Bioorganic Chemistry最新文献

{"title":"Design, synthesis and antitumor activity evaluation of novel modified 18β-glycyrrhetinate derivatives as PPARγ agonists","authors":"Hongyan Lin ,&nbsp;Shuaijun Cui ,&nbsp;Xinye Xu ,&nbsp;Qingqing Chen ,&nbsp;Jiazi Ge ,&nbsp;Dongxuan Ai ,&nbsp;Jie Zhu ,&nbsp;Yuheng Tao ,&nbsp;Liqun Wang ,&nbsp;Lingyu Ruan ,&nbsp;Wenhao Ge","doi":"10.1016/j.bioorg.2025.108307","DOIUrl":"10.1016/j.bioorg.2025.108307","url":null,"abstract":"<div><div>18β-Glycyrrhetinic acid (18β-GA) is the main active component of licorice and one of the most promising lead compounds in traditional Chinese herbal medicine. Previous studies have shown that 18β-GA can act as a PPARγ agonist to exert antitumor activity. However, the number of reported 18β-GA derivatives as PPARγ agonists is limited and they have significant toxic side effects, which greatly restricts their application and development. To obtain highly effective and low-toxic PPARγ agonists, through structure-activity relationship (SAR) analysis, we constructed a molecular library of 18β-GA derivatives containing 13,440 compounds and screened out 14 novel 18β-GA ester derivatives. The selected compounds were evaluated for their antitumor activity in vitro. The results showed that most of the compounds exhibited strong anti-proliferative activity against five human cancer cell lines, especially the human colon cancer cell line HT-29, without significant toxicity to normal cell lines. Among them, <strong>C1</strong> had the strongest anti-proliferative activity against HT-29, with an IC₅₀ value of 12.25 μM, which was 12 times higher than that of its parent nucleus 18β-GA. <strong>C1</strong> can block the cell cycle of HT-29 cells in G2/M phase, significantly inhibit their migration and induce their apoptosis. Molecular docking and dynamics simulation results suggested that <strong>C1</strong> could stably bind to the active pocket of PPARγ. Further PPARγ activity analysis and drug-likeness prediction results indicated that <strong>C1</strong> could act as a PPARγ agonist to exert antitumor effects and had certain drug-likeness, which is worthy of further study.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108307"},"PeriodicalIF":4.5,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of novel oleanolic acid glycoside derivatives targeting PTP1B/PI3K/AKT signaling pathway for the treatment of breast cancer","authors":"Xiaoping Song ,&nbsp;Lina Wang ,&nbsp;Yao Liu ,&nbsp;Kefan Xu ,&nbsp;Panpan Cai ,&nbsp;Jinqiu Liu ,&nbsp;Qingchao Liu ,&nbsp;Daidi Fan","doi":"10.1016/j.bioorg.2025.108296","DOIUrl":"10.1016/j.bioorg.2025.108296","url":null,"abstract":"<div><div>Protein tyrosine phosphatase 1B (PTP1B) has been identified as a key drug target for anti-tumor drug development. Oleanolic acid (OA) has been proved to be an inhibitor of PTP1B, but its poor water solubility, low bioavailability and poor activity in vivo limit its clinical efficacy. In this study, a total of 47 new OA derivatives including heteroatom derivatives, ester derivatives, amino substitution derivatives and Schiff base derivatives were designed and synthesized. Among them, OA-Br-1 had stronger inhibition and selectivity on PTP1B than OA, with IC₅₀ value of 7.08 ± 5.05 μM for PTP1B and 222.28 ± 0.11 μM for TCPTP. In addition, OA-Br-1 significantly inhibited the proliferation and induced apoptosis of breast cancer cells, and in vivo nude mice experiments also showed that OA-Br-1 could inhibit the growth of breast tumors. Then network pharmacology was used to predict the targets of OA-Br-1, and the PPI network map between compound - breast cancer - target was constructed. The results showed that the probability value of PTPN1 ranked first among all predicted targets, which was consistent with the results of enzyme activity experiments in vitro. The enrichment results of KEGG pathway and GO functional annotation analysis showed that the effect of OA-Br-1 on breast cancer was significantly correlated with the PI3K/AKT pathway. Subsequent Western Blot results also proved that OA-Br-1 could significantly inhibit the expression of PTP1B, p-PI3K and p-AKT, indicating that OA-Br-1 played an anti-breast cancer role through the PTP1B/PI3K/AKT signaling pathway. Collectively, these findings identify OA-Br-1 as a promising PTP1B inhibitor for breast cancer treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108296"},"PeriodicalIF":4.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143478807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“Triazole-linked thiazolidinedione-Benzothiazole hybrids: Design and biological evaluation as AChE inhibitors”","authors":"Aya M. Almatary ,&nbsp;Mohammad M. Al-Sanea ,&nbsp;Eman E. Nasr ,&nbsp;Abdullah Haikal ,&nbsp;Gary S. Thompson ,&nbsp;Amira Abood ,&nbsp;Mahmoud A.A. Ibrahim ,&nbsp;Abdullah A. Elgazar ,&nbsp;Abdelrahman Hamdi","doi":"10.1016/j.bioorg.2025.108295","DOIUrl":"10.1016/j.bioorg.2025.108295","url":null,"abstract":"<div><div>Novel 2,4-thiazolidinedione-benzothiazole-triazole hybrids (<strong>7a-7l</strong>) were designed and synthesized as therapeutic agents with pleotropic activity for Alzheimer's disease (AD). These compounds were evaluated for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities. Compound <strong>7k</strong>, exhibited exceptional AChE inhibition (IC₅₀ = 0.083 μM), while compound <strong>7d</strong>, showed potent activity (IC₅₀ = 0.119 μM). Kinetic studies revealed that <strong>7k</strong> was able to exert its action through mixed types of inhibition. Also, the anti-inflammatory potential of these lead compounds was assessed in LPS-stimulated RAW 264.7 macrophages. Both compounds demonstrated significant dose-dependent inhibition of key inflammatory mediators, including NO, TNF-α, IL-6, and IL-1β at non-cytotoxic concentrations (≤10 μM). Notably, compound <strong>7k</strong> exhibited superior anti-inflammatory activity, achieving 92 % NO inhibition, 65 % TNF-α reduction, and 61.1 % IL-1β suppression at 10 μM. Moreover, compound <strong>7k</strong> exerted neuroprotective activity against H₂O₂ induced neurotoxicity in SH-Sy5y cell line leading to reduction in LDH, ROS levels and improving cell survival. Finally, compound <strong>7k</strong> was able to prevent Aβ aggregation at IC₅₀ = 5 μM. Molecular docking studies provided structural insights into the possible binding interactions of compounds <strong>7d</strong> and <strong>7k</strong> within the AChE active site. The stability and binding energies of compounds <strong>7d</strong> and <strong>7k</strong> complexed with AChE were assessed over 100 ns molecular dynamics simulations and compared with Donepezil. The MM/GBSA binding energy calculations indicated that compound <strong>7k</strong> exhibited a higher affinity for AChE in comparison with compound <strong>7d</strong> and Donepezil, with Δ<em>G</em>_binding values of −46.1, −42.6, and − 24.0 kcal/mol, respectively. These findings suggest that these novel hybrid molecules represent promising multi-target therapeutic candidates for AD treatment, effectively addressing both cholinergic dysfunction and neuroinflammation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108295"},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143478808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Talaromyketides A-I: Nine polyketides with anti-inflammatory activity from a soil fungus Talaromyces sp. KYS-41","authors":"Dong-Xue Jia ,&nbsp;Ying Li ,&nbsp;Xiang-Yu Liu ,&nbsp;Wen-Jing Gao ,&nbsp;Chu-Hong Fang ,&nbsp;Ming-Jun Lv ,&nbsp;Jin-Hai Yu ,&nbsp;Jian-Min Yue","doi":"10.1016/j.bioorg.2025.108275","DOIUrl":"10.1016/j.bioorg.2025.108275","url":null,"abstract":"<div><div>A chemical investigation into fermentation product of <em>Talaromyces</em> sp. KYS-41, a fungus isolated from Kunyu Mountain soil, resulted in the discovery and identification of 27 polyketides. Notably, talaromyketides A-I (<strong>1</strong>–<strong>9</strong>) are reported for the first time, with talaromyketides A-C (<strong>1</strong>–<strong>3</strong>) being three pair of enantiomers. Talaromyketides A-D (<strong>1</strong>–<strong>4</strong>) display novel frameworks and are regarded as products resulting from oxidative ring-opening and/or subsequent rearrangement of the bibenzyl derivatives. Talaromyketide A (<strong>1</strong>) exhibits a scaffold comprising an isochroman-1,4-dione, whereas talaromyketide B (<strong>2</strong>) showcases the structural backbone of a naphthalen-1(<em>4H</em>)-one. Talaromyketides C (<strong>3</strong>) and D (<strong>4</strong>) are the outcomes of oxidative ring-opening of one of the phenyl rings in bibenzyl derivatives. Biological evaluations demonstrated that compounds <strong>2b</strong>, <strong>9</strong>, and <strong>18–21</strong> show significant anti-inflammatory activity with IC₅₀ values within 10 μM. By inhibiting the activation of NF-κB/MAPK signaling pathways, (−)-1<em>S</em>-talaromyketide B (<strong>2b</strong>) is involved in suppression of inflammatory response and shows significant pharmacological effects in vivo on zebrafish model.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108275"},"PeriodicalIF":4.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semi-rational engineering of a novel halohydrin dehalogenase from Sneathiella limimaris for the enantioselective synthesis of (S)-5-phenoxymethyl-2-oxazolidinone","authors":"Ji Ding ,&nbsp;Jinsong Song ,&nbsp;Shengbo Huang ,&nbsp;Chuanhua Zhou ,&nbsp;Feng Xue","doi":"10.1016/j.bioorg.2025.108292","DOIUrl":"10.1016/j.bioorg.2025.108292","url":null,"abstract":"<div><div>Enantiomerically pure 2-oxazolidinones are widely used as chiral auxiliaries in organic synthesis, but there is an unmet need for more effective methods to access these compounds. Here we report the identification and semi-rational engineering of the halohydrin dehalogenase <em>Sl</em>HHDH from <em>Sneathiella limimaris</em> for the highly enantioselective ring-opening of phenyl glycidyl ether (PGE) with cyanate to yield (<em>S</em>)-5-phenoxymethyl-2-oxazolidinone. After single and combinatorial mutagenesis, the best enantioselective triple mutant, F15W/A137T/N179L achieved an enantioselectivity of 97 %, with an <em>E</em> valu<em>e</em> of 154. In addition, it could accept a wider range of PGEs to generate corresponding (<em>S</em>)-5-phenoxymethyl-2-oxazolidinones, whereby the product <em>ee</em> values increased from less than 5 % in wild-type <em>Sl</em>HHDH to between 81 and 96 % in the triple mutant. Structural analysis of <em>Sl</em>HHDH and mutant F15W/A137T/N179L in complex with the substrate PGE showed that changes of the substrate-binding pocket in the mutant position <em>R-</em>PGE farther from the catalytic residues, which may explain the enhanced enantioselectivity. This mutant has great potential as a biocatalyst for the first synthesis of chiral (<em>S</em>)-5-phenoxymethyl-2-oxazolidinones.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108292"},"PeriodicalIF":4.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and anti-tumor activity of BTK inhibitor Orelabrutinib derivatives","authors":"Jin Cai,&nbsp;Xintong Qin,&nbsp;Xiaomin Zhao","doi":"10.1016/j.bioorg.2025.108278","DOIUrl":"10.1016/j.bioorg.2025.108278","url":null,"abstract":"<div><div>Bruton tyrosine kinase (BTK), a non-receptor tyrosine kinase falling within the Tec kinase family, forms an essential part of the B cell receptor (BCR) signaling cascade. It has come to be regarded as a potential drug target for addressing a wide range of diseases, with a particular focus on hematopoietic malignancies and autoimmune disorders related to B lymphocytes. In the present study, by uncovering the binding mechanisms of the inhibitor Orelabrutinib with BTK, we identified four crucial structural elements requisite for the inhibition. Using scaffold hopping strategies, 28 novel derivatives belonging to the tricyclic and pyridine amide series were designed and synthesized from the lead compound Orelabrutinib. The outcomes revealed that <strong>11a</strong> and <strong>11k</strong> were able to effectively restrain the growth and migration of the tumor cell TMD8 upon comparing their in vitro activities, meriting further examination.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108278"},"PeriodicalIF":4.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Volatile oils of Schisandra chinensis (Turcz.) Baill alleviates Parkinson's disease by activating the Nrf2 pathway to positively regulate autophagy and oxidative stress","authors":"Si-Yi Wang ,&nbsp;Meng-Meng Li ,&nbsp;Ye Sun ,&nbsp;Jia-Tong Wu ,&nbsp;Wei Guan ,&nbsp;Yi-Kai Jiang ,&nbsp;Hong-Yan Yao ,&nbsp;Xiao-Xue He ,&nbsp;Jiu-jiang Yan ,&nbsp;Qing-shan Chen ,&nbsp;Li-Li Zhang ,&nbsp;Anam Naseem ,&nbsp;Xiao-Chi Ma ,&nbsp;Hai-Xue Kuang ,&nbsp;Bing-You Yang ,&nbsp;Yan Liu","doi":"10.1016/j.bioorg.2025.108277","DOIUrl":"10.1016/j.bioorg.2025.108277","url":null,"abstract":"<div><div><em>Schisandra chinensis</em> (Turcz.) Baill, which is frequently used in health products and drinks, is recognized for its high content of essential oils that could have protective effects against PD, despite the lack of complete understanding of its pharmacological mechanisms. This research aims to examine how ESC can affect autophagy signaling pathways and activate the Nrf2/HO-1 pathway to effectively decrease oxidative damage, thus shedding light on the possible anti-PD effects of this treatment. The results demonstrated that ESC significantly reduced behavioral issues linked to Parkinson's disease in a mouse model that was induced by MPTP and safeguarded dopaminergic neurons that expressed tyrosine hydroxylase. Moreover, ESC boosted the antioxidant capability of Nrf2, assisted with autophagy processes, and finally decreased protein expression levels of Keap1, HO-1, MAPK, mTOR, and ERK. According to in vitro studies, ESC treatment had a significant reduction in H₂O₂-induced cytotoxicity and oxidative stress levels, which suggests that Nrf2 targets ESC after treatment. The activation of both autophagy and Nrf2 antioxidant pathways was assessed using western blotting. In conclusion, ESC exhibits the potential to suppress oxidative stress by activating Nrf2 in response to autophagy, which is positioned as a promising pharmaceutical candidate, especially for the management and treatment of PD and related disorders.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108277"},"PeriodicalIF":4.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143453214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential edaravone/benzocyclopentenone derivatives alleviate cerebral ischemia reperfusion injury as neuroprotective agents","authors":"Qing Zeng ,&nbsp;Huilan Li ,&nbsp;Zunhua Yang ,&nbsp;Ziwei Zhang ,&nbsp;Mai Zhang ,&nbsp;Fukang Yang ,&nbsp;Puyuan Gao ,&nbsp;Xian Huangfu ,&nbsp;Yuanying Fang","doi":"10.1016/j.bioorg.2025.108288","DOIUrl":"10.1016/j.bioorg.2025.108288","url":null,"abstract":"<div><div>Based on the scaffold of edaravone, a clinically approved neuroprotective agent, a series of edaravone/benzocyclopentenone hybrid derivatives were designed, synthesized and evaluated for their biological activities in vitro and in vivo. Most of the compounds demonstrated promising neuroprotective effects, with derivatives containing benzofuranone or indanone as core moiety showing particularly strong activity. Among all derivatives, 17 compounds exhibited significantly improved neuronal cell viabilities compared to edaravone in an OGD/R model with rat primary neuronal cells, along with favorable safety profiles and blood-brain barrier permeability. Notably, compound <strong>13</strong>, which includes a fluoro-substituted benzofuranone fragment, displayed the most potent neuroprotective effect in vitro and effectively reduced cerebral infarct area in vivo.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108288"},"PeriodicalIF":4.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSH-responsive paclitaxel prodrug used in chemotherapy in combination with photodynamic therapy","authors":"Qianqian Qi,&nbsp;Zhanyu Zhang,&nbsp;Dun Wang","doi":"10.1016/j.bioorg.2025.108289","DOIUrl":"10.1016/j.bioorg.2025.108289","url":null,"abstract":"<div><div>The lack of targeting and poor solubility of anti-tumor drugs are two major limitations to the outcome of tumor therapy. To address the inherent drawbacks, we designed a novel prodrug of paclitaxel (PTX), HP-PTX. This HP-PTX prodrug contains a PEGylated heptamethylene cyanine dye (PEG-IR808–1) that was conjugated to PTX via a redox-sensitive disulfide bond. The moiety of IR808–1 acts as a tumor-targeting ligand, enabling HP-PTX not only to target tumor cells, but also to localize to mitochondria and generate ROS under 808 nm laser irradiation to wound cellular mitochondria thus exerting cytotoxic effect. Meanwhile, in vitro cellular uptake assays showed that HP-PTX possesses MCF-7 cell tumor targeting specificity which was attributed to the preferential uptake of heptamethine cyanine dye mediated by the overexpressed organic anion-transporting polypeptides (OATP) on MCF-7 cell membrane. Near-infrared in vivo imaging showed that incorporation of polyethylene glycol effectively prolonged prodrug's half-life in vivo. In addition, in vivo experiments showed that with combinational therapy strategy HP-PTX was able to kill cancer cells with high efficiency (69.52 %) without notable toxic side effects compared to PTX. These results are evidence of the potential of the tumor-targeting prodrug HP-PTX for the treatment of breast cancer.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108289"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143474838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of highly potent mTOR inhibitors aimed at suppressing the progression of acute myeloid leukemia","authors":"Yuanyuan Li ,&nbsp;Qiu Han ,&nbsp;Qiwen Sun ,&nbsp;Xue Wang ,&nbsp;Yunsheng Ran ,&nbsp;Yifei Ma ,&nbsp;Jiangrong Lu ,&nbsp;Ziqi Jin ,&nbsp;Jing Huang ,&nbsp;Yujie Wang ,&nbsp;Jianta Wang ,&nbsp;Yue'e Chai ,&nbsp;Hongliang Li ,&nbsp;Ji-Quan Zhang","doi":"10.1016/j.bioorg.2025.108287","DOIUrl":"10.1016/j.bioorg.2025.108287","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is a common hematological malignancy with complex etiology; however, current standard chemotherapy regimens for AML show limited efficacy and unsatisfactory tolerability. Herein, a novel class of trisubstituted triazine mTOR inhibitors was designed and synthesized, and the optimal compound, <strong>HPT-11</strong>, exhibited potent inhibition against mTOR kinase and Molm-13 cell proliferation activities with inhibitory IC₅₀ values of 0.7 and 12 nM, respectively. An antitumor mechanism investigation demonstrated that <strong>HPT-11</strong> could potently block the downstream signaling pathway of mTOR and effectively induce apoptosis and autophagy. In addition, in vitro metabolic stability tests further confirmed the stable profiles of <strong>HPT-11</strong> in artificial gastrointestinal fluids, rat plasma, and liver microsomes incubating conditions. Overall, our current medicinal chemistry work confirmed that compound <strong>HPT-11</strong> is a potent mTOR inhibitor with promising activity in vitro, suggesting its potential as a candidate for further development in the treatment of AML.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108287"},"PeriodicalIF":4.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143488235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}