European Journal of Medicinal Chemistry最新文献_第4页

Discovery of a novel tau PET tracer: Design, synthesis, radio-labeling, and preclinical evaluations 一种新型tau PET示踪剂的发现：设计、合成、放射性标记和临床前评估

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-03 DOI: 10.1016/j.ejmech.2025.118542

Dongping Yao , Ni Zhang , Qian Yao , Yongmei Xie , Rong Tian , Xiaoai Wu , Weihong Kuang

Nitrogen-containing heterocyclic small molecule derivatives have been proved to possess potent affinity with tau aggregates. A series of imidazo[1,2-a]pyridine analogues were designed and synthesized for the screen of potential highly selective tau targeted PET tracers. Structure activity relationship study of these compounds led to the discovery of compound 28, which showed high affinity with tau aggregates (K_i = 0.99 nM). Compound 28 also displayed fast pharmacokinetic properties which are suitable to be developed as PET tracers. Based on the direct S_NAr radiofluorination, ¹⁸F-28 was successfully produced with high radiochemical yield. In vitro stability tests and log D_7.4 measurement indicated ¹⁸F-28 hold suitable physicochemical parameters for blood-brain-barrier (BBB) penetration and in vivo PET brain imaging. In micro-PET imaging studies, high initial brain uptake was observed with ¹⁸F-28 in normal mice and P301L transgenic mice, as well as a fast clearance from brain. ¹⁸F-28 was also evaluated in non-human primates, which also displayed a fast in and fast out accumulation in the brain. According to the autoradiographic analysis of ¹⁸F-28 with human brain tissues, positive deposits in temporal lobe can be confirmed, which is well agreed with immunohistochemistry results with tau-antibodies. Therefore, the preclinical results revealed compound 28 holds the potential to be developed as a potent and selective tau aggregate targeted PET tracer, and further optimizations and evaluations may still be needed.

含氮杂环小分子衍生物已被证明与tau聚集体具有强亲和力。设计并合成了一系列咪唑[1,2- A]吡啶类似物，用于筛选潜在的高选择性tau靶向PET示踪剂。通过对这些化合物的结构活性关系研究，发现化合物28与tau聚集体具有较高的亲和力（Ki = 0.99 nM）。化合物28具有快速药动学特性，适合开发为PET示踪剂。在直接SNAr放射性氟化的基础上，成功地制备了18F-28，具有较高的放射化学产率。体外稳定性测试和log D7.4测量表明，18F-28具有适合血脑屏障（BBB）穿透和体内PET脑成像的理化参数。在微pet成像研究中，在正常小鼠和P301L转基因小鼠中观察到18F-28的高初始脑摄取，并快速从脑中清除。18F-28也在非人类灵长类动物中进行了评估，它们在大脑中也表现出快进快出的积累。根据18F-28与人脑组织的放射自显像分析，可以证实颞叶有阳性沉积，这与tau抗体的免疫组织化学结果很好地一致。因此，临床前研究结果表明，化合物28有潜力成为一种有效的、选择性的tau聚集体靶向PET示踪剂，可能还需要进一步的优化和评估。

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引用次数: 0

Pyrazole carboxylic acid borneol esters: Novel neuroprotective agents with rapid, efficient brain penetration for the treatment of ischemic stroke 吡唑羧酸冰片酯：新型神经保护剂，具有快速、有效的脑渗透治疗缺血性脑卒中

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.ejmech.2025.118553

Siyi Li , Yulu Wu , Wang Chen , Peng Zhu , Xin Lu , Jiaming Li , Xiaodong Ma , Xueyang Jiang

Ischemic stroke (IS) is an acute cerebrovascular condition marked by a high incidence, disability rate, and mortality. Edaravone and Dexborneol Concentrated Injection Solution (EDB) has been approved to improve neurological symptoms, daily living activities, and functional impairments resulting from acute IS. Our previous studies showed that replacing the benzene ring of Edaravone (Eda) with pyridine enhances its free radical scavenging capacity. In this study, we further oxidized the methyl group of Eda to a carboxylic acid and used a structural hybridization strategy with (+)-borneol to synthesize a series of pyrazole carboxylic acid borneol esters. We evaluated the free radical scavenging ability of the synthesized compounds, identifying candidate compound B16, which outperforms Eda. The IC₅₀ values of B16 against DPPH and ABTS free radicals were 7.98 μM and 5.50 μM, respectively. Cellular studies have shown that B16 maintains intracellular redox homeostasis and mitochondrial function, while also alleviating DNA damage in an oxygen - glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell model, demonstrating excellent neuroprotective effects. Further in vivo pharmacodynamic studies have demonstrated that B16 not only restores cerebral blood flow and significantly reduces infarct size in middle cerebral artery occlusion/reperfusion (MCAO/R) mice, but also improves sensory and motor functions, and promotes the recovery of neuronal cells and the blood-brain barrier (BBB) in the brain. Notably, B16 exhibits excellent BBB permeability and shows promising brain exposure levels within 5 min of administration. Preliminary biosafety studies indicated no obvious organ toxicity from B16. Collectively, the pyrazole carboxylic acid borneol ester compound B16 holds promise as a candidate for anti-IS treatment.

缺血性脑卒中是一种急性脑血管疾病，其特点是发病率高、致残率高、死亡率高。依达拉奉Dexborneol浓缩注射溶液（EDB）已被批准用于改善急性IS引起的神经系统症状、日常生活活动和功能损伤。我们的前期研究表明，用吡啶取代依达拉奉（Eda）的苯环可以增强其清除自由基的能力。在本研究中，我们进一步将Eda的甲基氧化为羧酸，并与(+)-冰片采用结构杂交策略合成了一系列吡唑羧酸冰片酯。我们评估了合成化合物的自由基清除能力，确定了候选化合物B16，其效果优于Eda。B16对DPPH和ABTS自由基的IC50值分别为7.98 μM和5.50 μM。细胞研究表明，在氧-葡萄糖剥夺/再灌注（OGD/R）诱导的SH-SY5Y细胞模型中，B16维持细胞内氧化还原稳态和线粒体功能，同时也减轻DNA损伤，显示出良好的神经保护作用。进一步的体内药效学研究表明，B16不仅能恢复大脑血流，显著减小大脑中动脉闭塞/再灌注（MCAO/R）小鼠的梗死面积，还能改善感觉和运动功能，促进脑内神经元细胞和血脑屏障（BBB）的恢复。值得注意的是，B16具有良好的血脑屏障通透性，并在给药5分钟内显示出良好的脑暴露水平。初步的生物安全性研究表明B16没有明显的器官毒性。总的来说，吡唑羧酸冰片酯化合物B16有望成为抗is治疗的候选药物。

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引用次数: 0

Synthesis, antidepressant evaluation and computational insights on substituted pyrazoles as selective MAO-A inhibitors 取代吡唑作为选择性MAO-A抑制剂的合成、抗抑郁评价和计算见解

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.ejmech.2026.118556

Diksha Choudhary , Rajwinder Kaur , Kailash Jangid , Vinod Kumar , Bhupinder Kumar , Thishana Singh , Amritpal Kaur , Shareen Singh , Manjinder Singh , Thakur Gurjeet Singh , Balakumar Chandrasekaran

A series of pyrazole derivatives was designed, synthesized, and characterized spectroscopically. All the synthesized compounds were pharmacologically evaluated by in vitro and in vivo methods for their antidepressant activity. Amongst, VK16 and VK19 were the most potent inhibitors of the MAO-A enzyme with IC₅₀ values of 0.06 ± 0.017 μM and 0.09 ± 0.019 μM, respectively, showing comparable efficacy to that of the reference standards. Additionally, these compounds were tested for their reversibility potential and found to be reversible inhibitors of the MAO-A enzyme, as a 100-fold dilution with the substrate solution restored over 68 % enzymatic activity. The in vivo FST and TST results corroborated well with the findings from in vitro MAO inhibition. Further, antioxidant properties were assessed using in vitro assays and the compounds were computationally analyzed through molecular docking, MD simulation, and DFT studies (in silico). The molecular docking results revealed that the compounds showed stronger interactions with key amino acid residues and better docking scores than the studied standard drugs. All selected compounds demonstrated favorable ADME properties, including good blood–brain barrier penetration and gastrointestinal absorption. Molecular dynamics simulations and DFT studies also confirmed the stability of VK16 and VK19 within the MAO-A binding site. Overall, VK16 and VK19 are emerged as promising antidepressant candidates, warranting further investigation for clinical development.

设计、合成了一系列吡唑衍生物，并对其进行了光谱表征。所有合成的化合物通过体外和体内方法进行了抗抑郁活性的药理学评价。其中，VK16和VK19对MAO-A酶的抑制作用最强，IC50值分别为0.06±0.017 μM和0.09±0.019 μM，与对照品的抑制作用相当。此外，对这些化合物的可逆性潜力进行了测试，发现它们是MAO-A酶的可逆抑制剂，与底物溶液稀释100倍可恢复超过68%的酶活性。体内FST和TST的结果与体外MAO抑制的结果相吻合。此外，使用体外实验评估抗氧化性能，并通过分子对接、MD模拟和DFT研究（在硅中）对化合物进行计算分析。分子对接结果表明，与标准药物相比，化合物与关键氨基酸残基的相互作用更强，对接分数更高。所有选定的化合物都表现出良好的ADME特性，包括良好的血脑屏障穿透和胃肠道吸收。分子动力学模拟和DFT研究也证实了VK16和VK19在MAO-A结合位点内的稳定性。总的来说，VK16和VK19是有希望的抗抑郁候选药物，值得进一步研究临床开发。

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引用次数: 0

Synthesis and biological evaluation of phenanthridine derivatives as dual-target inhibitors of DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1), and potential antitumor agents 苯苯三啶衍生物作为DNA拓扑异构酶IB （TOP1）和酪氨酸-DNA磷酸二酯酶1 （TDP1）双靶点抑制剂和潜在抗肿瘤药物的合成和生物学评价

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.ejmech.2025.118541

Jian-Mei Gao , Huilong Xie , Zi-Qiang Wang , Yu Huang , Yifan Ouyang , Yan Su , Nan Chao , Wenbo Yan , Hui Yuan , Junxun Zhou , Mei-Mei Zhang , Jiaxin He , Zhou Hong , Jiunlong Yang , Yanru Fan , Chang-Cai Bai , Yu Zhang , Huang Zeng , Hao Yang

Tumor resistance to chemotherapy, driven in part by DNA repair mechanisms, presents a major obstacle in cancer treatment. DNA topoisomerase 1B (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) are key enzymes involved in DNA replication and repair, and their coordinated activity can contribute to tumor cell survival and resistance to TOP1-targeted agents. In this study, a novel series of phenanthridine derivatives was rationally designed, synthesized, and evaluated for their potential as dual inhibitors of TOP1 and TDP1. Several compounds exhibited potent inhibitory activity against both targets, with compound C13 identified as a lead candidate, displaying strong inhibition of TOP1 (++++) and effective inhibition of TDP1 (IC₅₀ = 17.8 ± 1.3 μM). In vitro, C13 showed notable antiproliferative effects against multiple cancer cell lines, particularly A549 cells (IC₅₀ = 0.89 ± 0.25 μM), and induced apoptosis and suppressed clonogenic growth in a dose-dependent manner. Mechanistic studies revealed that C13 disrupts DNA repair pathways, and its combination with topotecan resulted in synergistic antitumor efficacy. Molecular dynamics simulations confirmed stable binding between C13 and both targets, while in vivo studies demonstrated low acute toxicity, favorable pharmacokinetic parameters, and pronounced tumor suppression. These findings highlight the promise of dual TOP1/TDP1 inhibition for overcoming tumor drug resistance and support the further development of C13 as a potential anticancer agent.

肿瘤对化疗的耐药性部分是由DNA修复机制驱动的，这是癌症治疗的一个主要障碍。DNA拓扑异构酶1B （TOP1）和酪氨酸-DNA磷酸二酯酶1 （TDP1）是参与DNA复制和修复的关键酶，它们的协同活性有助于肿瘤细胞的存活和对TOP1靶向药物的抗性。本研究合理设计、合成了一系列新的菲咯啶衍生物，并对其作为TOP1和TDP1双重抑制剂的潜力进行了评价。一些化合物对这两个靶点都有较强的抑制活性，其中化合物C13被确定为主要候选化合物，对TOP1（++++）和TDP1有较强的抑制作用（IC50 = 17.8±1.3 μM）。体外实验结果显示，C13对多种肿瘤细胞系，特别是A549细胞（IC50 = 0.89±0.25 μM）具有明显的抗增殖作用，并呈剂量依赖性诱导细胞凋亡和抑制克隆生长。机制研究表明，C13破坏DNA修复途径，与拓扑替康联合可产生协同抗肿瘤效果。分子动力学模拟证实了C13与这两个靶点之间的稳定结合，而体内研究显示了低急性毒性，良好的药代动力学参数和明显的肿瘤抑制作用。这些发现强调了TOP1/TDP1双重抑制在克服肿瘤耐药方面的前景，并支持了C13作为潜在抗癌药物的进一步开发。

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引用次数: 0

Rational design, synthesis and characterization of novel chimeric peptides containing the kappa-opioid agonists CR845 and dynorphin A-derived peptides 含有阿片受体激动剂CR845和肌啡肽a衍生肽的新型嵌合肽的合理设计、合成和表征

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.ejmech.2025.118534

Xiaodi Zhang , Shichao Zhang , Shuyuan Wu , Biao Xu , Jiamin Feng , Xuanran Hu , Ning Li , Nan Zhang , Mengna Zhang , Quan Fang

Recently, κ-opioid receptor (KOR) agonists have been attractive therapeutic candidates for the treatment of pain and pruritus. To advance the development of effective and safer peripherally restricted KOR agonists, we designed, synthesized, and evaluated 21 novel chimeric peptides incorporating the N-terminal tetrapeptide sequence of CR845 and the C-terminal “address” domain derived from dynorphin A. In vitro calcium mobilization assays confirmed the selective and full KOR agonism for all the compounds. Among these, analogues 4, 9, and 17 emerged as optimized analogues, exhibiting potent analgesic and antipruritic effects comparable to those of CR845 after subcutaneous administration, through the activation of the peripheral KOR. Additionally, subcutaneous administration of these 3 optimized analogues induced sedation without eliciting aversion or depressive-like side effects. Notably, analogue 4 was selected as the final candidate due to its high potency in KOR agonism and minimal sedative effects, making it the most promising drug candidate for the development of efficient and safe antinociceptive and antipruritic therapies.

最近，κ-阿片受体（KOR）激动剂已成为治疗疼痛和瘙痒的有吸引力的治疗候选药物。为了促进有效和更安全的外周限制性KOR激动剂的开发，我们设计、合成并评估了21种新型嵌合肽，这些嵌合肽包含CR845的n端四肽序列和来自dynorphin a的c端“地址”结构域。体外钙动员实验证实了所有化合物的选择性和完全的KOR激动作用。其中，类似物4,9和17被认为是优化的类似物，通过激活周围KOR，在皮下给药后表现出与CR845相当的有效镇痛和止痒作用。此外，皮下施用这3种优化的类似物可诱导镇静，而不会引起厌恶或抑郁样副作用。值得注意的是，类似物4被选为最终候选药物，因为它在KOR激动作用中具有高效力和最小的镇静作用，使其成为开发有效和安全的抗痛觉和止痒疗法的最有希望的候选药物。

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引用次数: 0

Design, semisynthesis, and anti-inflammatory activity evaluation of a terphenyllin compound library for alleviating ulcerative colitis 缓解溃疡性结肠炎的terphenyllin化合物文库的设计、半合成和抗炎活性评价

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-02 DOI: 10.1016/j.ejmech.2025.118539

Cui-Fang Wang , Tian-Yi Zhou , Liu-Xia Lv , Xi-Zhen Cao , Jun-Na Yin , Wen-Hui Wang , Qian-Qian Jing , Yu-Cheng Gu , Mei-Yan Wei , Guang-Ying Chen , Chang-Lun Shao

Ulcerative colitis (UC) is a chronic idiopathic enteritis, seriously affecting patients’ quality of life and significantly increasing the risk of cancer. We screened a marine natural product-derived library and identified a derivative (a4) of natural terphenyllin (1) as the bioactive scaffold for anti-inflammatory activity. To improve its activity, a total of 101 derivatives (a1–a29, b1–b40, and c1–c32) of a4 were rationally designed and semisynthesized. Among them, c13 (CHNQD-03005) emerged as the optimal lead, displaying the most potent inhibitory efficacy on the production of TNF-α, IL-6, and IL-1β with IC₅₀ values ranging from 0.095 μM to 0.45 μM. Notably, c13 (1 mg/kg, p.o.) demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, together with a favorable safety profile (MTD >100 mg/kg, p.o.). Mechanistically, c13 alleviated colitis by suppressing the expression of inflammatory signaling iNOS/COX-2, and downregulating the levels of NO, TNF-α, IL-6, and IL-1β. In conclusion, this study provided a promising oral natural terphenyllin derivative c13, which inhibited multiple inflammatory pathways to impede colitis progression, as a therapeutic candidate in the treatment of UC for further development.

溃疡性结肠炎（UC）是一种慢性特发性肠炎，严重影响患者的生活质量，显著增加患癌风险。我们筛选了一个海洋天然产物衍生的文库，并确定了天然terphenyllin(1)的衍生物（a4）作为抗炎活性的生物活性支架。为提高其活性，对a4的101个衍生物（a1-a29、b1-b40和c1-c32）进行了合理设计和半合成。其中，c13 （CHNQD-03005）对TNF-α、IL-6和IL-1β的抑制作用最强，IC50值在0.095 μM ~ 0.45 μM之间。值得注意的是，c13 （1 mg/kg, p.o.）在dss诱导的溃疡性结肠炎小鼠模型中表现出显著的治疗效果，同时具有良好的安全性（MTD >100 mg/kg, p.o.）。机制上，c13通过抑制炎症信号iNOS/COX-2的表达，下调NO、TNF-α、IL-6和IL-1β的水平来缓解结肠炎。总之，本研究提供了一种有前景的口服天然terphenyllin衍生物c13，它可以抑制多种炎症途径，阻止结肠炎的进展，作为UC治疗的候选药物，有待进一步开发。

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引用次数: 0

A novel RANKL-targeted selenyl quinolinamide alleviates ovariectomy-induced bone loss through inhibiting ROS, MAPK and NF-κB signaling pathways 一种新的靶向rankl的硒基喹啉酰胺通过抑制ROS、MAPK和NF-κB信号通路减轻卵巢切除术诱导的骨质流失

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2026-01-01 DOI: 10.1016/j.ejmech.2025.118533

Lele Yi , Yifan Ping , Xiaolong Ye , Shaoli Wang , Yao Wu , Lingling Zhou , Xiangrui Song , Haojin Chen , Bin Li , Yixin Mao , Yang Chen , Zhihao Yu , Weiwei Xue , Jing Wang , Shengbin Huang , Zengqiang Song

The osteoclast is the only bone cell responsible for bone resorption, intracellular reactive oxygen species (ROS) are key signaling factors that regulate RANKL-induced osteoclast differentiation. Organoselenium compounds have been demonstrated with good antioxidant activity by scavenging ROS. However, these compounds exerting anti-osteoclastogenesis activity by reducing ROS levels have not been reported. In this study, a series of selenyl quinolinamides were synthesized using a novel, simple, and metal-free method at room temperature, and their osteoclastogenesis inhibitory effects in vitro were tested. The most promising compound 3w with an IC₅₀ value of 0.577 μM, markedly inhibited RANKL-induced osteoclast formation, bone resorption, and osteoclast-specific genes and proteins expressions in vitro. Additionally, 3w suppressed RANKL-stimulated intracellular ROS levels by inhibition of ROS production and promotion of ROS scavenging, and inhibited downstream MAPK and NF-κB signaling pathways. In vivo, 3w significantly prevented bone loss in ovariectomized osteoporosis mice. Moreover, 3w could bind to RANKL and interfere with RANKL-RANK interaction. Our findings may offer a valuable direction for the development of novel organoselenium-based antiosteoporosis agents.

破骨细胞是唯一负责骨吸收的骨细胞，细胞内活性氧（ROS）是调控rankl诱导的破骨细胞分化的关键信号因子。有机硒化合物已被证明具有清除活性氧的良好抗氧化活性。然而，这些化合物通过降低ROS水平发挥抗破骨细胞生成活性尚未见报道。本研究采用一种新颖、简单、无金属的方法在室温下合成了一系列硒基喹啉酰胺，并对其体外破骨细胞生成抑制作用进行了实验研究。最有希望的化合物3w， IC50值为0.577 μM，在体外显著抑制rankl诱导的破骨细胞形成、骨吸收和破骨细胞特异性基因和蛋白的表达。此外，3w通过抑制ROS产生和促进ROS清除来抑制rankl刺激的细胞内ROS水平，并抑制下游的MAPK和NF-κB信号通路。在体内，3w可显著预防去卵巢骨质疏松小鼠的骨质流失。此外，3w可以结合RANKL并干扰RANKL- rank的相互作用。我们的研究结果可能为新型有机硒类抗骨质疏松药物的开发提供有价值的方向。

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引用次数: 0

Promiscuously bioactive compounds are prevalent in widely used commercial drug repurposing libraries 在广泛使用的商业药物再利用文库中，混杂的生物活性化合物是普遍存在的

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-12-31 DOI: 10.1016/j.ejmech.2025.118550

Huabin Hu , James Bowers , Justin Shumate , Louis Scampavia , Timothy P. Spicer , Xiangyan Yi , Albert A. Antolin , Jonathan B. Baell

The discovery of new therapeutics typically begins with screening compound collections against specific disease targets to identify bioactive small molecules. However, subsequent optimization is both time-consuming and costly, leading researchers to search for desired bioactivity in already-approved drugs with the hope of accelerating clinical development – a strategy often termed drug repurposing. While this strategy may seem beneficial, it carries significant risks, in particular with respect to lack of intellectual property control required to navigate regulatory pathways to the clinic. In this study, we have identified the more concerning phenomenon that widely used drug repurposing libraries are disproportionately populated by promiscuous compounds. Researchers lacking adequate medicinal chemistry expertise may overlook the spurious behaviors linked to certain molecular scaffolds, which can result in the advancement of misleading compounds into clinical trials. This misstep not only wastes scientific and financial resources but also could pose serious risks to patient safety by potentially enrolling them in ineffective trials. We call upon the biomedical community to implement rigorous validation processes for screening hits and to systematically exclude problematic compounds from drug repurposing libraries, thereby increasing the translational rate of future drug repurposing initiatives.

新疗法的发现通常始于筛选针对特定疾病靶点的化合物集合，以确定生物活性小分子。然而，随后的优化既耗时又昂贵，导致研究人员在已经批准的药物中寻找所需的生物活性，以期加速临床开发-一种通常被称为药物再利用的策略。虽然这一策略似乎是有益的，但它也有很大的风险，特别是缺乏知识产权控制，无法通过监管途径进入临床。在这项研究中，我们发现了一个更令人担忧的现象，即广泛使用的药物再利用文库中充斥着混杂的化合物。缺乏足够药物化学专业知识的研究人员可能会忽视与某些分子支架相关的虚假行为，这可能导致误导性化合物进入临床试验。这一失误不仅浪费了科学和财政资源，而且可能会使患者参与无效的试验，从而对患者安全构成严重风险。我们呼吁生物医学界实施严格的筛选命中验证程序，并系统地从药物再利用文库中排除有问题的化合物，从而提高未来药物再利用倡议的转化率。

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引用次数: 0

Discovery of novel and potent harringtonine derivative P2 via systematic structure-activity Optimization: Semi-Synthesis, anti-leukemia activity, and mechanism study 新型强效哈灵顿碱衍生物P2的系统构效优化：半合成、抗白血病活性及机制研究

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-12-31 DOI: 10.1016/j.ejmech.2025.118546

Zhongli Xu , Shuting Shen , Xinyu Ding , Xiaoyu Wang , Dejin Zhang , Yuanchao Li , Ping Xing , Hongli Chen , Fang Bai , Qianqian Yin , Biao Jiang

Natural harringtonine derivatives, isolated from cephalotaxus species, exhibit potent antiproliferative activity against hematological malignancies, particularly myeloid leukemia. However, systematic structure-activity relationship (SAR) studies for harringtonine derivatization remain limited. Herein, we employed nucleophilic epoxy ring-opening reactions using halogen, azido and thiophenol nucleophiles to rapidly construct a structurally diverse harringtonine derivative library. Subsequent comprehensive SAR investigation was then conducted to explore almost all modifiable positions on the side chain (1′, 2′, 3′, 4′, 5′) and position 2 of the cephalotaxine core. Significantly, we demonstrated for the first time that the metabolically labile 4′-ester group could be replaced by ether or hydroxyl group. Structure-activity optimization led to the discovery of novel derivative P2, featuring a 3′-ethoxy group and a 5′-(3,4-dimethoxyphenyl) sulfide. P2 exhibited a ∼10-fold increase in antiproliferative potency against human leukemic cell lines compared to homoharringtonine (HHT). The potent mechanism underlying P2's anti-leukemic effects involve potent inhibition of protein synthesis, leading to the preferential reduction of short-lived proteins crucial for cell survival, including c-Myc and Mcl-1. Molecular docking study revealed that P2 adopts a distinct binding mode within the ribosome, resulting in a more favorable interaction profile and enhanced binding stability. Our findings provide valuable insights to guide the future structural optimization of harringtonine derivatives. Furthermore, P2 has been identified as a promising anti-leukemic candidate and warrants further development.

从头杉属植物中分离出的天然三尖杉碱衍生物，对血液系统恶性肿瘤，特别是髓性白血病具有有效的抗增殖活性。然而，系统的构效关系（SAR）的研究仍然有限。本研究采用亲核环氧开环反应，利用卤素、叠氮和噻吩类亲核试剂，快速构建了结构多样的杉酸酯衍生物文库。随后进行了全面的SAR调查，以探索侧链上几乎所有可改变的位置（1 ',2 ',3 ',4 ',5 '）和头孢噻嗪核心的2号位置。值得注意的是，我们首次证明了代谢不稳定的4 ' -酯基团可以被醚或羟基取代。通过结构活性优化，发现了具有3 ' -乙氧基和5 ' -（3,4-二甲氧基苯基）硫化物的新型衍生物P2。P2对人白血病细胞系的抗增殖能力比同杉碱（HHT）提高了10倍。P2抗白血病作用的潜在机制涉及对蛋白质合成的有效抑制，导致对细胞存活至关重要的短寿命蛋白优先减少，包括c-Myc和Mcl-1。分子对接研究表明，P2在核糖体内采用不同的结合模式，具有更有利的相互作用谱，增强了结合稳定性。本研究结果为今后三叉杉碱衍生物的结构优化提供了有价值的指导。此外，P2已被确定为有希望的抗白血病候选药物，值得进一步开发。

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引用次数: 0

Targeting HSP70 protein-protein interactions for cancer precision Therapy: Mechanisms, structures, and inhibitor strategies 靶向HSP70蛋白蛋白相互作用用于癌症精确治疗：机制、结构和抑制剂策略

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry

Pub Date : 2025-12-31 DOI: 10.1016/j.ejmech.2025.118552

Long-tian Li, Yue-ying Yang, Shi-chen Zhang, Ji-fang Zhang, Chao Gao, Xu Zhu, Xin-yang Li

Dysregulated protein homeostasis and aberrant signaling pathways are established hallmarks of cancer. Among key molecular players, heat shock protein 70 (HSP70) exerts critical oncogenic functions by forming stable protein–protein interactions (PPIs) with co-chaperones and client proteins, thereby sustaining malignant signaling, suppressing apoptosis, and promoting drug resistance. However, conventional ATPase inhibitors targeting HSP70 face clinical limitations, including target conservation, systemic toxicity, and induction of the heat shock response. Inhibitors targeting HSP70 PPIs demonstrate superior selectivity, reduced toxicity, and enhanced resistance. This review systematically examines the mechanisms through which major HSP70-mediated PPIs drive tumor progression and treatment resistance. Furthermore, we provide structural insights into druggable PPI interfaces localized to the HSP70 nucleotide-binding domain (NBD) and C-terminal TPR-recognition motif, critically evaluating recent advances in the development of small-molecule and peptide-based PPI inhibitors. Together, these analyses offer new perspectives for advancing precision cancer therapeutics.

蛋白质稳态失调和信号通路异常是癌症的标志。在关键分子中，热休克蛋白70 （HSP70）通过与共伴侣蛋白和客户蛋白形成稳定的蛋白相互作用（PPIs）发挥关键的致癌功能，从而维持恶性信号传导、抑制细胞凋亡和促进耐药。然而，传统的靶向HSP70的atp酶抑制剂面临着临床局限性，包括靶标保护、全身毒性和诱导热休克反应。靶向HSP70 PPIs的抑制剂表现出优越的选择性、降低的毒性和增强的耐药性。这篇综述系统地探讨了hsp70介导的PPIs驱动肿瘤进展和治疗耐药性的机制。此外，我们提供了定位于HSP70核苷酸结合域（NBD）和c端tpr识别基序的可药物PPI界面的结构见解，批判性地评估了小分子和肽基PPI抑制剂的最新进展。总之，这些分析为推进精确的癌症治疗提供了新的视角。

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