Bioorganic Chemistry最新文献_第10页

Novel 5,7-Diazaindole-based ERK5 inhibitor induces endoplasmic reticulum stress and mitochondrial apoptosis in non-small cell lung Cancer 新型5,7-二氮唑类ERK5抑制剂诱导非小细胞肺癌内质网应激和线粒体凋亡。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-16 DOI: 10.1016/j.bioorg.2026.109512

Binbin Tian , Yunjie Li , Pengyu Xue , Renhao Chen , Shuo Lv , Luqian He , Gaoyang Lin , Jun Xiao , Lin Long , Guorui Cao , Chuanlong Guo , Longjiang Huang

The extracellular signal-regulated kinase 5 (ERK5) signaling pathway represents a promising therapeutic target for non-small cell lung cancer (NSCLC), yet the development of potent and selective inhibitors remains a challenge. Leveraging the 5,7-diazaindole scaffold, a privileged structure in kinase inhibitor discovery, we designed, synthesized, and evaluated a novel series of derivatives as potential ERK5 inhibitors. Among them, compound I1 emerged as the most potent candidate, demonstrating significant anti-proliferative activity against A549 human lung cancer cells with an IC₅₀ of 40.1 μM. Critically, an in vitro kinase assay confirmed that I1 is a direct ERK5 inhibitor, exhibiting potent inhibition of purified ERK5 kinase activity with an IC₅₀ of 403.4 nM. Structure-activity relationship (SAR) studies underscored the critical importance of the unsaturated 1,2,3,6-tetrahydropyridine ring, the amide carbonyl group, and the N1H moiety for optimal activity. Molecular docking revealed that I1 binds robustly within the ERK5 ATP-binding site (PDB: 6HKM), forming key hydrogen bonds with Met140, Asp138, and Asp200, and exhibiting a more favorable binding mode than its analogues. Mechanistic studies indicated that I1 functions as a direct ERK5 inhibitor, suppressing both ERK5 phosphorylation and total protein expression. This ERK5 inhibition triggered a multi-modal anti-tumor mechanism, including the induction of endoplasmic reticulum stress, mitochondrial dysfunction (characterized by reactive oxygen species accumulation and loss of membrane potential), and ultimately, activation of the mitochondrial apoptotic pathway. Importantly, I1 exhibited significant dose-dependent tumor growth suppression in a Lewis lung carcinoma mouse model without causing observable toxicity, highlighting its potential as a promising lead compound for targeted NSCLC therapy.

细胞外信号调节激酶5 （ERK5）信号通路是非小细胞肺癌（NSCLC）的一个有希望的治疗靶点，但开发有效的选择性抑制剂仍然是一个挑战。利用5,7-二氮吲哚支架（激酶抑制剂发现中的特权结构），我们设计、合成并评估了一系列新的衍生物作为潜在的ERK5抑制剂。其中，化合物I1成为最有效的候选者，对A549人肺癌细胞表现出显著的抗增殖活性，IC₅0为40.1 μM。关键的是，一项体外激酶试验证实I1是一种直接的ERK5抑制剂，表现出对纯化ERK5激酶活性的有效抑制，IC₅0为403.4 nM。构效关系（SAR）研究强调了不饱和1,2,3,6-四氢吡啶环、酰胺羰基和N1H部分对最佳活性的至关重要。分子对接发现I1在ERK5 atp结合位点（PDB: 6HKM）内稳定结合，与Met140、Asp138和Asp200形成关键氢键，并表现出比其类似物更有利的结合模式。机制研究表明I1作为ERK5直接抑制剂，抑制ERK5磷酸化和总蛋白表达。这种ERK5抑制触发了多模式的抗肿瘤机制，包括诱导内质网应激、线粒体功能障碍（以活性氧积累和膜电位丧失为特征），并最终激活线粒体凋亡途径。重要的是，I1在Lewis肺癌小鼠模型中表现出明显的剂量依赖性肿瘤生长抑制，而没有引起可观察到的毒性，这突出了其作为靶向非小细胞肺癌治疗先导化合物的潜力。

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引用次数: 0

Construction of the chiral 24R-OH squalamine intermediate by an engineered ketoreductase from Rhodococcus sp. 红球菌工程酮还原酶构建手性24R-OH角鲨胺中间体。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-16 DOI: 10.1016/j.bioorg.2026.109515

Hong Li, Zhen Du, Yanxia Lin, Zhe Zhang, Min Wu, Yihua Zhong, Shan Li, Lei Zhang

The 24R-OH construction remains a bottleneck in squalamine synthesis. In this study, a ketoreductase from Rhodococcus sp. was screened out, which could catalyze the conversion of 7α-hydroxy-5α-cholestan-3, 24-dione to the key intermediate (7α, 24R)-dihydroxy-5α-cholestan-3-one (24R-OH). A mechanism-driven computational design strategy was employed, and regional engineering targeting the substrate channel (D42A), flexible regions (P89G, P158S), and a structural stabilization zone (A327P) was conducted to generate the quadruple mutant D42A/P89G/P158S/A327P. Under the reaction conditions at 10 mg/mL substrate and 25% (v/v) isopropanol, the mutant achieved a conversion of 99.1% with a diastereomeric excess of >99.9%. Further investigation through molecular dynamics simulations, free energy calculations, and hydrogen-bonding network analysis revealed that the mutation facilitated substrate access and product release while stabilizing the protein structure. This study provides a robust and industrially viable biosynthetic route for efficiently producing 24R-OH, the key intermediate in the squalamine synthesis.

24R-OH结构仍然是角鲨胺合成的瓶颈。本研究从红球菌中筛选出一种酮还原酶，该酶可催化7α-羟基-5α-胆甾醇- 3,24 -二酮转化为关键中间体(7α, 24R)-二羟基-5α-胆甾醇-3-one （24R- oh）。采用机制驱动的计算设计策略，针对衬底通道（D42A）、柔性区域（P89G、P158S）和结构稳定区（A327P）进行区域工程，生成四重突变体D42A/P89G/P158S/A327P。在10 mg/mL底物和25% （v/v）异丙醇的反应条件下，突变体的转化率为99.1%，非对映异构体过剩率为99.9%。通过分子动力学模拟、自由能计算和氢键网络分析的进一步研究表明，该突变促进了底物进入和产物释放，同时稳定了蛋白质结构。该研究为高效生产角鲨胺合成的关键中间体24R-OH提供了一条可靠且工业上可行的生物合成途径。

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引用次数: 0

(Z)-4-(substituted benzylidene)-2-phenyl-1H-imidazol-5(4H)-ones are sensitive to tyrosinases of different origins: In vitro and in vivo insights (Z)-4-（取代苄基）-2-苯基- 1h -咪唑-5(4H)- 1对不同来源的酪氨酸酶敏感：体外和体内观察

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-16 DOI: 10.1016/j.bioorg.2026.109514

Hee Jin Jung , Hyeon Seo Park , Yeonsoo Jeong , Hyejin Kang , Minchang Kim , Hyunju Lee , Hyunhee Ju , Hae Young Chung , Yujin Park , Hyung Ryong Moon

We used Staudinger azide reduction and Knoevenagel condensation reactions to synthesize 13 different (Z)-4-(substituted benzylidene)-2-phenyl-1H-imidazol-5(4H)-one (BPIO) analogs (1−13) that hybridize a β-phenyl-α,β-unsaturated carbonyl scaffold with a 2-phenyl-1H-imidazol-5(4H)-one moiety, as potential tyrosinase (TYR) inhibitors. Eight BPIO analogs showed mushroom TYR (mTYR) inhibitory efficacy comparable to or superior to that of kojic acid (KA). Kinetic analyses were performed to determine the mTYR inhibition mechanism of BPIO analogs. Kinetic findings were supported by docking experiments. The cellular TYR inhibitory activity of analogs 6, 8, 10, and 11 was shown to be responsible for their anti-melanogenic potency in B16F10 cells. Analog 8, which showed limited inhibitory activity against mTYR, potently inhibited melanin biosynthesis in B16F10 cells. This result may be due to structural differences between B16F10 TYR and mTYR. Several tested analogs exhibited high potency in a zebrafish embryo depigmentation assay, with analog 1 potently producing nearly pigment-free zebrafish larvae at 100 μM. The results of this study suggest that these BPIO analogs are sensitive to structural differences between TYRs from different organisms, and that melanin inhibitory activities of individual BPIO analogs are highly specific to the TYR used. Individual BPIO analogs may therefore selectively inhibit TYRs from different organisms.

我们使用Staudinger叠氮化物还原和Knoevenagel缩合反应合成了13种不同的(Z)-4-（取代苄基）-2-苯基- 1h -咪唑-5(4H)- 1 （BPIO）类似物（1−13），它们将β-苯基-α，β-不饱和羰基支架与2-苯基- 1h -咪唑-5(4H)- 1片段杂交，作为潜在的酪氨酸酶（TYR）抑制剂。8种BPIO类似物对蘑菇TYR （mTYR）的抑制效果与曲酸（KA）相当或优于曲酸。动力学分析确定了BPIO类似物的mTYR抑制机制。动力学发现得到了对接实验的支持。类似物6、8、10和11的细胞TYR抑制活性被证明是它们在B16F10细胞中抗黑素生成效力的原因。类似物8对mTYR的抑制活性有限，但能有效抑制B16F10细胞的黑色素合成。这一结果可能是由于B16F10 TYR和mTYR之间的结构差异。几种被测试的类似物在斑马鱼胚胎脱色试验中表现出很高的效力，其中类似物1在100 μM下可以产生几乎无色素的斑马鱼幼虫。本研究结果表明，这些BPIO类似物对来自不同生物的TYR之间的结构差异敏感，并且单个BPIO类似物的黑色素抑制活性对所使用的TYR具有高度特异性。因此，单个BPIO类似物可能选择性地抑制来自不同生物体的tyr。

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引用次数: 0

Antifungal activity of AR-12 and its derivatives against clinically relevant fusarium solani isolates in keratitis AR-12及其衍生物对临床相关的角膜炎镰刀菌的抗真菌活性

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-16 DOI: 10.1016/j.bioorg.2026.109516

Yihui Ma , Lei Han , Yujuan Wang , Shuiping Jiang , Xiaofang Gao

Keratitis infections caused by Fusarium species are on the rise globally, posing a significant challenge for treatment due to the intrinsic resistance mechanisms associated with these fungi. AR-12 (OSU-03012) is a celecoxib-derived protein kinase inhibitor with characteristic scaffold of 1,5-diaryl-3-trifluoropyrazole, originally developed as an antitumor agent that reached Phase I clinical trials, but has since shown activity against a broad spectrum of pathogens, including fungi, bacteria, and viruses. In an effort to expand the therapeutic options available for Fusarium keratitis, this study evaluated the antifungal efficacy of AR-12 against Fusarium solani isolates responsible for keratitis infections. The results showed that the minimum inhibitory concentration (MIC) of AR-12 against these isolates ranged from 2 to 8 μg/mL, comparable to that of the control antifungal agent voriconazole. Subsequently, we performed systematic chemical modifications of AR-12 and investigate the structure-activity relationships (SAR). Moreover, solubility measurements of the active derivatives identified compound B8 as exhibiting the optimal balance between antifungal efficacy and hydrophobicity. Further investigations with B8 revealed morphological changes and the disruption of the cell membrane. This study underscores the potential of AR-12's chemical scaffold as a valuable foundation for the development of potent antifungal drugs.

镰刀菌引起的角膜炎感染在全球呈上升趋势，由于与这些真菌相关的内在耐药机制，对治疗构成了重大挑战。AR-12 （OSU-03012）是一种塞来昔布衍生的蛋白激酶抑制剂，具有1,5-二芳基-3-三氟吡唑的特征支架，最初是作为抗肿瘤药物开发的，已达到I期临床试验，但后来显示出对多种病原体的活性，包括真菌、细菌和病毒。为了扩大角膜炎镰刀菌的治疗选择，本研究评估了AR-12对角膜炎感染的梭兰镰刀菌分离株的抗真菌效果。结果表明，AR-12的最低抑菌浓度（MIC）为2 ~ 8 μg/mL，与对照抗真菌剂伏立康唑相当。随后，我们对AR-12进行了系统的化学修饰，并研究了构效关系（SAR）。此外，活性衍生物的溶解度测量表明，化合物B8在抗真菌功效和疏水性之间表现出最佳的平衡。对B8的进一步研究显示形态学改变和细胞膜破坏。这项研究强调了AR-12的化学支架作为开发有效抗真菌药物的宝贵基础的潜力。

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引用次数: 0

Engineered N-terminal modified α/β-hybrid peptides with enhanced selectivity and stability: Multi-target antibacterials for combating MRSA 具有增强选择性和稳定性的工程n端修饰α/β杂化肽：用于对抗MRSA的多靶点抗菌药物

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-14 DOI: 10.1016/j.bioorg.2026.109495

Jyoti Kumari , Aminur Rahman Sarkar , Beenish Rashid , Arti Rathore , Shifa Firdous , Rubina Chowdhary , Biplab Sarkar , Rakshit Manhas , Rajkishor Rai , Avisek Mahapa

Cytotoxicity, hemolytic effects, poor enzymatic stability and high manufacturing costs are the major challenges associated with the clinical development of antibacterial peptides. We designed and synthesized a new series of short cationic α/β-hybrid peptides (TH-01, TH-02, and TH-03) by incorporating a urea bond in place of a traditional amide bond and an N-terminal THPA moiety. These modifications were strategically incorporated to enhance antibacterial activity, structural stability, and cellular selectivity, also allowing detailed mechanistic investigation. Remarkably, the synthesized peptides retained antimicrobial activity, achieving an MIC of 1.5–12.5 μM (0.9–7.5 μg/ml) against MRSA, along with enhanced selectivity and stability. The subsequent mechanistic studies revealed that these peptides showed bactericidal activity by utilizing multi-targeted mechanisms, including lysis of the cell membrane, interaction with genomic DNA and induction of reactive oxygen species. Overall, this class of α/β-hybrid peptides represents a promising advancement toward the development of short, stable, and selective antimicrobial agents, offering valuable new strategies for combating antimicrobial resistance.

细胞毒性、溶血作用、酶稳定性差和制造成本高是抗菌肽临床开发的主要挑战。我们设计并合成了一系列新的短阳离子α/β-杂化肽（TH-01， TH-02和TH-03），通过尿素键代替传统的酰胺键和n端THPA片段。这些修饰被战略性地加入以增强抗菌活性、结构稳定性和细胞选择性，也允许详细的机制研究。值得注意的是，合成的肽保留了抗菌活性，对MRSA的MIC为1.5-12.5 μM (0.9-7.5 μg/ml)，同时增强了选择性和稳定性。随后的机制研究表明，这些肽通过多靶点机制显示出杀菌活性，包括细胞膜的裂解、与基因组DNA的相互作用和活性氧的诱导。总的来说，这类α/β-杂化肽代表了开发短、稳定和选择性抗菌药物的有希望的进展，为对抗抗菌药物耐药性提供了有价值的新策略。

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引用次数: 0

Copper(II)-catalysed one-pot synthesis of thiazole/benzothiazole-based isoquinolin-1(2H)-ones as potential cytotoxic and VEGFR-2 inhibitors 铜（II）催化一锅合成噻唑/苯并噻唑基异喹啉-1(2H)- 1作为潜在的细胞毒性和VEGFR-2抑制剂。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-14 DOI: 10.1016/j.bioorg.2026.109506

Shivam Gupta , A. Ezhilmathe , Mary Sravani Galla , Chandraiah Godugu , Nagula Shankaraiah

A facile one-pot annulation method for the synthesis of diverse bioactive thiazole/benzothiazole-based isoquinolin-1(2H)-one frameworks was accomplished. This approach involves the Ullman-type coupling of halo-substituted phenyl thiazolamides with various alkyl cyanoacetates employing copper (II) chloride as sustainable catalyst and water as co-solvent. Further, in silico studies were revealed the compound's selectivity towards kinase inhibition. Eventually, these derivatives were evaluated for their in vitro cytotoxicity against various cancer cell lines such as MCF-7, HCT-116, A549, HEPG-2, and HEK-293 (normal cell line). Among them, compound 3h has displayed significant cytotoxicity with an IC₅₀ value of 7.75 ± 0.37 μM on HCT-116 cell line. Next, the compound 3h has also ability to induce apoptosis, which is examined through various staining assays like AO/EtBr, JC-1, and ROS. An ADP Glo kinase kit is utilised to evaluate the kinase inhibitory activity with most potent compound 3h, and showed an IC₅₀ value of 1.94 μM, which is comparable to that of the standard drug sunitinib (IC₅₀ of 400 nM). Finally, this straightforward one-pot annulation protocol is amenable in the generation of a library of new thiazole/benzothiazole-based heterocyclic compounds as potential cytotoxic and VEGFR-2 inhibitors in cancer drug discovery.

采用一锅环法制备了多种具有生物活性的噻唑/苯并噻唑基异喹啉-1(2H)- 1骨架。该方法采用氯化铜（II）作为可持续催化剂，水作为共溶剂，将卤代苯基噻唑胺与各种烷基氰乙酸酯进行ullman型偶联。此外，在计算机上的研究揭示了该化合物对激酶抑制的选择性。最后，对这些衍生物的体外细胞毒性进行了评估，以对抗各种癌细胞系，如MCF-7、HCT-116、A549、HEPG-2和HEK-293（正常细胞系）。其中化合物3h对HCT-116细胞株具有显著的细胞毒性，IC50值为7.75±0.37 μM。其次，化合物3h还具有诱导细胞凋亡的能力，这可以通过AO/EtBr、JC-1和ROS等染色试验来检验。利用ADP Glo激酶试剂盒对最有效化合物3h的激酶抑制活性进行评价，其IC50值为1.94 μM，与标准药物舒尼替尼的IC50值相当（IC50为400 nM）。最后，这种简单的一锅环化方案适用于新噻唑/苯并噻唑基杂环化合物库的生成，这些化合物可作为癌症药物发现中的潜在细胞毒性和VEGFR-2抑制剂。

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引用次数: 0

Discovery and mechanistic insights of novel Piperlongumine analogs as potent Bcr-Abl kinase inhibitors 新型胡椒明类似物作为有效的Bcr-Abl激酶抑制剂的发现和机制见解。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-14 DOI: 10.1016/j.bioorg.2026.109508

Guanglong Zhang , Xuesha Long , Xue Yang , Chengpeng Li , Jiao Meng , Yuguo Zheng , Fuqiang Ren , Zhenchao Wang

In the exploration and discovery of potential anticancer candidates with novel mechanisms of action, a series of novel piperlongumine (PL) analogs was designed and synthesized. The majority of compounds demonstrated significant anti-proliferative effects in vitro, particularly with the 2-Cl analogs C1-C16. Notably, compound C5 exhibited the most potent anti-proliferative activity against K562 cells (IC₅₀ = 0.11 μM). Inspiringly, C5 was also found to selectively enhance the accumulation of ROS and induce apoptosis. Transcriptomic analysis revealed that the differentially expressed genes (DEGs) primarily encompassed apoptotic, PI3K/AKT signaling pathways, and other associated information. Molecular docking results revealed that C5 exhibited robust hydrogen bond interactions with specific amino acid residues in the Imatinib-Bcr-Abl^WT and Ponatinib-Bcr-Abl^T315I protein kinase models, suggesting a plausible binding model based on the docking scores. The findings suggest that C5 exhibits promising potential as a highly efficacious for an anti-leukemia agent, thereby providing a valuable avenue for further exploration and application.

在探索和发现具有新的作用机制的潜在抗癌候选药物的过程中，设计和合成了一系列新的胡椒隆明（PL）类似物。大多数化合物在体外表现出显著的抗增殖作用，特别是对2-Cl类似物C1-C16。其中化合物C5对K562细胞的抗增殖活性最强（IC50 = 0.11 μM）。令人鼓舞的是，C5还被发现选择性地增加ROS的积累并诱导细胞凋亡。转录组学分析显示，差异表达基因（DEGs）主要包含凋亡、PI3K/AKT信号通路和其他相关信息。分子对接结果显示，C5在Imatinib-Bcr-AblWT和Ponatinib-Bcr-AblT315I蛋白激酶模型中与特定氨基酸残基表现出强大的氢键相互作用，这表明基于对接分数的结合模型是合理的。研究结果表明，C5作为一种高效的抗白血病药物具有良好的潜力，从而为进一步的探索和应用提供了宝贵的途径。

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引用次数: 0

Lometrexol targets MRPL2 to suppress NSCLC via dual regulation of mitochondrial ribosomal activity and nuclear PDCD11/ Ca2+ signaling 洛美曲醇通过双重调控线粒体核糖体活性和核PDCD11/ Ca2+信号传导，靶向MRPL2抑制NSCLC。

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-14 DOI: 10.1016/j.bioorg.2026.109509

Xuehang Jin , Lvjun Zhang , Kailing Pan , Chiqing Ying , Dan Zhu

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, necessitating novel therapeutic targets. Recent studies emphasize the significance of mitochondrial ribosomal proteins (MRPs) in cancer, showing altered expression in different cancers and their potential as prognostic biomarkers and therapeutic targets. We identified that MRPL2 was upregulated in NSCLC and decreased expression of MRPL2 diminished tumorigenicity of NSCLC. Mechanistically, USP21 directly interacts with and stabilized MRPL2 via deubiquitination process through its USP domain. Moreover, The upregulation of MRPL2 influenced mitochondrial function via its localization to mitochondria, facilitating its role in ribosomal activity. Additionally, our findings indicated that MRPL2 can also enhance the intracellular calcium signaling pathway through its nuclear localization and interaction with PDCD11, thereby playing a regulatory role in the progression of NSCLC. Furthermore, we identified lometrexol as a potential MRPL2 inhibitor that can hinder NSCLC development. Taken together, we identify a MRPL2-regulated ribosomal and non-ribosomal mechanism that involves the USP21/MRPL2/PDCD11/Ca²⁺ axis in NSCLC tumorigenesis, which could serve as a potential target for the treatment of NSCLC.

非小细胞肺癌（NSCLC）仍然是癌症相关死亡的主要原因，需要新的治疗靶点。最近的研究强调了线粒体核糖体蛋白（MRPs）在癌症中的重要性，显示了不同癌症中表达的改变及其作为预后生物标志物和治疗靶点的潜力。我们发现MRPL2在NSCLC中表达上调，MRPL2表达降低会降低NSCLC的致瘤性。在机制上，USP21通过其USP结构域直接与MRPL2相互作用并通过去泛素化过程稳定MRPL2。此外，MRPL2的上调通过定位线粒体影响线粒体功能，促进其在核糖体活性中的作用。此外，我们的研究结果表明，MRPL2还可以通过其核定位和与PDCD11的相互作用增强细胞内钙信号通路，从而在NSCLC的进展中发挥调节作用。此外，我们发现乐美曲醇是一种潜在的MRPL2抑制剂，可以阻碍NSCLC的发展。综上所述，我们确定了MRPL2调控的核糖体和非核糖体机制，涉及USP21/MRPL2/PDCD11/Ca2+轴在NSCLC肿瘤发生中，这可能作为治疗NSCLC的潜在靶点。

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引用次数: 0

Selectively and efficiently eliciting a ROS-dependent energy crisis within cancer cells through a mitochondria-targeted catechol-based diphenylhextriene 选择性和有效地通过线粒体靶向儿茶酚基二苯己三烯在癌细胞内引发ros依赖的能量危机

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-13 DOI: 10.1016/j.bioorg.2026.109505

Xia-Zhen Bao , Xiao-Rong Ren , Wei Tang , Yu Zhang , Zheng-Kai Deng , Fang Dai , Bo Zhou

To effectively trigger an energy crisis within cancer cells, we devised and synthesized mitochondria-targeted catechol-based diphenylpolyenes by coupling them with a triphenylphosphonium unit via a modular synthetic approach. The exploration of structure-activity relationships in terms of cytotoxicity discloses that Mito-DHH, a catechol-type diphenylhextriene that specifically targets mitochondria, is the most potent molecule among those tested, manifesting its preferential elimination of A549 cells (IC₅₀ = 0.25 μM) as opposed to normal L02 cells (IC₅₀ = 2.8 μM). In this regard, it outperforms doxorubicin and 5-fluorouracil, the commonly employed chemotherapy drugs. Mechanistic investigation affirms that the rapid accumulation of Mito-DHH within mitochondria of A549 cells enables its efficient auto-oxidation by leveraging the alkaline mitochondrial matrix to effectively and selectively generate reactive oxygen species (ROS). Through the generation of ROS, Mito-DHH initiates a ROS-dependent reduction of ATP levels within A549 cells in a dual-effect inhibitory pattern against both mitochondrial and glycolytic metabolisms, and the ultimate and selective apoptosis of A549 cells. This study takes Mito-DHH as an example to emphasize the universality of a ROS-generating strategy by targeting mitochondria in effectively inducing an energy crisis within cancer cells.

为了有效地引发癌细胞内的能量危机，我们设计并合成了线粒体靶向儿茶酚基二苯多烯，通过模块化合成方法将它们与三苯磷单元偶联。从细胞毒性的角度对结构-活性关系的探索表明，Mito-DHH是一种专门针对线粒体的儿茶酚型二苯基己三烯，是测试中最有效的分子，表现出其优先消除A549细胞（IC50 = 0.25 μM），而不是正常L02细胞（IC50 = 2.8 μM）。在这方面，它优于常用的化疗药物阿霉素和5-氟尿嘧啶。机制研究证实，A549细胞线粒体内mitto - dhh的快速积累使其能够利用碱性线粒体基质有效和选择性地产生活性氧（ROS），从而实现有效的自氧化。mitto - dhh通过生成ROS，启动A549细胞内ATP水平的ROS依赖性降低，对线粒体代谢和糖酵解代谢产生双效抑制，最终导致A549细胞选择性凋亡。本研究以mitto - dhh为例，通过靶向线粒体有效诱导癌细胞内能量危机，强调ros生成策略的普遍性。

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引用次数: 0

Toward multi-target therapy: Design, synthesis and mechanistic profiling of some novel acyl-thiosemicarbazides, as MAO and aromatase inhibitors 迈向多靶点治疗：一些新型酰基硫代氨基脲的设计、合成和机理分析，作为MAO和芳香化酶抑制剂

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry

Pub Date : 2026-01-13 DOI: 10.1016/j.bioorg.2026.109489

Ahmet Avci , Hayrünnisa Taşci , Begüm Nurpelin Sağlık Özkan , Nadire Özenver , Birsen Tozkoparan , Nesrin Gökhan Kelekçi

Monoamine oxidases A and B (MAO-A/MAO-B) catalyze the oxidative deamination of serotonin, norepinephrine, and dopamine, whereas aromatase (CYP19A1) mediates the rate-limiting conversion of androgens into estrogens. Dysregulation across these enzymatic axes links endocrine status to neurochemical balance, with clinical implications in hormone-dependent cancers and mood/cognitive disorders. Motivated by this crosstalk, multi-target-directed ligands (MTDLs) that attenuate both MAO activity and estrogen biosynthesis could address disease complexity while simplifying polypharmacy. Thiosemicarbazides are privileged scaffolds that combine hydrogen-bonding capacity with tunable lipophilicity and π-surface area, making them attractive for engaging the hydrophobic cavities of MAO isoforms and the heme-proximal pocket of aromatase. Here, we report the design, synthesis, and biological evaluation of two matched series of acyl thiosemicarbazides (benzoxazolinone vs. benzimidazole cores). Several compounds achieve sub-micromolar and in multiple cases sub-0.10 μM—potency against MAO-A, MAO-B, and aromatase. Structure–activity relationships (SAR) are delineated, molecular docking and dynamics simulations provide mechanistic insight, and balanced dual and triple-active lead candidates are proposed for further pharmacological investigation.

单胺氧化酶A和B （MAO-A/MAO-B）催化5 -羟色胺、去甲肾上腺素和多巴胺的氧化脱胺，而芳香化酶（CYP19A1）介导雄激素向雌激素的限制性转化。这些酶轴的失调将内分泌状态与神经化学平衡联系起来，在激素依赖性癌症和情绪/认知障碍中具有临床意义。在这种串扰的激励下，多靶点定向配体（mtdl）可以降低MAO活性和雌激素的生物合成，从而在简化多药治疗的同时解决疾病的复杂性。硫代氨基脲是一种结合了氢键能力、可调亲脂性和π比表面积的特殊支架，使其对MAO同型体的疏水空腔和芳香化酶的血红素近端口袋具有吸引力。在这里，我们报道了两个匹配系列的酰基硫代氨基脲（苯并恶唑啉酮和苯并咪唑核心）的设计、合成和生物学评价。一些化合物对MAO-A、MAO-B和芳香化酶的效价达到亚微摩尔，在许多情况下达到0.10 μ m以下。结构-活性关系（SAR）的描述，分子对接和动力学模拟提供了机制的见解，并提出了平衡的双活性和三活性先导候选物进一步的药理研究。

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