Bioorganic & Medicinal Chemistry Letters最新文献

Substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives as anti-invasion agents 取代1-（苯并[d]噻唑-2-基）-3-苯脲衍生物作为抗侵入剂。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-31 DOI: 10.1016/j.bmcl.2026.130568

Reilly K. Gwinn , Padmanabhan Mannangatti , Shahid Maqbool Mir , Shikha Kumari , Mai K. Le , Swadesh K. Das , Paul B. Fisher , Webster L. Santos

Developing small molecule drugs to treat metastatic cancer remains challenging and relies on the identification of novel druggable targets within the multistep metastatic cascade. To this end, the pro-metastatic scaffolding protein, MDA-9/Syntenin-1 was identified and confirmed as a suitable target uniquely involved in the multiple stages of metastasis. Recently, the first-in class PDZ1 domain inhibitor for MDA-9, PDZ1i, was identified displaying significant anti-invasion activity improving survival in an in vivo glioblastoma and in multiple metastatic cancer mouse models. Herein, we report a focused library of substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives inspired by the anti-invasion and anti-metastatic agent, PDZ1i. Our studies revealed that 1-(benzo[d]thiazol-2-yl)-3-phenylurea analogs bearing 6-trifluoromethyl (3y) and 6-bromo (3aa) substituents display anti-invasion activity comparable to PDZ1i. However, compounds 3y and 3aa displayed overall decreased cancer cell selectivity and MDA-9 activity relative to PDZ1i. Nonetheless, the reported 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives serve as promising starting points for future development of small molecule anti-invasion agents with potential to prevent and treat metastatic cancers.

开发小分子药物来治疗转移性癌症仍然具有挑战性，并且依赖于在多步骤转移级联中识别新的可药物靶点。为此，促转移支架蛋白MDA-9/Syntenin-1被鉴定并证实是一个独特参与多阶段转移的合适靶点。最近，一类MDA-9的PDZ1结构域抑制剂PDZ1i被发现在体内胶质母细胞瘤和多发性转移癌小鼠模型中表现出显著的抗侵袭活性，提高了生存率。在此，我们报道了一个受抗侵袭和抗转移剂PDZ1i启发的取代的1-（苯并[d]噻唑-2-基）-3-苯脲衍生物的重点文库。我们的研究表明，含有6-三氟甲基（3y）和6-溴（3aa）取代基的1-（苯并[d]噻唑-2-基）-3-苯脲类似物具有与PDZ1i相当的抗入侵活性。然而，与PDZ1i相比，化合物3y和3aa总体上显示出癌细胞选择性和MDA-9活性的降低。尽管如此，报道的1-（苯并[d]噻唑-2-基）-3-苯脲衍生物为未来开发具有预防和治疗转移性癌症潜力的小分子抗侵袭药物提供了有希望的起点。

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引用次数: 0

Design, synthesis, and mechanism of anti-cancer activity of novel spiro tetramic acids 新型螺旋体四聚酸的设计、合成及其抗癌作用机理。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-29 DOI: 10.1016/j.bmcl.2026.130566

Shi Xiang , Mengjiao Lv , Chenghao Wang , Zhichao Wang , Hui Chen , Pei Lv , Chao Yang

Targeted therapies have pioneered a more effective new pathway in cancer treatment by leveraging their precision-targeting advantages. Spiro tetramic acids are a kind of unique pyrrolidine-2,4-dione core structure containing a spiro ring structure, primarily employed as agro-chemicals with limited application in the field of anti-cancer. In this paper, fourteen novel 3-acetyl and 3-phenyl spiro tetramic acids were designed, synthesized, and evaluated for anti-proliferation in cancer cells. 3-Acetyl and 3-phenyl spirotetramic acids exhibited toxic effects against tested cancer cell lines. Among the 14 compounds, compound 8d was the most effective against RKO and H1299 with Half Maximal Inhibitory Concentration (IC₅₀) 3 ± 1 and 19 ± 2 μM. Further molecular structural prediction, bioinformatics analysis, and molecular docking revealed that compound 8d may target MMP1, MMP7 and PLK1. Additionally, 8d induced cell cycle arrest in G1 phase by increasing the expression of p21 protein and decreasing the expression of CCND1 and CCNB1 proteins. 8d also induced cell apoptosis through the mitochondrial pathways, as evidenced by alterations in the expressions of pertinent proteins, including Bcl-2 and Bax. These results indicated that the novel spirotetramine derivative 8d is a potential anti-cancer candidate drug and provides a new structural basis for the development of anti-cancer drugs.

靶向治疗利用其精确靶向的优势，为癌症治疗开辟了一条更有效的新途径。螺旋四羧酸是一种独特的含有螺旋环结构的吡咯烷-2,4-二酮核心结构，主要用作农用化学品，在抗癌领域的应用有限。本文设计、合成了14种新型的3-乙酰基和3-苯基螺四酸，并对其在癌细胞中的抗增殖作用进行了评价。3-乙酰基和3-苯基螺戊酸对所测试的癌细胞表现出毒性作用。14个化合物中，化合物8d对RKO和H1299的抑制效果最好，IC50分别为3 ± 1和19 ± 2 μM。进一步的分子结构预测、生物信息学分析和分子对接表明，化合物8d可能靶向MMP1、MMP7和PLK1。此外，8d通过增加p21蛋白的表达，降低CCND1和CCNB1蛋白的表达，诱导细胞周期阻滞在G1期。8d还通过线粒体途径诱导细胞凋亡，相关蛋白包括Bcl-2和Bax的表达改变证明了这一点。这些结果表明，新的螺虫胺衍生物8d是一种潜在的抗癌候选药物，为抗癌药物的开发提供了新的结构基础。

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引用次数: 0

Integrated approach to design 5-indolyl-pyrazoles as anti-TB agent 5-吲哚吡唑抗结核药物的综合设计。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-30 DOI: 10.1016/j.bmcl.2026.130534

K. Mohammed Zabiulla , Prabodh Ranjan , Archakam Ranganatham , Mohd Athar , Shivaraj Yellappa

This study reports a structure-guided design, synthesis, and biological evaluation of a novel class of hybrid molecules combining indole and pyrazole scaffolds-both known for their broad pharmacological profiles. A series of 5-indolyl-pyrazole derivatives (n = z1–z44) were synthesized and characterized through ¹H/¹³C NMR and HR-MS analysis. The synthesized compounds were screened against H37Rv and two multidrug-resistant clinically isolated strains M.tb* and M.tb**. Several derivatives (notably z1 and z8) showed potent inhibition at concentrations as low as 25 μg/mL may be even more potent at lower concentrations and a comparative analysis could be possible. Complementary molecular docking studies were conducted using the InhA enzyme (PDB ID: 4TZK), a validated target in mycolic acid biosynthesis. Lead compounds demonstrated favorable binding energies (e.g., −6.35 kcal/mol for z1), engaging key active-site residues (PHE97, MET103, PHE149, TYR158) through hydrophobic, π-stacking, and van der Waals interactions, alongside critical contact with the NAD⁺ cofactor. Interaction fingerprint analysis correlated ligand-residue contacts with biological activity, underscoring the importance of aromatic planarity and substituent modulation for effective InhA inhibition. This integrated synthetic-biological-computational workflow lays a promising foundation for the development of next-generation anti-TB agents with improved efficacy against resistant strains.

本研究报告了一种结构导向的设计、合成和生物学评价的新型杂化分子结合吲哚和吡唑支架-两者都以其广泛的药理特征而闻名。合成了一系列5-吲哚吡唑衍生物（n = z1-z44），并通过1H/13C NMR和HR-MS对其进行了表征。合成的化合物对H37Rv和临床分离的两种多重耐药菌株M.tb*和M.tb**进行了筛选。几种衍生物（特别是Z1和Z8）在低至25 μg/mL的浓度下显示出有效的抑制作用，可能在更低的浓度下更有效，并可能进行比较分析。利用InhA酶（PDB ID: 4TZK）进行了互补分子对接研究，InhA酶是霉菌酸生物合成的一个有效靶标。先导化合物表现出良好的结合能（例如，z1的结合能为-6.35 kcal/mol），通过疏水、π叠加和范德华相互作用与关键活性位点残基（PHE97、MET103、PHE149、TYR158）结合，并与NAD+辅因子进行临界接触。相互作用指纹图谱分析将配体-残基接触与生物活性联系起来，强调芳香平面性和取代基调节对有效抑制InhA的重要性。这种综合合成-生物-计算工作流程为开发下一代抗结核药物奠定了良好的基础，提高了对耐药菌株的疗效。

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引用次数: 0

Synthesis and anticancer activity of parthenolide-based PROTACs for IKKβ degradation 基于parthenolide的IKKβ降解PROTACs的合成及抗癌活性研究

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-02-05 DOI: 10.1016/j.bmcl.2026.130571

Zhenxi Su , Yiwu Wu , Yijie Su , Yuhan He , Jieyin Liu , Deng-Gao Zhao

Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological evaluation of a novel series of parthenolide-based PROTACs. Among them, compound 8 exhibited potent anti-proliferative activity, especially against triple-negative breast cancer MDA-MB-231 cells. Mechanistic studies revealed that 8 acts as an effective IKKβ degrader, inducing degradation via the ubiquitin-proteasome system (DC₅₀ = 7.15 μM, 91.24% degradation at 10 μM). Furthermore, treatment with 8 was associated with significant apoptosis and G1-phase cell cycle arrest in MDA-MB-231 cells. This work provides initial evidence that the parthenolide scaffold can be leveraged for targeted protein degradation, supporting the future development of IKKβ-directed degraders.

Parthenolide是一种天然的IκB激酶β (IKKβ)抑制剂。将其转化为PROTAC（蛋白水解靶向嵌合体）可能会提高药理学疗效。在此，我们报道了一系列新的基于parthenolide的PROTACs的设计，合成和生物学评价。其中，化合物8对三阴性乳腺癌MDA-MB-231细胞表现出较强的抗增殖活性。机制研究表明，8作为一种有效的IKKβ降解剂，通过泛素-蛋白酶体系统诱导降解（DC50 = 7.15 μM，在10 μM下降解率为91.24%）。此外，在MDA-MB-231细胞中，8与显著的细胞凋亡和g1期细胞周期阻滞有关。这项工作提供了初步证据，证明parthenolide支架可以用于靶向蛋白质降解，支持未来开发ikk β定向降解物。

引用次数: 0

Allyl-functionalized calix[4]resorcinarenes against breast cancer cells: Synthesis, cytotoxicity, apoptosis induction, and computational insights 烯丙基功能化杯状[4]间苯二甲酸脂抗乳腺癌细胞：合成、细胞毒性、细胞凋亡诱导和计算见解。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-13 DOI: 10.1016/j.bmcl.2026.130540

Anggit Fitria , Yehezkiel Steven Kurniawan , Eti Nurwening Sholikhah , Harno Dwi Pranowo , Jumina

The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (4a–4f) as cytotoxic agents. These derivatives were obtained via the O-allylation of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 4-hydroxybenzaldehyde with resorcinol, pyrogallol, or 2-methylresorcinol. All compounds were examined for their in vitro anticancer activity against human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, analogue 4a exhibited moderate cytotoxicity in breast cancer cell lines, i.e., MCF-7 cells (IC₅₀ = 8.27 μM), showing notable cytotoxicity in the low micromolar range, comparable to that of cisplatin and within the same order of magnitude as doxorubicin. Accompanied by apoptosis profiling, compound 4a at 1 × and 2 × IC₅₀ showed a concentration-dependent increase in apoptosis cell death compared to untreated controls. Meanwhile, computational studies were conducted to explore potential interactions with EGFR as a putative target, suggesting that compound 4a may possibly interact with EGFR through hydrogen bonding and hydrophobic contacts.

本文研究了几种烯丙基功能化杯状[4]间苯二甲酸酯（4a-4f）的合成和生物学测定。这些衍生物是通过3-甲氧基-4-羟基苯甲醛（香兰素）和4-羟基苯甲醛与间苯二酚、邻苯三酚或2-甲基间苯二酚的o -烯丙基化得到的。研究了所有化合物对人乳腺癌细胞株（MDA-MB-231和MCF-7）的体外抗癌活性。其中,模拟4向MCF-7表现出显著的细胞毒性细胞(IC50 = 8.27 μM),超过了顺铂(IC50 = 22.39 μM)和接近阿霉素(IC50 = 1.67 μM)。4a在1 × 和2 × IC50的凋亡谱显示，与未治疗的对照组相比，凋亡细胞死亡呈浓度依赖性增加。此外，分子对接和分子动力学模拟表明，4a通过氢键与Asp813和Arg817强相互作用，并通过疏水接触与Asp831强相互作用。这些残基是关键靶点，并支持其作为有希望的抗癌候选物的潜力。

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引用次数: 0

Combined antitumor efficacy of a new tanshinone IIA analog and irinotecan with alleviating gastrointestinal side effect 新型丹参酮IIA类似物与伊立替康联合抗肿瘤及减轻胃肠道副作用的疗效观察。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-27 DOI: 10.1016/j.bmcl.2026.130563

Junfeng Wang , Jiamin Luo , Zhiguo Mang , Shuai Zhang , Chengtao Sun , Guoyin Kai , Huan Xu , Hao Li

1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-b]furan-7,10,11(6H)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therapy and alleviate its gastrointestinal side effect. The combined cytotoxicity on HT29 and HCT116 colorectal cancer cells induced by TA401 and CPT-11 was comprehensively evaluated in vitro. The classical apoptosis pathway, including Bax, BCL-2, caspase 3, the phosphorylation level of ERK and AKT, was also examined to illustrate molecular mechanisms of the synergistic apoptosis both in vitro and in vivo. Synergistic suppression of colorectal cancer cell proliferation by TA401 and CPT-11 was observed at a fixed ratio (TA401:CPT-11 at 1:20). The apoptosis induced by combined treatment was triggered by activation of classical apoptotic pathway and decreased expression of TOP I, which was further confirmed in vivo. In addition, diarrheic side effect of CPT-11 was reduced by TA401 in the combined treatment. TA401 effectively promoted the anti-tumor effects of CPT-11 with alleviated side effects, which may be developed as a potential candidate for the combined therapy with CPT-11 against colorectal cancer.

新合成的丹参酮IIA类似物1,6,6-三甲基-2-（（4-甲基哌嗪-1-酰基）甲基）phenanthrol[1,2-b]furan-7,10,11(6H)-trione （TA401）是为了增强CPT-11联合治疗的抗肿瘤作用，减轻其胃肠道副作用。综合评价TA401和CPT-11对HT29和HCT116结直肠癌细胞的体外联合细胞毒性。我们还检测了经典的凋亡通路，包括Bax、BCL-2、caspase 3、ERK和AKT的磷酸化水平，以阐明体外和体内协同凋亡的分子机制。在固定比例（TA401:CPT-11: 1:20）下，观察到TA401和CPT-11协同抑制结直肠癌细胞增殖。联合处理诱导的细胞凋亡是通过激活经典凋亡通路和降低TOP I的表达而触发的，这在体内得到了进一步的证实。此外，TA401在联合治疗中减少了CPT-11的腹泻副作用。TA401可有效促进CPT-11的抗肿瘤作用，且副作用减轻，可能成为与CPT-11联合治疗结直肠癌的潜在候选药物。

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引用次数: 0

Synthesis and characterization of bicyclo[1.1.0]butane amides and 5-methylene-3-azabicyclo[5.1.0]octan-4-ones as covalent modifiers 双环[1.1.0]丁烷酰胺和5-亚甲基-3-氮杂环[5.1.0]辛烷-4-酮共价改性剂的合成与表征。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-02-05 DOI: 10.1016/j.bmcl.2026.130572

Karis Texidor , Dilhumar Uyghur , Noah Wiese , Lindsey O. Davis , Mandy Green , Farjana Sharmen , Adil Ijaz , Kamani M. Barnes , Madison Bagett , Jishi Ye , Stacy M. Abbang , Wenying Piao , Jason Ying Kuen Chan , Yuen-Keng Ng , Vivian W.Y. Lui , Marco Orecchioni , Matteo Borgini

Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate “undruggable” proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of N-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both N-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected N-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.

共价抑制剂作为强大的治疗药物重新出现，提供了调节“不可药物”蛋白质的能力，包括传统药物发现努力无法实现的致癌驱动因素。扩大亲电基团的曲目仍然是共价药物发现的关键前沿。在这里，我们报道了Rh(I)催化的n-烯丙基双环[1.1.0]丁烷酰胺（BCB酰胺）的环异构化反应，通过菌株释放反应进入5-亚甲基-3-氮杂环[5.1.0]辛烷-4-酮（MABO）支架。n -烯丙基BCB酰胺和mabo都可以与亲核试剂反应，这突出了它们作为共价药物设计的亲电基团的潜力。对谷胱甘肽的动力学分析显示，选定的n -烯丙基BCB酰胺和mabo的半衰期与（±）-sotorasib相当，其对映体纯形式已获得FDA批准作为抗癌药物。在人源性头颈部鳞状细胞癌（HNSCC）模型中进行生物学评价，鉴定出能够调节癌细胞生长的特异性BCB酰胺和MABO化合物。在基础和激活条件下，通过流式细胞术对人外周血单核细胞（PBMCs）和单核细胞系THP-1中LDH释放的监测来评估化合物的毒性。总之，这些发现表明BCB酰胺和mabo代表了共价药物发现的亲电支架的有希望的类别。

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引用次数: 0

Design, synthesis, and biological evaluation of cytochrome P450 CYP11A1 inhibitors 细胞色素P450 CYP11A1抑制剂的设计、合成和生物学评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-31 DOI: 10.1016/j.bmcl.2026.130567

Dongyu Wang , Shengkai Cui , Jingyi Yuan, Yuyang Li, Yujie Zhang, Yuao Zhang, Weizheng Fan, Chunlei Tang

This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.

本研究通过开发新的CYP11A1抑制剂来解决去势抵抗性前列腺癌的耐药性问题，CYP11A1是雄激素合成的关键限速酶。以临床候选药物Opevesostat为基础，以4h -pyran-4- 1为核心，设计并合成了两个系列共23个新化合物，以探索C2和C6位点的构效关系。化合物II-4表现出有效的抑制活性（在100 nM时95.2%;IC₅₀ = 26.7 nM），与Opevesostat （IC₅₀ = 20.4 nM）相当。重要的是，II-4对CYP1A2、2C9和2D6表现出优异的选择性（提高了2- 4倍），这归因于其C6甲基与Ile 84之间的疏水相互作用。这些结果突出了II-4作为一种具有优化活性和选择性的先导化合物，为克服前列腺癌治疗的耐药提供了有价值的见解。

引用次数: 0

Development of coumarin-3-thiosemicarbazones and coumarin-3-oximes as potent inhibitors of mushroom tyrosinase/tyrosine hydroxylase 香豆素-3-硫代氨基脲和香豆素-3-肟作为蘑菇酪氨酸酶/酪氨酸羟化酶有效抑制剂的研究进展

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-02-10 DOI: 10.1016/j.bmcl.2026.130583

Luiz Alberto Ferreira , Angelo Matheus Torres Santos , Rodrigo Cabral de Araújo-Filho , Emanuelly Karla Araújo-Padilha , Clara Andrezza Crisóstomo Bezerra Costa , Johnnatan Duarte de Freitas , Joanna Cytarska , Krzysztof Z. Łączkowski , Edeildo Ferreira da Silva-Júnior , Silvia Helena Cardoso

Tyrosinase is a copper-dependent oxidase that catalyzes the rate-limiting steps of melanogenesis, directly linking its overexpression to hyperpigmentation disorders and melanoma progression. Previously our researcher team found that a coumarin–thiosemicarbazone analog exhibited potent anti-tyrosinase activity (IC₅₀ = 42.16 ± 5.16 μM). Herein, as part of our efforts in this field of study, we report the synthesis and biological evaluation of a new series of coumarin derivatives functionalized with thiosemicarbazone and/or oxime moieties as potent tyrosinase inhibitors. The most active compound, B5, exhibited an IC₅₀ value of 21.91 ± 0.26 μM, showing 3.3- and 17.6-fold higher inhibitory potency than kojic and ascorbic acids, respectively. Kinetic studies revealed a mixed inhibition pattern, suggesting multiple enzyme–inhibitor interactions. In silico 100-ns molecular dynamics simulations against Agaricus bisporus tyrosinase (PDB ID: 2Y9X) confirmed the structural stability of the B5–tyrosinase complex, with a mean RMSD of 1.85 Å for the enzyme and 0.3 Å for the ligand. The thiosemicarbazone moiety played a pivotal role in complex stabilization through hydrogen bonding and coordination with catalytic Cu²⁺ ions, while hydrophobic and π-stacking contacts contributed to binding persistence. Altogether, these findings highlight compound B5 as a promising lead compound for developing next-generation tyrosinase inhibitors with potential dermatological and photoprotective applications.

酪氨酸酶是一种铜依赖性氧化酶，催化黑素形成的限速步骤，其过度表达与色素沉着症和黑色素瘤进展直接相关。之前我们的研究小组发现香豆素-硫代氨基脲类似物具有有效的抗酪氨酸酶活性（IC50 = 42.16±5.16 μM）。在此，作为我们在这一研究领域的一部分，我们报道了一系列新的香豆素衍生物的合成和生物学评价，这些衍生物被硫代氨基脲和/或肟基团功能化，作为有效的酪氨酸酶抑制剂。最活跃的化合物B5的IC₅₀值为21.91±0.26 μM，其抑制效力分别比曲酸和抗坏血酸高3.3倍和17.6倍。动力学研究显示混合抑制模式，表明多种酶抑制剂相互作用。针对双孢蘑菇酪氨酸酶（PDB ID: 2Y9X）的100-ns分子动力学模拟证实了b5 -酪氨酸酶复合物的结构稳定性，酶的平均RMSD为1.85 Å，配体的平均RMSD为0.3 Å。硫代氨基脲部分通过氢键和催化Cu2+离子的配位在络合物的稳定中起关键作用，而疏水和π堆积接触则有助于结合的持久性。总之，这些发现突出了化合物B5作为开发下一代酪氨酸酶抑制剂的有希望的先导化合物，具有潜在的皮肤和光保护应用。

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引用次数: 0

Novel anticancer paeonol derivatives possessing a nitric oxide donor moiety as TrxR inhibitors: design, synthesis, biological evaluation 具有一氧化氮供体片段的新型抗癌丹皮酚衍生物作为TrxR抑制剂：设计、合成和生物学评价。

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2026-06-01 Epub Date: 2026-01-23 DOI: 10.1016/j.bmcl.2026.130555

Ce Shi , Weisen Zhong , Guowei Qiang , Panjunjie Ying , Junyu Guo , Yameng Si , Jie Mou

The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound 11f exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC₅₀ = 0.26 ± 0.17 μM in vitro; IC₅₀ = 0.33 μM in vivo). Furthermore, compound 11f induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.

肿瘤微环境（tumor microenvironment， TME）在肿瘤进展和治疗反应中起关键作用。在TME中，由活性氧（ROS）和一氧化氮（NO）介导的氧化还原过程在调节细胞间和细胞内信号传导中起着关键作用。在这项研究中，我们假设将no释放片段偶联到丹皮酚衍生物上，并引入查尔酮结构来增强硫氧还蛋白还原酶（TrxR）的靶向性，将产生具有有效抗癌活性的化合物。据此，合成了一系列单取代和双取代的硝酸盐衍生物。采用CCK-8法测定合成的化合物对BGC823、HCT116、Hep G2和MCF-7细胞系的抑制活性。在丹皮酚查尔酮衍生物中，化合物11f在测试的癌细胞组中表现出显著的抗增殖活性。体外IC50 = 0.26 ± 0.17 μM，体内IC50 = 0.33 μM，具有较强的TrxR抑制活性。此外，化合物11f诱导MCF-7细胞s期阻滞并促进细胞凋亡。这些发现强调了由于NO和ROS的协同作用，丹皮酚查尔酮衍生物具有增强的抗癌潜力。

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引用次数: 0