sub> of 0.31 μM, making it 16-fold more potent than DHA (IC<sub>50</sub> = 5.10 μM). The anti-proliferative mechanism did not involve cytotoxicity (SI = 54.13), indicating its superior safety profile compared to DHA (SI = 1.65).</div><div>Further mechanistic studies revealed that compound <strong>A3</strong> inhibits HCT-116 cell proliferation by modulating the expression of PI3K/AKT/mTOR and STAT3 proteins. STAT3 downregulation represses the expression of the critical ferroptosis protein glutathione peroxidase 4 (GPX4), aggravating the accumulation of reactive oxygen species (ROS) and depletion of glutathione (GSH). This redox imbalance triggers and accelerates ferroptosis. Additionally, <strong>A3</strong> also induces apoptosis by damaging mitochondria and influencing MAPK signaling. Compound <strong>A3</strong> arrested cells in the G2/M phase by regulating p53 expression. In an HCT-116 xenograft mouse model, compound <strong>A3</strong> exhibited significant anti-cancer efficacy, with a tumor growth inhibition rate of 58.7 %. Therefore, compound <strong>A3</strong> thus has the potential to serve as a lead compound for the development of new anti-tumor drugs.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"281 ","pages":"Article 117018"},"PeriodicalIF":6.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142541952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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European Journal of Medicinal Chemistry
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