Bioorganic & Medicinal Chemistry Letters最新文献

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Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-29 DOI: 10.1016/j.bmcl.2025.130116

Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie

The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (P < 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (P < 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (P < 0.05, P < 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (P < 0.05, P < 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (P < 0.05, P < 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (P < 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.

{"title":"Optimization of clofibrate by carvacrol results in a new hypolipidemic compound with low hepatic injury","authors":"Xinyi Shi , Yumiao Song , Xinyu Zhang , Ling Ding , Huizi Shangguan , Xin Wang , Jiping Liu , Yongheng Shi , Xinya Xu , Yundong Xie","doi":"10.1016/j.bmcl.2025.130116","DOIUrl":"10.1016/j.bmcl.2025.130116","url":null,"abstract":"<div><div>The hepatic injury caused by clofibrate (CF) is strongly associated with oxidative stress and inflammation. This study aims to develop a hypolipidemic compound that possesses antioxidant, anti-inflammatory properties and reduces liver injury. Carvacrol-clofibrate (CF-Carvacrol) was synthesized by optimizing the structure of CF by carvacrol. CF-Carvacrol showed significant lipid-lowering effects in hyperlipidemic mouse models induced by Triton WR 1339. The molecular docking results showed that CF-Carvacrol has a good affinity for PPAR-α. The liver injury study showed that CF-Carvacrol had significantly lower liver injury compared to CF. Manifested as a significant decrease in liver weight and liver coefficient (<em>P <</em> 0.01), as well as a significant decrease in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) (<em>P <</em> 0.01). Histopathology of liver tissue showed that the necrosis of liver cells, cytoplasmic looseness, nuclear degeneration, and infiltration of inflammatory cells were significantly reduced in the CF-Carvacrol group. CF-Carvacrol can significantly up-regulate the expression of Nrf2 and HO-1 in liver (<em>P <</em> 0.05, <em>P <</em> 0.01). The expression of inflammatory factors TNF-α and IL-6 in the liver was significantly down-regulation (<em>P <</em> 0.05, <em>P <</em> 0.01). The levels of superoxide dismutase (SOD) and glutathione (GSH) significantly increased (<em>P <</em> 0.05, <em>P <</em> 0.01), while the content of malondialdehyde (MDA) in lipid peroxidation significantly decreased (<em>P <</em> 0.01). These results revealed that CF-Carvacrol has significant hypolipidemic activity and mild liver injury, and may exert antioxidant and anti-inflammatory activity by activating the Nrf2/HO-1 signaling pathway to reduce liver injury.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130116"},"PeriodicalIF":2.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Synthesis and evaluation of KX-01 analogs with an exploration of linker attachment points for antibody-drug conjugates

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130114

Yeju Oh , Da Eun An , Jaebeom Park , Byumseok Koh , Kyung-Jin Cho , Hongjun Jeon

KX-01 (tirbanibulin, Klisyri®) is a recently FDA-approved drug for treating actinic keratosis, with a distinct dual mechanism of action combining microtubule disruption and non-ATP-competitive Src inhibition. This unique mechanism and novel chemotype highlight KX-01′s potential as a payload for antibody-drug conjugates. In this study, we synthesized and evaluated KX-01 derivatives to enhance anticancer potency and explore functional groups suitable for antibody conjugation. Notably, replacing the morpholine group with an N-benzoylpiperazine scaffold resulted in an analog with significantly improved in vitro antiproliferative activity, attributed to enhanced microtubule disruption and Src inhibition. Furthermore, introducing a phenol or aniline functionality as a common linker attachment point preserved substantial cytotoxicity. These results suggest the potential of KX-01 derivatives for future use as ADC payloads.

引用次数: 0

A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130113

Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar

Vancomycin intermediate-resistant Staphylococcus aureus (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical 1) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of 1 enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. 1 shows ∼30 % inhibition of ATPase activity in VraS and reduces vra gene auto-upregulation typical upon vancomycin exposure. Therefore, 1 inhibits VraS to block normal vra operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests 1 does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.

{"title":"A benzoxazolyl urea inhibits VraS and enhances antimicrobials against vancomycin intermediate-resistant Staphylococcus aureus","authors":"Emerson P. Heckler , Liaqat Ali , Shrijan Bhattarai , Brittnee Cagle-White , Nickalus C. Smith , Erik D. Moore , Robert A. Coover , May H. Abdel Aziz , Aurijit Sarkar","doi":"10.1016/j.bmcl.2025.130113","DOIUrl":"10.1016/j.bmcl.2025.130113","url":null,"abstract":"<div><div>Vancomycin intermediate-resistant <em>Staphylococcus aureus</em> (VISA) is a pathogen of concern. VraS, a histidine kinase, facilitates the VISA phenotype. Here, we reveal a benzoxazolyl urea (chemical <strong><em>1</em></strong>) that directly inhibits VraS and enhances vancomycin to below the clinical breakpoint against an archetypal VISA strain, Mu50. 50 μM of <strong><em>1</em></strong> enhances vancomycin 16-fold to 0.25 μg/mL. The MIC of oxacillin is enhanced 32-fold to 8 μg/mL, only slightly above its clinical breakpoint. The chemical also showed promising enhancement of oxacillin against several MRSA strains. <strong><em>1</em></strong> shows ∼30 % inhibition of ATPase activity in VraS and reduces <em>vra</em> gene auto-upregulation typical upon vancomycin exposure. Therefore, <strong><em>1</em></strong> inhibits VraS to block normal <em>vra</em> operon function, leading to potent enhancement of cell wall-directed antibiotics. Interestingly, a molecular modeling approach suggests <strong><em>1</em></strong> does not displace ATP from the active site, but acts elsewhere. While VraS inhibitors have previously been reported to function against MRSA, to the best of our knowledge, this is the first direct VraS inhibitor ever reported that shows significant enhancement of vancomycin against VISA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130113"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Nucleoside antiviral agents with atypical structures and new targets

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130110

Hui Xu , Baohu Li , Kai Tang , Jinfei Yang , Peng Zhan

Nucleoside analogs (NAs), as antiviral drugs, play a significant role in clinical medicine, constituting approximately 50 % of all antiviral therapies in current use. Nucleoside inhibitors function by mimicking the structure of natural nucleosides, integrating themselves into viral genetic material during replication, and subsequently inhibiting the virus’s ability to reproduce. They are used to treat a variety of viral infections, including herpes simplex, hepatitis B, and acquired immunodeficiency syndrome (AIDS). This review offers the development and mechanisms of atypical nucleoside antiviral agents that target novel sites on viral polymerase and other antiviral targets of nucleoside molecules, highlighting their significance in response to emerging viral threats like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

引用次数: 0

Derivatization of ophiobolin A and cytotoxicity toward breast and glioblastoma cancer stem cells: Varying the ketone and unsaturated aldehyde moieties

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-27 DOI: 10.1016/j.bmcl.2025.130112

Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo

To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT⁺) cell line.

{"title":"Derivatization of ophiobolin A and cytotoxicity toward breast and glioblastoma cancer stem cells: Varying the ketone and unsaturated aldehyde moieties","authors":"Jaquelin Aroujo , Haleigh Parker , Angela Boari , Evan Mason , Mackenzie U. Otakpor , Tania Betancourt , Alexander Kornienko , Maria Letizia Ciavatta , Marianna Carbone , Antonio Evidente , Joseph H. Taube , Daniel Romo","doi":"10.1016/j.bmcl.2025.130112","DOIUrl":"10.1016/j.bmcl.2025.130112","url":null,"abstract":"<div><div>To gain further insights into the importance of the unsaturated 1,4-ketoaldehyde moiety of ophiobolin A (OpA) for the potency and selectivity observed toward cancer stem cells, several derivatives were synthesized through controlled reduction and oxidations of the unsaturated aldehyde and ketone moieties. Structure elucidation of these new OpA derivatives was achieved through detailed NMR studies and comparison to OpA and known isolated congeners possessing variations in these regions. The relative stereochemistry of the newly generated stereocenters was determined by coupling constants in conjunction with conformational analyses (DFT) of the synthetic derivatives. The cytotoxicity of these derivatives was studied against breast cancer and glioblastoma cell lines possessing stem-cell like properties. In addition, the comparative activity toward HMLE and HMLE-TWIST mammary epithelial cells was studied, with the latter cell line representing an epithelial mesenchymal transition positive (EMT<sup>+</sup>) cell line.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130112"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-24 DOI: 10.1016/j.bmcl.2025.130111

Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen

Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC₅₀ = 14 nM, 83 % E_max) that did not elicit a β-arrestin-2 recruitment functional response (E_max < 10 %). Compound 39 demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound 39 exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (K_i) assays. These findings highlight compound 39 and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.

{"title":"Novel tertiary diarylethylamines as functionally selective agonists of the kappa opioid receptor","authors":"Thomas O. Schrader , Kym I. Lorrain , Matthew R. Nelli , Yu Xue , Yong Chen , Alexander Broadhead , Christopher Baccei , Austin Chen","doi":"10.1016/j.bmcl.2025.130111","DOIUrl":"10.1016/j.bmcl.2025.130111","url":null,"abstract":"<div><div>Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus <em>β</em>-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure–activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound <strong>39</strong>, a potent activator of G-protein signaling (GTPγS EC<sub>50</sub> = 14 nM, 83 % <em>E</em><sub>max</sub>) that did not elicit a <em>β</em>-arrestin-2 recruitment functional response (<em>E</em><sub>max</sub> < 10 %). Compound <strong>39</strong> demonstrated moderate to high intrinsic clearance in human hepatocytes and low potential for Pgp-mediated efflux when evaluated in the MDR1-MDCK permeability assay. Compound <strong>39</strong> exhibited 60- and 810-fold selectivities versus the related mu (MOR) and delta (DOR) opioid receptors in recombinant radioligand binding (<em>K</em><sub>i</sub>) assays. These findings highlight compound <strong>39</strong> and related structures as potential leads toward safe and tolerable therapeutics that target central nervous system (CNS) disorders for which KOR agonism could provide benefit.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"120 ","pages":"Article 130111"},"PeriodicalIF":2.5,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-23 DOI: 10.1016/j.bmcl.2025.130108

Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang

Screening of the ChemDiv molecular library in cholesterol media against Mycobacterium tuberculosis (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising in vitro activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure–activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC₅₀ = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.

引用次数: 0

Potent HIV‑1 protease inhibitors containing oxabicyclo octanol-derived P2-ligands: Design, synthesis, and X‑ray structural studies of inhibitor-HIV-1 protease complexes

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-21 DOI: 10.1016/j.bmcl.2025.130109

Arun K. Ghosh , Monika Yadav , Ashish Sharma , Megan Johnson , Ajay K. Ghosh , Rangu Prasad , Masayuki Amano , Oksana Gerlits , Andrey Kovalevsky , Hiroaki Mitsuya

We describe here the design, synthesis, and X-ray structural studies of a new class of HIV-1 protease inhibitors containing 8-oxabicyclo[3.2.1]octanol-derived P2 ligands. We investigated the functional effect of these stereochemically defined fused-poly cyclic ligands on enzyme inhibition and antiviral activity in MT-2 cells. The tricyclic core of 8-oxabicyclo[3.2.1]octan-6-ol is designed to interact with the residues in the S2 subsite of HIV-1 protease. The syntheses of the ligands were carried out using the [5+2]-cycloaddition as the key step. Several inhibitors exhibited potent enzyme inhibitory activity. High resolution room-temperature X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important molecular insights for further design and optimization of inhibitor potency.

引用次数: 0

Synthesis and biofilm inhibitory activity of cyclic dinucleotide analogues prepared with macrocyclic ribose-phosphate skeleton 大环核糖-磷酸骨架制备的环二核苷酸类似物的合成及其生物膜抑制活性。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-17 DOI: 10.1016/j.bmcl.2025.130107

Di Xie, Lingyun Xu, Shuwei Yuan, Jiayin Yan, Peng Zhou, Wenpei Dong, Jinliang Ma, Changpo Chen

Cyclic diguanosine monophosphate (c-di-GMP) is the key second messenger regulating bacterial biofilm formation related genes. Several c-di-GMP analogues have demonstrated biofilm inhibition activity. In this study, ribose-phosphate macrocyclic skeleton containing 1′-azido groups was constructed, and CDN analogues were prepared via click chemistry. The biofilm formation inhibition activity of the analogues was evaluated, and compound 17 illustrated better activity than c-di-GMP. This high-throughput strategy could be extended to synthesize cyclic analogues for biological research and immunotherapeutic development.

环二鸟苷单磷酸（c-di-GMP）是调控细菌生物膜形成的关键第二信使基因。一些c-二gmp类似物已经显示出生物膜抑制活性。本研究构建了含有1′-叠氮基的磷酸核糖大环骨架，并通过点击化学制备了CDN类似物。化合物17抑制生物膜形成的活性优于c-di-GMP。这种高通量策略可以扩展到合成生物研究和免疫治疗开发的环状类似物。

引用次数: 0

Synthesis of harmaline N-9 derivatives and investigation of in vitro anticancer activity 毒蜂碱N-9衍生物的合成及体外抗癌活性研究。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-01-13 DOI: 10.1016/j.bmcl.2025.130106

Yongjian Liu , Hao Liu , Shuqi Li , Shaojun Yu , Heng Chen , Jinling Ge , Yonggang Liu

Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for in vitro anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC₅₀ of compound HL22 against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound HL22 significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by HL22. The ¹H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.

鱼尾草碱作为一种天然化合物，具有广泛的药理活性。本研究合成了22种新型的鳗碱衍生物，并对HCT116、MCF7和MGC803三种癌细胞进行了体外抗增殖活性筛选。修饰位点位于正离子的N-9位。化合物HL22对HCT116、MGC803和MCF7的24小时IC50分别为3.84±0.11 μM、5.26±0.46 μM和8.67±0.13 μM。化合物HL22显著降低MGC803细胞的迁移能力。HL22也能抑制MGC803细胞的单克隆形成。1H NMR代谢组学分析表明，抗增殖机制可能与甘氨酸、丝氨酸和苏氨酸的代谢，牛磺酸和次牛磺酸的代谢，谷胱甘肽的代谢，烟酸和烟酰胺的代谢有关。本研究的意义在于，首次探索了经修饰的汉麻碱N-9衍生物的抗癌活性。

{"title":"Synthesis of harmaline N-9 derivatives and investigation of in vitro anticancer activity","authors":"Yongjian Liu , Hao Liu , Shuqi Li , Shaojun Yu , Heng Chen , Jinling Ge , Yonggang Liu","doi":"10.1016/j.bmcl.2025.130106","DOIUrl":"10.1016/j.bmcl.2025.130106","url":null,"abstract":"<div><div>Harmaline as a natural compound possessed a wide range of pharmacological activities. In this study, 22 novel harmaline-based derivatives were synthesized and screened for <em>in vitro</em> anti-proliferation activity against three cancer cell lines, HCT116, MCF7, and MGC803. The modification site was at the position N-9 of harmaline. The 24-hour IC<sub>50</sub> of compound <strong>HL22</strong> against HCT116, MGC803, and MCF7 was 3.84 ± 0.11 μM, 5.26 ± 0.46 μM, and 8.67 ± 0.13 μM, respectively. Compound <strong>HL22</strong> significantly reduced the migratory ability of MGC803 cells. The monoclonal formation of MGC803 cells was also inhibited by <strong>HL22</strong>. The <sup>1</sup>H NMR metabolomics analysis suggested that the antiproliferative mechanism could be associated for the metabolism of glycine, serine and threonine, the metabolism of taurine and hypotaurine, glutathione metabolism, and the metabolism of nicotinic acid and nicotinamide. The significance of this study is that the anti-cancer activity of the modified N-9 derivatives of harmaline has been explored for the first time.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"119 ","pages":"Article 130106"},"PeriodicalIF":2.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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

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Bioorganic & Medicinal Chemistry Letters

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