Bioorganic & Medicinal Chemistry Letters最新文献_第9页

Worm-like gold nanocrystals fabricated using a self-assembling peptide and inducing cell death upon exposure to near infrared light 使用自组装肽制备的蠕虫状金纳米晶体，并在暴露于近红外光下诱导细胞死亡。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-11 DOI: 10.1016/j.bmcl.2025.130472

Soo-Ang Ahn , Kazutoshi Ishida , Ryuki Watanabe , Takahito Imai , Masayuki Yamasaki , Kin-ya Tomizaki

Gold nanorods (GNRs) can perform photothermal energy conversion by absorbing near-infrared (NIR) light and converting it to heat, and are therefore promising for applications in photothermal cancer therapy. However, to synthesize these nanorods, the highly cytotoxic compound cetyltrimethylammonium bromide (CTAB) is required. In the present study, to overcome this difficulty, we developed a method for synthesizing CTAB-free nanocrystals in the form of gold nanoworms (GNWs) using a self-assembling peptide exhibiting a positively-charged nuclear localization signal (NLS) sequence. We investigated the photothermal conversion performance of the GNWs and their ability to induce cell death under NIR irradiation. Based on transmission electron microscopy observations, the NLS-GNWs were determined to be approximately 80 nm in length and 9 nm in width. Their photothermal conversion efficiency was estimated to be 0.27 ± 0.06. Interestingly, in the absence of NLS-GNWs, following three cycles of NIR light exposure for 5 min at an intensity of 5 W/cm² separated by 10 min intervals, no significant change in cytotoxicity of HeLa cells was observed compared with the control. However, in the presence of NLS-GNWs, the cell viability after the first, second and third cycles was approximately 25 %, 18 % and 10 %, respectively. The intracellular localization of NLS-GNWs was also investigated using fluorescein labelled-NLS-GNWs, and it was found that many of the GNWs were present at the nuclei of the HeLa cells. The positively-charged NLS-GNWs are thought to have been attracted to the relatively acidic surfaces of the cancer cells.

金纳米棒（gnr）可以通过吸收近红外（NIR）光并将其转化为热来进行光热能量转换，因此在光热癌症治疗中有很好的应用前景。然而，为了合成这些纳米棒，需要高度细胞毒性的化合物十六烷基三甲基溴化铵（CTAB）。在本研究中，为了克服这一困难，我们开发了一种方法，利用具有正电荷核定位信号（NLS）序列的自组装肽，以金纳米蠕虫（GNWs）的形式合成不含ctab的纳米晶体。我们研究了GNWs的光热转换性能及其在近红外照射下诱导细胞死亡的能力。通过透射电镜观察，确定NLS-GNWs的长度约为80 nm，宽度约为9 nm。其光热转换效率估计为0.27 ± 0.06。有趣的是，在没有NLS-GNWs的情况下，在以5 W/cm2的强度间隔10 min照射3个周期5 min后，与对照组相比，HeLa细胞的细胞毒性没有明显变化。然而，在NLS-GNWs存在的情况下，第一次、第二次和第三次循环后的细胞存活率分别约为25 %、18 %和10 %。使用荧光素标记的NLS-GNWs也研究了NLS-GNWs的细胞内定位，发现许多GNWs存在于HeLa细胞的细胞核中。带正电的NLS-GNWs被认为是被癌细胞相对酸性的表面所吸引。

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引用次数: 0

Identification of a novel small-molecule inhibitor of heterochromatin protein 1 一种新型异染色质蛋白小分子抑制剂的鉴定。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-09 DOI: 10.1016/j.bmcl.2025.130469

Akari Tokuyama , Yasunobu Yamashita , Ryo Maeda , Toshiki Akiyama , Yuri Takada , Ryunosuke Yoshino , Hiroki Kato , Shengwang Yu , Yukihiro Itoh , Makoto Tachibana , Takayoshi Suzuki

Heterochromatin protein 1 (HP1), one of the epigenetic “reader” proteins, recognizes trimethylated lysine 9 of histone H3 (H3K9me3) to repressively regulate gene transcription by promoting chromatin aggregation. Overexpression of HP1 plays a role in the growth of various cancer cells. Therefore, inhibiting its interaction with H3K9me3 is considered a promising therapeutic strategy for cancer treatment. This study aimed to identify small molecules that bind to HP1 and inhibit the HP1/H3K9me3 interaction. We performed in silico screening of the compounds from the Osaka University Library and selected 61 virtual hit compounds. As a result of in vitro evaluation of the hits by an HP1/H3K9me3 interaction inhibition assay, we identified compound 1, which exhibited 36 % inhibitory activity at 100 μM. Furthermore, the structural optimization of 1 led to the identification of (R)-18 (IC₅₀: 18.1 μM)—a novel small molecule that inhibits the HP1/H3K9me3 interaction.

异染色质蛋白1 （Heterochromatin protein 1, HP1）是一种表观遗传“阅读器”蛋白，它识别组蛋白H3 （H3K9me3）的三甲基化赖氨酸9，通过促进染色质聚集来抑制基因转录。HP1的过表达在多种癌细胞的生长中起作用。因此，抑制其与H3K9me3的相互作用被认为是一种很有前景的癌症治疗策略。本研究旨在鉴定与HP1结合并抑制HP1/H3K9me3相互作用的小分子。我们对来自大阪大学图书馆的化合物进行了计算机筛选，并选择了61个虚拟命中化合物。通过体外HP1/H3K9me3相互作用抑制实验，我们鉴定出化合物1，在100 μM下具有36% %的抑制活性。此外，通过对1的结构优化，鉴定出抑制HP1/H3K9me3相互作用的新型小分子(R)-18 （IC50: 18.1 μM）。

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引用次数: 0

Lysine-reactive tag system for cell-surface protein labeling via N-acyl-N-alkyl sulfonamide chemistry 通过n -酰基- n -烷基磺酰胺化学方法标记细胞表面蛋白的赖氨酸反应性标记系统。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-09 DOI: 10.1016/j.bmcl.2025.130470

Vikram Thimaradka, Tomonori Tamura, Itaru Hamachi

Target-selective and site-specific incorporation of a desired functionality into a membrane protein endogenously expressed in cells is a great challenge in chemical biology. Here, we describe a versatile strategy for covalent chemical modification of short peptide tag-fused membrane proteins expressed in cells. This method is based on the recognition-driven reaction of a lysine-containing short histidine tag (KH6 or H6K sequence) and a binuclear nickel (II)-nitrilotriacetic acid (BisNi²⁺-NTA) complex probe containing a lysine-reactive N-acyl-N-alkyl sulfonamide (NASA). Our reactive peptide tag system enabled the selective modification of cell-surface proteins with affinity tags or fluorescent probes through a simple one-step protocol. In this study, we fused the KH6 or H6K tag to cell-surface proteins such as Neuroligin-1, epidermal growth factor receptor (EGFR), and Neurexin-1β, and achieved selective chemical modification of these proteins in live cells. Furthermore, we demonstrated that our short peptide tag allows efficient labeling not only when introduced at the protein termini but also when incorporated internally.

在细胞内源性表达的膜蛋白中靶向选择性和位点特异性结合是化学生物学中的一个巨大挑战。在这里，我们描述了在细胞中表达的短肽标签融合膜蛋白的共价化学修饰的通用策略。该方法基于含有赖氨酸的短组氨酸标签（KH6或H6K序列）和含有赖氨酸反应性n-酰基-n -烷基磺酰胺（NASA）的双核镍(II)-硝基三乙酸（BisNiNTA）配合物探针的识别驱动反应。我们的活性肽标签系统通过简单的一步协议，可以用亲和标签或荧光探针选择性修饰细胞表面蛋白。在这项研究中，我们将KH6或H6K标签与细胞表面蛋白如Neuroligin-1、表皮生长因子受体（EGFR）和Neurexin-1β融合，并在活细胞中实现了这些蛋白的选择性化学修饰。此外，我们证明了我们的短肽标签不仅可以在蛋白质末端引入，而且可以在内部结合时进行有效的标记。

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引用次数: 0

Evaluation of the antibacterial activity of diverse coumarin [3,4]-fused tetrahydroheterocycles 不同香豆素[3,4]-融合四氢杂环的抗菌活性评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-09 DOI: 10.1016/j.bmcl.2025.130468

Xiyan Tang, Jie Pang, Yanmin Huang, Jianguo Cui, Chunfang Gan, Zhiping Liu

Three novel classes of coumarin [3,4]-fused tetrahydroheterocyclics were synthesized in one step using donor-acceptor cyclopropane diesters as 1,3-dipoles via a facile [3 + 2]/[3 + 3] annulation/lactonization strategies. The antibacterial activities of these compounds were evaluated against two species of animal-derived pathogenic bacteria (Staphylococcus aureus, Escherichia coli) and three species of plant-derived pathogenic bacteria (Xanthomonas citri, Pseudomonas oryzae, Fusarium oxysporum). The results showed that coumarin-fused tetrahydrofuran compounds (e.g., 3aa, 3ac and 3ae) exhibited significant selective antibacterial activity against Staphylococcus aureus with a minimum inhibitory concentration (MIC) of 2 μg/mL, while no obvious inhibitory effect was observed against other tested strains. Coumarin-fused tetrahydropyridazines (e.g., 7ad, 7ae, 7ah and 7ag) displayed excellent antibacterial activity against Pseudomonas oryzae and Fusarium oxysporum, with an MIC value of 2 μg/mL for all, and their antibacterial effect was significantly superior to that of osthol (the positive control). In contrast, coumarin-fused tetrahydro-1,2-oxazines showed relatively weak antibacterial activity, only compounds 5 ac and 5ak exerted moderate inhibitory effects on Staphylococcus aureus and Pseudomonas oryzae, both with an MIC value of 4 μg/mL. The findings of this study provide an important theoretical basis for the design and synthesis of novel coumarin-fused tetrahydroheterocyclic antibacterial agents.

本研究系统评价了三类香豆素融合物[3,4]-四氢杂环化合物对两种动物源致病菌——金黄色葡萄球菌和大肠杆菌，以及三种植物致病菌——柑橘黄单胞菌、稻谷假单胞菌和尖孢镰刀菌的抑菌活性。结果表明，香豆素融合的四氢呋喃衍生物（如3aa、3 ac和3ae； MIC = 2 μg/mL）对金黄色葡萄球菌具有明显的选择性抗菌活性。与香豆素融合的四氢吡啶类化合物对稻瘟病假单胞菌和尖孢镰刀菌均有较强的抑菌活性，其最低抑菌浓度（MIC）为2 μg/mL（如7ae、7ah和7ag），显著优于阳性对照虫床子素。相比之下，香豆素融合的四氢-1,2-恶嗪类似物表现出相对较弱的广谱抗菌活性。这些发现为设计和合成新型香豆素类杂环抗菌剂提供了坚实的理论基础，并为今后的研究方向提供了有价值的指导。

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引用次数: 0

Targeting telomerase for lung cancer: design and synthesis of acridine hybrids with in vitro and in vivo evaluation 靶向端粒酶治疗肺癌：吖啶杂合体的设计与合成及其体外和体内评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-08 DOI: 10.1016/j.bmcl.2025.130465

Keerti Vishwakarma, Rajdeep Dey, Hardik Bhatt

Lung cancer remains the leading cause of cancer-related deaths worldwide, emphasizing the need for effective targeted therapeutics. Telomerase, which is aberrantly activated in most lung tumors, is an attractive molecular target; however, the clinical translation of its inhibitors has been limited. In this study, we employed a rational design approach that integrated pharmacophore modeling, virtual screening, QSAR, and molecular docking to develop acridine–thiadiazole hybrids as potential telomerase inhibitors. Guided by pharmacophore-based virtual screening and 3D-QSAR studies, 32 derivatives were synthesized through an optimized route for synthesis and evaluated for anticancer activity. Several compounds displayed potent sub-micromolar cytotoxicity against A549 lung cancer cells with minimal toxicity toward Vero cells. Among them, compound 28 emerged as the most potent, exhibiting nanomolar activity and strong telomerase inhibition, while compounds 21, 29, and 39 also demonstrated significant efficacy. Mechanistic studies confirmed apoptosis induction, inhibition of clonogenic survival, and telomerase suppression. In vivo evaluation in a benzo[a]pyrene-induced lung cancer model further validated the therapeutic potential of these hybrids, showing reduced tumor burden, restoration of antioxidant balance, and preservation of lung architecture. Collectively, these findings highlight acridine–thiadiazole hybrids, particularly compound 28, as promising, selective telomerase inhibitors for lung cancer therapy.

肺癌仍然是世界范围内癌症相关死亡的主要原因，强调需要有效的靶向治疗。端粒酶在大多数肺肿瘤中异常激活，是一个有吸引力的分子靶标；然而，其抑制剂的临床翻译是有限的。在本研究中，我们采用了一种合理的设计方法，将药效团建模、虚拟筛选、QSAR和分子对接结合起来，开发了吖啶-噻二唑杂合体作为潜在的端粒酶抑制剂。在基于药物团的虚拟筛选和3D-QSAR研究的指导下，通过优化的合成路线合成了32种衍生物，并对其抗癌活性进行了评价。几种化合物对A549肺癌细胞显示出有效的亚微摩尔细胞毒性，而对Vero细胞的毒性很小。其中，化合物28的药效最强，具有纳米摩尔活性和较强的端粒酶抑制作用，而化合物21、29和39也表现出显著的疗效。机制研究证实了细胞凋亡诱导，抑制克隆生存和端粒酶抑制。在苯并[a]芘诱导的肺癌模型中的体内评估进一步验证了这些杂交体的治疗潜力，显示出减轻肿瘤负担，恢复抗氧化平衡，并保留肺结构。总的来说，这些发现突出了吖啶-噻二唑混合物，特别是化合物28，作为有希望的选择性端粒酶抑制剂用于肺癌治疗。

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引用次数: 0

α2C Adrenoceptor antagonist KMCA-0011 alleviated depressive-like behaviors in a maternal separation mouse model α2C肾上腺素受体拮抗剂KMCA-0011减轻母鼠分离模型的抑郁样行为。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-07 DOI: 10.1016/j.bmcl.2025.130467

Kobeom Seo , Mijin Jeon , Ju Eun Han , Jinwon Hong , Do Hyeon Kim , Jung Hwan Choi , Seo Yun Jung , Kyeong-Man Kim , Dong Hyun Kim , Jong Hoon Ryu , Jae Yeol Lee

Despite the widespread use of monoaminergic antidepressants, their clinical efficacy is often limited by delayed onset and adverse effects. Targeting the α_2C adrenoceptor (AR) has emerged as a promising strategy to overcome these limitations. Here, a series of benzoxazole and oxalamide derivatives were designed, synthesized, and biologically evaluated as potential antidepressants targeting α_2C AR. Among them, 11e (KMCA-0011), 21b (KMCA-0002), and 21e (KMCA-0028) exhibited the highest binding affinity. Molecular docking studies provided a rationale for the differences in their binding affinities. These compounds demonstrated antagonistic activity by inhibiting ERK phosphorylation without agonistic effects. In a maternal separation (MS) mouse model, all three compounds significantly alleviated depressive-like behaviors, with 11e (KMCA-0011) and 21e (KMCA-0028) showing the most consistent efficacy. Mechanistically, 11e (KMCA-0011) increased hippocampal brain-derived neurotrophic factor (BDNF) levels and restored corticosterone-induced impairments in long-term potentiation (LTP), indicating modulation of synaptic plasticity. Additionally, 11e (KMCA-0011) and 21e (KMCA-0028) displayed favorable ADME profiles, including high plasma stability and minimal CYP inhibition. Given the predicted limited blood–brain barrier (BBB) permeability of 21e (KMCA-0028), these results collectively identify 11e (KMCA-0011) as a promising lead compound that demonstrates robust antidepressant-like activity, likely mediated through α_2C AR antagonism and BDNF-dependent neuroplastic mechanisms.

尽管单胺类抗抑郁药广泛使用，但其临床疗效往往受到延迟起效和不良反应的限制。靶向α2C肾上腺素受体（AR）已成为克服这些局限性的一种有希望的策略。本研究设计、合成了一系列苯并恶唑和草酰胺衍生物，并对其作为靶向α2C AR的潜在抗抑郁药进行了生物学评价。其中，11e （KMCA-0011）、21b （KMCA-0002）和21e （KMCA-0028）的结合亲和力最高。分子对接研究为它们的结合亲和力差异提供了理论依据。这些化合物通过抑制ERK磷酸化而无激动作用显示出拮抗活性。在母鼠分离（MS）模型中，三种化合物均能显著缓解抑郁样行为，其中11e （KMCA-0011）和21e （KMCA-0028）的效果最为一致。在机制上，11e （KMCA-0011）增加了海马脑源性神经营养因子（BDNF）水平，恢复了皮质酮诱导的长期增强（LTP）损伤，表明突触可塑性的调节。此外，11e （KMCA-0011）和21e （KMCA-0028）显示出良好的ADME谱，包括高血浆稳定性和最小的CYP抑制。考虑到21e （KMCA-0028）预测的血脑屏障（BBB）渗透率有限，这些结果共同确定11e （KMCA-0011）是一种有前景的先导化合物，显示出强大的抗抑郁样活性，可能通过α2C AR拮抗和bdnf依赖的神经可塑性机制介导。

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引用次数: 0

Design, synthesis, α-glucosidase inhibitory activity, and molecular docking of novel pyrazolyl–porphyrin hybrids as potential antidiabetic agents 新型吡唑啉-卟啉复合物的设计、合成、α-葡萄糖苷酶抑制活性及分子对接

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-05 DOI: 10.1016/j.bmcl.2025.130462

Sagar Vijay Kumar Peddakotla , Suresh Lingala , Onkara Perumal , M. Amaravathi , G.V.P. Chandramoulia

A novel series of A₂B₂ and A₄ type porphyrin derivatives bearing pyrazole moieties was efficiently synthesized and structurally characterized. These pyrazolyl–porphyrins were evaluated for their α-glucosidase inhibitory activity using Saccharomyces cerevisiae α-glucosidase as the target enzyme. In vitro enzyme assays and kinetic studies revealed that compounds 6c, 7b, and 6d exhibited inhibitory effects comparable to the standard drug Acarbose. Notably, compound 6c demonstrated the highest potency, with an IC₅₀ value of (31.36 μM), closely matching that of Acarbose (31.69 μM) under identical experimental conditions. In silico molecular docking studies further supported the biological data, showing that compound 6c interacts with key residues within the enzyme's active site in a binding mode similar to Acarbose. These findings suggest that pyrazolyl–porphyrin hybrids, particularly compound 6c, hold promise as potential α-glucosidase inhibitors for the development of antidiabetic agents.

合成了一系列新的含吡唑基团的A2B2和A4型卟啉衍生物，并对其进行了结构表征。以酿酒酵母菌α-葡萄糖苷酶为靶酶，对这些吡唑啉卟啉进行α-葡萄糖苷酶抑制活性评价。体外酶分析和动力学研究表明，化合物6c、7b和6d具有与标准药物阿卡波糖相当的抑制作用。值得注意的是，化合物6c表现出最高的效力，其IC₅0值为（31.36 μM），与相同实验条件下的阿卡波糖（31.69 μM）非常匹配。硅分子对接研究进一步支持了生物学数据，表明化合物6c以类似于阿卡波糖的结合模式与酶活性位点内的关键残基相互作用。这些发现表明吡唑啉-卟啉复合物，特别是化合物6c，有望成为潜在的α-葡萄糖苷酶抑制剂，用于开发抗糖尿病药物。

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引用次数: 0

Identification of affinity-optimized peptide binders of a viral protease for chemical genetic applications 一种病毒蛋白酶亲和优化肽结合物的鉴定及其化学遗传学应用。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-05 DOI: 10.1016/j.bmcl.2025.130463

Fernando Banales-Mejia , Emily M. Dieter , Kyler J. Radmall , Glenna W. Foight , Douglas M. Fowler , Dustin J. Maly

Chemically-controlled genetic tools are useful for studying biological systems due to their ability to dose-dependently and temporally modulate intracellular function. Chemically-disrupted proximity (CDP) systems, which involve the pre-localization of two interacting protein components that can be disrupted with a small molecule, are complementary to more commonly used chemically-inducible dimerization (CID) systems. However, fewer CDP systems have been developed, and the genetically-encoded protein components have not been as optimized for intracellular applications. Here, we describe a transcriptional activation reporter assay for screening the intracellular interaction between the 21-amino acid peptide ANR and HCVp NS3a, which are the genetically-encoded components of a CDP system that utilizes clinically-approved antiviral drugs. We used this assay to screen a library of single amino acid substitution ANR variants and identified several that increase the intracellular interaction between ANR and NS3a. By combining affinity-optimized single substitutions, we achieved improved transcriptional activation and engineered an autoinhibited signaling switch with low basal activity. Together, our study describes a functional assay for screening genetically-encoded CDP components and a more optimized version of ANR for intracellular applications.

化学控制的遗传工具对研究生物系统是有用的，因为它们具有剂量依赖性和时间调节细胞内功能的能力。化学破坏接近（CDP）系统，涉及两个相互作用的蛋白质成分的预定位，可以被一个小分子破坏，是更常用的化学诱导二聚化（CID）系统的补充。然而，开发的CDP系统较少，并且遗传编码的蛋白质成分尚未针对细胞内应用进行优化。在这里，我们描述了一种转录激活报告试验，用于筛选21个氨基酸肽ANR和HCVp NS3a之间的细胞内相互作用，它们是使用临床批准的抗病毒药物的CDP系统的遗传编码成分。我们使用该方法筛选了一个单氨基酸替代ANR变体库，并确定了几个增加ANR与NS3a之间细胞内相互作用的变体。通过结合亲和优化的单替换，我们实现了更好的转录激活，并设计了一个具有低基础活性的自抑制信号开关。总之，我们的研究描述了一种筛选遗传编码CDP成分的功能分析和一种用于细胞内应用的更优化的ANR版本。

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引用次数: 0

An efficient approach to flavan-4-ols via radiolysis and their inhibitory activity against cytokine production 黄酮类-4-醇的辐射分解及其对细胞因子的抑制活性。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-05 DOI: 10.1016/j.bmcl.2025.130464

Gyeong Han Jeong , Ha-Yeon Song , Hanui Lee , Byung Yeoup Chung , Kyung-Bon Lee , Hyoung-Woo Bai

Facile structural modification of naringin (1) induced by γ-irradiation produced five novel hydroxymethylated flavan-4-ols, namely, narinflavans A (2), B (3), C (4), D (5), and E (6). The structures of the newly synthesized flavan derivatives were determined through comprehensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) analyses, whereas their absolute configurations were confirmed by electronic circular dichroism (ECD) spectroscopy. The new unusual flavan derivatives 4 and 5 containing a hydroxymethyl, instead of a ketone moiety, exhibited significantly modulated inhibitory effects on cytokine production than the parent compound. These results highlight γ-irradiation as an efficient one-step approach to generate structurally novel flavan-4-ols with biological functions.

γ辐照对柚皮素(1)进行了简单的结构修饰，产生了5种新的羟甲基化黄烷-4-醇，即柚皮素A(2)、B(3)、C(4)、D(5)和E(6)。通过综合一维（1D）和二维（2D）核磁共振（NMR）分析确定了新合成的黄烷衍生物的结构，并通过电子圆二色性（ECD）光谱确定了它们的绝对构型。新的不寻常的黄烷衍生物4和5含有一个羟甲基，而不是酮，对细胞因子产生的抑制作用比母体化合物显著调节。这些结果表明，γ辐照是一种高效的一步法，可生成具有生物学功能的结构新颖的黄烷-4-醇。

引用次数: 0

Gallium Hematoporphyrin inhibits Mycobacteroides abscessus in vitro, including biofilm formation and stability 血卟啉镓体外抑制脓肿分枝杆菌，包括生物膜的形成和稳定性

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-11-05 DOI: 10.1016/j.bmcl.2025.130466

Seoung-ryoung Choi , Bradley E. Britigan , Prabagaran Narayanasamy

The nontuberculous mycobacterial (NTM) pathogen, Mycobacteroides abscessus, can cause severe pulmonary infections. Emerging multidrug resistance to current antibiotics poses significant challenges for treatment of M. abscessus infections. Thus, new antibiotics are needed, preferably ones that target new microbial pathways. Earlier, we examined the in vitro inhibitory activities of several gallium compounds, Ga(NO₃)₃, GaCl₃, gallium meso-tetraphenylporphyrin (GaTP) and gallium nanoparticles (GaNP), against intra- and extracellular M. abscessus. We have previously shown that these gallium compounds function by disrupting microbial iron/heme acquisition and utilization. Here, we explored an alternative therapeutic approach using gallium hematoporphyrin (GaHP), a toxic heme analogue. GaHP inhibited growth of clinical M. abscessus isolates, with MICs in range of 0.5 and 1 μg/ml. GaHP was more active than rifampin against M. abscessus, showed synergism with clarithromycin, and induced ROS formation in M. abscessus. GaHP also inhibited biofilm formation of both smooth and rough M. abscessus colony morphotypes. GaHP also disrupted preformed biofilms by both M. abscessus morphotypes. Hence, GaHP could be a potential lead compound for development of anti-NTM agents that targets heme-metabolism of M. abscessus.

非结核分枝杆菌（NTM）病原体，脓肿分枝杆菌，可引起严重的肺部感染。新出现的对现有抗生素的多药耐药性对脓肿分枝杆菌感染的治疗提出了重大挑战。因此，需要新的抗生素，最好是针对新的微生物途径的抗生素。在此之前，我们研究了几种镓化合物Ga(NO3)3、GaCl3、中四苯基卟啉镓（GaTP）和纳米镓（GaNP）对细胞内和细胞外脓疡分枝杆菌的体外抑制活性。我们之前已经证明这些镓化合物通过破坏微生物铁/血红素的获取和利用而起作用。在这里，我们探索了使用血卟啉镓（GaHP）的替代治疗方法，这是一种有毒的血红素类似物。GaHP抑制临床脓肿分枝杆菌分离株的生长，mic在0.5 ~ 1 μg/ml范围内。GaHP对脓肿支原体的活性高于利福平，与克拉霉素有协同作用，并诱导脓肿支原体ROS的形成。GaHP还抑制光滑和粗糙的脓肿分枝杆菌菌落形态的生物膜形成。GaHP还破坏了两种形态的脓肿分枝杆菌预先形成的生物膜。因此，GaHP可能是开发针对脓肿支原体血红素代谢的抗ntm药物的潜在先导化合物。

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引用次数: 0