Bioorganic Chemistry最新文献

{"title":"Mycobacterium tuberculosis d-alanine:d-alanine ligase as a case study in the measurement of competitive kinetic isotope effects for dimerization reactions","authors":"Patrick L. Fernandez,&nbsp;Andrew S. Murkin","doi":"10.1016/j.bioorg.2025.108332","DOIUrl":"10.1016/j.bioorg.2025.108332","url":null,"abstract":"<div><div>The small magnitudes of some kinetic isotope effects (KIEs), including those associated with ¹³C, necessitate a highly precise experimental approach involving the competition of light and heavy substrates. Provided the reaction is first order in the labeled substrate, the product isotopologue ratio converges to the initial reactant isotopologue ratio at completion, but the same is not true for dimerization reactions simply because the product diverges into four distinct isotopologues. The relative populations of these dimers deviate from the statistical distribution under the influence of a KIE. Accordingly, the current study aims to demonstrate this concept by analyzing the relative ¹³C placement in <span>d</span>-alanine:<span>d</span>-alanine-<span>d</span>-alanine:<span>d</span>-alanine at reaction completion for the dimerization of D-[1-¹³C]alanine catalyzed by <em>Mycobacterium tuberculosis</em> <span>d</span>-alanine:<span>d</span>-alanine ligase (Ddl). Using ¹³C NMR spectroscopy and Fourier-transform ion cyclotron mass spectrometry, the relative distributions of the four dimer isotopologues were determined. The ratio of the mono-labeled dimers with ¹³C at the C-terminus to that with ¹³C at the N-terminus yielded a relative KIE of 1.011 ± 0.004 for the acyl carbon. This result suggests that the rate-limiting step of the Ddl-catalyzed reaction involves peptide bond formation—either nucleophilic attack by the amino group or collapse of the resulting tetrahedral intermediate. This method of analysis, to the best of our knowledge, is the first of its kind for obtaining competitive KIEs in enzyme-catalyzed dimerization reactions.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108332"},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563128","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":"Tuning the lipophilicity of new ciprofloxacin derivatives in selected ESKAPE bacteria with emphasis on E. coli mutants","authors":"Emilia Cassese ,&nbsp;Dominik Koszelewski ,&nbsp;Anna Brodzka ,&nbsp;Deepak S. Wavhal ,&nbsp;Paweł Kowalczyk ,&nbsp;Ryszard Ostaszewski","doi":"10.1016/j.bioorg.2025.108324","DOIUrl":"10.1016/j.bioorg.2025.108324","url":null,"abstract":"<div><div>The objective of the present study was to improve the antimicrobial profile of ciprofloxacin by introducing a peptidomimetic function. A ciprofloxacin C3 carboxyl group was modified <em>by a</em> three-component Passerini reaction conducted under micellar conditions. The series of newly synthesized peptidomimetics was evaluated for their possible in vitro antibacterial activity toward including selected LPS-varied <em>E. coli</em> strains. A preliminary exploration of ciprofloxacin-based peptidomimetic analogues as novel antimicrobial agents was carried out to determine the basic characteristics of the structure responsible for the observed biological activity. The collected data demonstrated that an appropriate modification of the C3 position of ciprofloxacin significantly extends and improves antimicrobial activity, particularly against LPS-varied <em>E. coli</em> strains, which may cause various diseases such as urinary tract infections (UTI), enteric / diarrheal disease, and sepsis/meningitis. Furthermore, the antimicrobial activities of peptidomimetics against selected Gram-positive and Gram-negative bacterial strains belonging to ESKAPE bacteria (<em>A. baumannii, P. aeruginosa, E. cloacae</em>, and <em>S. aureus</em>) were investigated. All synthesized ciprofloxacin derivatives were found to be more potent antibacterial agents than the native compound. Most importantly, the introduction of a short aliphatic substituent into the peptidomimetic structure allowed to enhance and extend the activity of modified ciprofloxacin not only to the native <em>E. coli</em> strain but also to all of its tested mutants. The results showed that all tested peptidomimetics have enhanced antimicrobial activities (MIC values from 0.22 to 2.19 μM) as compared to ciprofloxacin (MIC = 0.62 to 3.44 μg/mL). Furthermore, the cytotoxicity of sixteen derivatives was measured using the MTT test on BALB/c3T3 mouse fibroblast cell lines. Cytotoxicity studies revealed that the tested substances exert a similar or lower effect on cell proliferation than that observed for native ciprofloxacin. This study presents that it is possible to extend the antimicrobial activity of ciprofloxacin by appropriate modification of its structure, which can prolong its use. This is very important in light of the reports incoming on pathogens in nosocomial infections that acquire resistance to this antibiotic.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108324"},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549832","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":"Research on enhancing enzymatic degradation of anti-digestive peptides containing D-amino acids through N-terminal acetylation","authors":"Shuaishuai Cui ,&nbsp;Cunxin Guo ,&nbsp;Liang Yan ,&nbsp;Yujian He ,&nbsp;Li Wu","doi":"10.1016/j.bioorg.2025.108337","DOIUrl":"10.1016/j.bioorg.2025.108337","url":null,"abstract":"<div><div>The incorporation of D-amino acids can influence the structure and enzymatic stability of proteins or peptides, especially when they are introduced at enzyme cleavage sites, significantly inhibiting the enzymatic hydrolysis of peptides. The abnormal accumulation of these peptides has been linked to age-related conditions, including cataracts and Alzheimer's disease. N-terminal acetylation, an essential post-translational modification, significantly enhances the physicochemical properties of peptides and plays an essential role in regulating their performance within biological systems. This research examined the impact of N-terminal acetylation on the enzymatic hydrolysis of peptides incorporating D-amino acids. Enzymatic activity assessments showed that N-terminal acetylation greatly promoted the enzymatic breakdown of these peptides by Proteinase K (PROK), with the substrate decay rate constant for the acetylated peptide Ac-6-w increasing by 17.5 times. This enhancement was specific to serine-type proteases, which exhibited a comparable cleavage pattern. Molecular docking further demonstrated that N-terminal acetylation improved interactions within the catalytic triad of serine proteases, leading to faster enzymatic degradation. The results provide novel insights into the impact of N-terminal acetylation on the enzymatic behavior of peptides incorporating D-amino acids, and they propose a potential approach for targeting these peptides to preserve normal physiological functions.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108337"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549831","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":"Berberrubine as a novel TrxR inhibitor enhances cisplatin sensitivity in the treatment of non-small cell lung cancer","authors":"Yajun Chu ,&nbsp;Qiuying Nie ,&nbsp;Xiedong Zhou ,&nbsp;Junwei Yang ,&nbsp;Jianguo Fang ,&nbsp;Junmin Zhang","doi":"10.1016/j.bioorg.2025.108329","DOIUrl":"10.1016/j.bioorg.2025.108329","url":null,"abstract":"<div><div>Thioredoxin reductase (TrxR, <em>TXNRD</em>) is an essential enzyme implicated in the processes of cancer development and progression, positioning it as a promising target for cancer therapeutics. In this study, we employed target-based structural screening to identify berberrubine (BRB), a natural product characterized by an unprecedented isoquinoline scaffold that differs from known TrxR inhibitors. Our findings demonstrate that BRB serves as an effective inhibitor of TrxR, both in the context of the purified enzyme and within cancer cells. Since TrxR is highly expressed in non-small cell lung cancer (NSCLC) and is linked to patient prognosis and drug resistance, our results demonstrate, for the first time, that BRB can enhance the sensitivity of cisplatin to impede the proliferation of A549 cells, which was further confirmed in a xenograft model. The primary reason for cisplatin resistance in NSCLC is the DNA repair mechanism of apoptotic tumor cells. Our subsequent mechanistic investigation discovered that BRB selectively inhibits TrxR and impairs the biologically functional thioredoxin, which ultimately inhibits DNA synthesis and repair in cancer cells. Inhibition of TrxR by BRB led to a significant ROS accumulation in A549 cells, which contributed to oxidative stress-mediated apoptosis when used in combination with cisplatin. Our results conclude that BRB is a novel chemical entity of TrxR inhibitor that can increase the effectiveness of cisplatin in slowing down the growth of NSCLC both in vitro and in vivo. This provides a new perspective on the potential application of the combination of the two in the treatment of NSCLC.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108329"},"PeriodicalIF":4.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563194","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":"Diverse anti-inflammatory lindenane sesquiterpenoid hetero- or homo-dimers from Chloranthus holostegius var. shimianensis","authors":"Jie Wen,&nbsp;Mengmeng Yu,&nbsp;Houli Jiang,&nbsp;Yi Zhu,&nbsp;Danyang Zhang,&nbsp;Mingzhe Yang,&nbsp;Lingyi Kong,&nbsp;Jun Luo","doi":"10.1016/j.bioorg.2025.108327","DOIUrl":"10.1016/j.bioorg.2025.108327","url":null,"abstract":"<div><div>Twenty-seven dimeric lindenane sesquiterpenoid (LS) derivatives, including thirteen new hetero- or homo-dimers (<strong>1−13</strong>), were discovered from rare Chloranthaceae plant <em>Chloranthus holostegius</em> var. <em>shimianensis</em>. Their structures were elucidated by a combination of HRMS, spectroscopic analysis, single-crystal X-ray diffraction and CD exciton chirality method. Fortunoids D-G (<strong>1–4</strong>) and chlorfortunones C-F (<strong>5–8</strong>) are rare hetero-dimers of lindenane with eudesmane or acrane sesquiterpenoid through classical [4 + 2] cycloaddition respectively, and <strong>9–13</strong> are homo-LS dimers with low oxidation at C4′/13′/15′. Anti-inflammatory potential of these new isolates was evaluated by screening the IL-1<em>β</em> inhibition in THP-1 cells. Compounds <strong>2–4</strong> exhibited moderate anti-inflammatory effect (IC₅₀ ≈ 10 μM) at non-cytotoxic concentrations (cell viability &gt;80 %), and subsequent investigation on <strong>2</strong> demonstrated that it inhibited IL-1<em>β</em> production by inhibiting NLRP3 inflammasome activation but not the assembly. Based on the structural features of these LS dimers, the abundance of hetero-LS dimers and the low oxidation level at C4'/13'/15' of homo-LS dimers might be the chemotaxonomic characteristics distinguished from other Chloranthus species.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108327"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563300","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 bifunctional small molecules targeting PD-L1/VISTA with favorable pharmacokinetics for cancer immunotherapy","authors":"Yao Xiao ,&nbsp;Yaru Shi ,&nbsp;Chuxiao Shao ,&nbsp;Wubing Tang ,&nbsp;Hao Liu ,&nbsp;Jianjun Chen ,&nbsp;Shuanghu Wang ,&nbsp;Binbin Cheng","doi":"10.1016/j.bioorg.2025.108323","DOIUrl":"10.1016/j.bioorg.2025.108323","url":null,"abstract":"<div><div>In this work, we designed and synthesized a series of bifunctional PD-L1/VISTA (V-domain immunoglobulin suppressor of T-cell activation) small molecule inhibitors. Among them, <strong>S8</strong> showed acceptable PD-L1 inhibitory effects (IC₅₀ = 1.4 μM, HTRF assay) and VISTA binding activity (<em>K</em>_D = 2.1 μM, ITC assay). BLI, ITC, and DSF assays further confirmed its dual action mode. Notably, <strong>S8</strong> exhibited desirable <em>in vivo</em> pharmacokinetic properties, featuring a respectable oral bioavailability of 34.2 %. Moreover, oral administration of <strong>S8</strong> led to a 40 % reduction in tumor weight and a 51 % decrease in tumor volume in a B16-F10 tumor model, better than the positive control an anti-PD-L1 antibody, and <strong>CA-170</strong>. PK-PD studies show that the plasma level of unbound <strong>S8</strong> covered the biochemical IC₅₀ concentration determined by ITC and HTRF assays, which is consistent with the strong antitumor activity observed <em>in vivo</em>. Analysis of tumor-infiltrating lymphocytes (TILs) <em>via</em> flow cytometry suggested that <strong>S8</strong> activated the tumor immune microenvironment to exert its anti-cancer effects. In summary, <strong>S8</strong> represents a dual PD-L1/VISTA inhibitor with potential for further investigation as a dual-function immunotherapeutic agent.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108323"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550588","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":"Nonenzymatically modified mRNA for regulating translation and apoptosis by modulating Cancer epigenetics","authors":"Tasnima Alam Asa ,&nbsp;Chabungbam Dhurbachandra Singh ,&nbsp;Thokchom Simander Singh ,&nbsp;Saleh Salahi ,&nbsp;Kazi Morshed Alom ,&nbsp;Young Jun Seo","doi":"10.1016/j.bioorg.2025.108328","DOIUrl":"10.1016/j.bioorg.2025.108328","url":null,"abstract":"<div><div>In this study, we employed imidazole-activated natural or modified guanosine derivatives to extend the 3′ ends of mRNA using a nonenzymatic method beyond 30 poly-A tails. We evaluated their impact on the translation activity in cell studies using three genes: GFP, Luciferase, and Apoptin. The assessments were conducted through cell imaging, fluorescence, luminescence, western blot analysis, and RT-qPCR to evaluate varying apoptosis-mediated EZH2 expression in cancer epigenetics, among the compounds tested GMP-2-amino-IM, 2′O-Me-2-amino-IM, and N7-(2-MePy)-GMP-IM. The sugar-modified 2′O-Me-GMP-2-amino-IM demonstrated the most favorable results as mRNAs treated with this compound exhibited higher expression levels with promising mRNA stability relative to the control mRNA (without any extension) and other tested compounds. Subsequently, we transfected cancer cells with nonenzymatically modified apoptin mRNAs by utilizing the three imidazole-activated guanosine derivatives compounds and monitored the induced apoptosis. These findings suggest that 2′O-Me-2-amino-IM-modified apoptin mRNA could serve as a promising tool for cancer therapy by inducing apoptosis while selectively modulating EZH2 expression, a key regulator in oncogene suppression.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108328"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534421","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":"Reniochalistatin E: A potentiating agent and a potential novel drug delivery platform","authors":"Kameron R. Wildeman,&nbsp;Matthew Barnett,&nbsp;Anthony Fatino,&nbsp;Chamitha Weeramange,&nbsp;Ryan J. Rafferty","doi":"10.1016/j.bioorg.2025.108331","DOIUrl":"10.1016/j.bioorg.2025.108331","url":null,"abstract":"<div><div>Peptides, both linear and cyclic, have begun to emerge as a viable therapeutic for the treatment of various diseases. As such, synthesizing these linear and macrocyclic peptides as natural product targets or related structural analogs can help us to understand their biological importance. Reniochalistatin E is a proline-rich macrocyclic peptide natural product first synthesized in 2017 by our laboratory, and screening against various cancerous cell lines revealed moderate to low cytotoxicity as a sole agent. We next became interested in studying this compound as a potentiating agent to identify any synergistic effects. Indeed, reniochalistatin E was unveiled to show potential intramolecular pi-stacking that enhanced the cytotoxicity of clinically used anti-cancer agents. To exploit this unique characteristic, attention was directed towards the modification of the tryptophan residue to enhance the synergistic effect with additional cytotoxic agents. To this, a phenylalanine-tryptophan exchange was undertaken to probe this hypothesis and was found to possess no detectable cytotoxicity variation. Together, the data collected supports further exploration with drug conjugate handles en route towards a novel drug delivery platform.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108331"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534419","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":"Macrolide sesquiterpene pyridine alkaloids from the roots of Tripterygium regelii and their anti-inflammatory activity","authors":"Dawei Li ,&nbsp;Qi Jia ,&nbsp;Qi Zhao ,&nbsp;Jintao Sun ,&nbsp;Jianming Yu ,&nbsp;Huan Chen ,&nbsp;Linlin Sui ,&nbsp;Aijing Leng ,&nbsp;Ping Guo ,&nbsp;Chao Wang","doi":"10.1016/j.bioorg.2025.108330","DOIUrl":"10.1016/j.bioorg.2025.108330","url":null,"abstract":"<div><div>Eleven new macrolide sesquiterpene pyridine alkaloids (<strong>1</strong>–<strong>8</strong> and <strong>10</strong>–<strong>12</strong>) and twelve known congeners (<strong>9</strong> and <strong>13</strong>–<strong>23</strong>) were isolated from <em>Tripterygium regelii</em> roots. Their structures were identified through NMR, HRESIMS, and X-ray crystallography. Additionally, their anti-inflammatory activity was evaluated using a dual luciferase screening system based on aryl hydrocarbon receptor (AHR) activation, as well as a lipopolysaccharide (LPS)-induced macrophage model. Compounds <strong>7</strong> and <strong>13</strong> were found to significantly activate AHR, inhibit nitric oxide production, suppress the JNK and NF-κB/NLRP3 signaling pathways, and reduce inflammation-related proteins expression, including IL-6 and COX 2. This study not only expands the chemical variety of macrolide sesquiterpene pyridine alkaloids but also suggests that compounds <strong>7</strong> and <strong>13</strong> could be potential candidates for inflammation-related disease treatment.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108330"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549739","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 and evaluation of novel Benzohydroxamic acid-indole derivatives as dual inhibitors of ADAM17 and HDAC2 with antitumor activity","authors":"Xiaoxuan Song ,&nbsp;Xin Tong ,&nbsp;Kaisi Yang ,&nbsp;Yiming Qi ,&nbsp;Wenwu Liu ,&nbsp;Yuzhu Sun ,&nbsp;Chengkang Wang ,&nbsp;Fanghua Xun ,&nbsp;Ziyi Wang ,&nbsp;Muxuan Jiang ,&nbsp;Yingshi Zhang ,&nbsp;Tianshu Ren ,&nbsp;Di Chen ,&nbsp;Shanbo Hou ,&nbsp;Aigang Song ,&nbsp;Huiyuan Gao ,&nbsp;Qingchun Zhao","doi":"10.1016/j.bioorg.2025.108308","DOIUrl":"10.1016/j.bioorg.2025.108308","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) has garnered significant attention from researchers due to its high recurrence rate and invasive characteristics. The design of drugs with dual-target combined effects represents a promising strategy in cancer treatment. Our observations suggest that ADAM17 and HDAC may inhibit the unfavorable prognostic signaling pathway Notch1 in HCC through distinct mechanisms, thereby suppressing tumor cell proliferation and metastasis. Consequently, this study utilized the ADAM17 inhibitor ZLDI-8 as a lead compound and developed a series of dual ADAM17/HDAC2 inhibitors by integrating strategies such as backbone leaping and pharmacophore fusion. We assessed the anti-hepatocellular carcinoma activity of these compounds, focusing on their anti-proliferative, pro-apoptotic, and anti-metastatic properties. Notably, ZSNI-21 effectively inhibited the proliferation of Bel-7402 cells and demonstrated significant anti-metastatic capabilities against HCC-LM3 cells, with its targeting confirmed. Additionally, its in vivo safety was validated. To date, there have been no reports on dual ADAM17/HDAC2 inhibitors, marking this as a novel endeavor.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"157 ","pages":"Article 108308"},"PeriodicalIF":4.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550587","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}