Bioorganic Chemistry最新文献

{"title":"Identification of mitoxantrone as a potent inhibitor of CDK7/Cyclin H via structure-based virtual screening and In-Vitro validation by ADP-Glo kinase assay","authors":"Tejaswi Somarowthu ,&nbsp;Rohan R. Patekar ,&nbsp;Sandip B. Bharate","doi":"10.1016/j.bioorg.2024.108111","DOIUrl":"10.1016/j.bioorg.2024.108111","url":null,"abstract":"<div><div>Cyclin-dependent kinases, CDK7 and CDK9 play critical roles in cancer by regulating transcriptional processes essential for cell proliferation and survival. Their dysregulation leads to aberrant gene expression, promoting oncogenic pathways and contributing to tumor growth and progression. This study aimed to identify a new chemotype for CDK7/9 inhibitors using a structure-based virtual screening approach. Our research led to the discovery of mitoxantrone as an inhibitor of CDK7/H and CDK9/T1 from a library of FDA-approved small molecule drugs. Mitoxantrone, a chemotherapy agent used to treat acute nonlymphocytic leukemia, works by disrupting DNA synthesis and repair, thus inhibiting cancer cell growth. The study found that mitoxantrone effectively inhibits both CDK7/H and CDK9/T1 with IC₅₀ values of 0.675 µM and 5.15 µM, respectively, while showing no inhibition of CDK2/E1 (IC₅₀ &gt; 100 µM) in <em>in-vitro</em> ADP-Glo kinase assay. It binds to the ATP pocket of CDK7 and CDK9, forming crucial H-bonds with MET 94 and CYS 106, respectively. It achieves dock scores of − 12.93 and − 12.59 kcal/mol, and MMGBSA binding energies of − 82.87 and − 81.59 kcal/mol, respectively. Molecular dynamics simulations over 100 ns confirmed stable interactions with MET 94 and CYS 106 in the hinge region of CDK7 and CDK9. The active site sequence alignment helped to understand the differential activity of mitoxantrone for CDK7, 9 and 2 inhibitions. The findings of the paper reveal a novel mechanism of mitoxantrone action that may contribute to its anticancer efficacy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108111"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941963","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":"2-Acylpyrrole-based alkaloids from the leaves of Sauropus spatulifolius and their α-glucosidase inhibitory activities","authors":"Xiao Xia ,&nbsp;Yan Lu ,&nbsp;Dao-Feng Chen","doi":"10.1016/j.bioorg.2025.108134","DOIUrl":"10.1016/j.bioorg.2025.108134","url":null,"abstract":"<div><div>Pyrrole alkaloids are a class of natural products with intriguing structures and promising biological actives. Within the <em>Sauropus</em> plants, these alkaloids are mainly present in <em>Sauropus spatulifolius</em>. An investigation of the leaves of <em>S. spatulifolius</em> <!-->was conducted to discover novel and bioactive pyrrole alkaloids. This study led to the identification of 38 alkaloids, including 21 new pyrrole alkaloids (<strong>1</strong> − <strong>5</strong>, <strong>13</strong>, <strong>16</strong>, <strong>19</strong> − <strong>23</strong>, <strong>26</strong> − <strong>31</strong>, <strong>33</strong>, <strong>35</strong>, and <strong>36</strong>), along with 17 related analogues (<strong>6</strong> − <strong>12</strong>, <strong>14</strong>, <strong>15</strong>, <strong>17</strong>, <strong>18</strong>, <strong>24</strong>, <strong>25</strong>, <strong>32</strong>, <strong>34 37</strong>, and <strong>38</strong>). The structures of the new compounds were elucidated by NMR, HRESIMS, electronic circular dichroism (ECD), and X-ray diffraction analysis. Notably, compounds <strong>28</strong> − <strong>31</strong> were identified as pyrrole alkaloids with unprecedented skeletons. Compounds <strong>28</strong> and <strong>29</strong> featured a 2-acylpyrrole alkaloid and a cinnamic acid heterodimers, while <strong>30</strong> and <strong>31</strong> possessed a pyrrolooxazinone scaffold with a 1,2-hexadecanediol moiety. These structures were rare in plants. Three compounds (<strong>27</strong>, <strong>31</strong>, and <strong>38</strong>) displayed <em>α</em>-glucosidase inhibitory activity. Particularly, compounds <strong>27</strong> (IC₅₀: 320.3 μM) and <strong>31</strong> (IC₅₀: 153.7 μM) exhibited stronger activity than that of acarbose (IC₅₀: 545.9 μM). Molecular docking studies showed the strong interactions of the three bioactive compounds with the <em>α</em>-glucosidase protein. Additionally, compounds <strong>27</strong>, <strong>31</strong>, and <strong>38</strong> showed significant effects on enhancing glucose consumption in HepG2 cells.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108134"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941965","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":"Synthesis, biological evaluation, and in silico studies of phenyl naphthalene-2-sulfonate derived thiosemicarbazones as potential carbonic anhydrase inhibitors","authors":"Javeria Eshal ,&nbsp;Hafiza Zara Tariq ,&nbsp;Jing Li ,&nbsp;Hina Aftab ,&nbsp;Halil Şenol ,&nbsp;Parham Taslimi ,&nbsp;Nastaran Sadeghian ,&nbsp;Rima D. Alharthy ,&nbsp;Muhammad Safwan Akram ,&nbsp;Rimsha Talib ,&nbsp;Zahid Shafiq","doi":"10.1016/j.bioorg.2024.108118","DOIUrl":"10.1016/j.bioorg.2024.108118","url":null,"abstract":"<div><div>A series of novel phenyl naphthalene-2-sulfonate-based thiosemicarbazones <strong>(5a-v)</strong> were synthesized and evaluated for their inhibitory activity against human carbonic anhydrases I and II (hCA I and hCA II). Compounds <strong>5d</strong> and <strong>5p</strong> demonstrated the highest inhibitory potency, with IC₅₀ values of 4.32 ± 0.02 nM and 5.24 ± 0.03 nM for hCA I, and 3.89 ± 0.01 nM and 4.72 ± 0.01 nM for hCA II, respectively. Notably, compound <strong>5d</strong> exhibited superior potency compared to the reference drug acetazolamide. The structure–activity relationship (SAR) analysis revealed that electron-withdrawing groups, particularly the dichlorophenyl group in <strong>5d</strong> and <strong>5p</strong>, enhanced inhibitory activity. Molecular docking and molecular dynamics simulations confirmed the high binding affinity of compound <strong>5d</strong>, with docking scores of −9.7 kcal/mol for hCA I and −9.5 kcal/mol for hCA II. Stability in MD simulations further supported its potent inhibitory action. ADMET predictions suggested that compounds <strong>5d</strong> and <strong>5p</strong> have favorable pharmacokinetic profiles. In conclusion, phenyl naphthalene-2-sulfonate-based thiosemicarbazones, especially compound <strong>5d</strong>, show strong potential as therapeutic agents targeting hCA I and hCA II.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108118"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963361","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 biological evaluation of Alisol B derivatives for potential treatment of non-alcoholic steatohepatitis","authors":"Nai-Rong Yu ,&nbsp;Suling Huang ,&nbsp;Zhen-Tao Deng ,&nbsp;Jiayue Wang ,&nbsp;Yu Shen ,&nbsp;Ying Leng ,&nbsp;Qin-Shi Zhao","doi":"10.1016/j.bioorg.2025.108132","DOIUrl":"10.1016/j.bioorg.2025.108132","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD), also known as metabolic dysfunction- associated with fatty liver disease (MAFLD), is one of the most prevalent chronic liver diseases globally. NAFLD is characterized by the accumulation of liver fat unrelated to excessive alcohol consumption. Non-alcoholic steatohepatitis (NASH) is the disease progression of NAFLD and could develop into cirrhosis and hepatocellular carcinoma. In previous studies, the preclinical efficacy of alisol B and alisol B 23-acetate against NASH and metabolic syndrome was identified. However, there is a paucity of literature pertaining to the specialized structural optimization of alisol B for the treatment of NASH. In this study, a series of alisol B derivatives (<strong>1</strong>–<strong>21</strong>) were designed, synthesized and evaluated in order to improve the activity of alisol B and to obtain candidate compounds for treating NASH. The effects of the synthesized compounds on de novo lipogenesis and α-SMA gene expression were tested to explore the preliminary structure–activity relationship (SAR). Compounds <strong>14</strong> and <strong>21</strong> were selected for further <em>in vivo</em> investigation. The high-fat diet plus carbon tetrachloride (HFD + CCl₄)-induced NASH mice model was employed for biological evaluation <em>in vivo</em>. Compounds <strong>14</strong> and <strong>21</strong> effectively improved hepatic steatosis, ballooning, inflammatory infiltration, and hepatic fibrosis in the livers of HFD + CCl₄ mice. Thus, <strong>14</strong> and <strong>21</strong> are promising lead compounds for the treatment of NASH.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108132"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997196","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":"Surface display and characterization of recombinant α-l-Rhamnosidase from Emiliania huxleyi on Pichia pastoris","authors":"Xi Xie ,&nbsp;Ziwei Guo ,&nbsp;Bihan Chen ,&nbsp;Li Lin ,&nbsp;Huifan Liu ,&nbsp;Gengsheng Xiao ,&nbsp;Qin Wang","doi":"10.1016/j.bioorg.2025.108121","DOIUrl":"10.1016/j.bioorg.2025.108121","url":null,"abstract":"<div><div>An α-<span>l</span>-Rhamnosidase gene with an open reading frame of 3192 bp encoding a 1036-amino acid protein (<em>Eh</em>Rha) was cloned from <em>Emiliania huxleyi</em> for flavonoid hydrolysis on the cell surface of <em>Pichia pastoris</em> (<em>P. pastoris</em>) strain GS115 by fusing with the anchor protein (<em>AGα1</em>) from <em>Saccharomyces cerevisiae</em>. Fluorescence microscopy and flow cytometry assays revealed that <em>Eh</em>Rha was successfully displayed on the cell surface of <em>P. pastoris</em> GS115. The enzyme activity assay and substrate specificity analysis showed that the enzyme activity of displayed <em>Eh</em>Rha was 78 U/g (cell wet weight). <em>Eh</em>Rha demonstrated a preference for the α-1,6 linkage <span>l</span>-rhamnose in hesperidin and rutin as its optimal substrates, while showing low activity towards the α-1,2 linkage <span>l</span>-rhamnose in naringin. Furthermore, <em>Eh</em>Rha demonstrated optimal activity at pH 7.0 and 30 °C, maintaining stability within a pH range of 4.5–9.0 at temperatures below 50 °C, and remained functional at temperatures ranging from 15 °C–30 °C. The enzyme activity was significantly enhanced by the presence of 10 mM Mn²⁺ and Fe³⁺, whereas 10 mM Ca²⁺ and 1 mM Fe³⁺ had an inhibitory effect. These findings suggested that displayed <em>Eh</em>Rha holds promise for enhancing the bioavailability of health-beneficial polyphenols in low-temperature processing applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108121"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997198","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":"Issue TOC","authors":"","doi":"10.1016/S0045-2068(25)00055-0","DOIUrl":"10.1016/S0045-2068(25)00055-0","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108175"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143138986","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":"Synthesis and antitumor activity of a novel class of covalent inhibitors of EGFR with 2-indolone backbone","authors":"Huayuan Tan ,&nbsp;Yue Zhou ,&nbsp;Fulian Li ,&nbsp;Chenlu Xu ,&nbsp;Chengpeng Li ,&nbsp;Jiao Meng ,&nbsp;Lihui Shao ,&nbsp;Bingqian Liu ,&nbsp;Danping Chen ,&nbsp;Zhurui Li ,&nbsp;Chenchen Li ,&nbsp;Jian Wu ,&nbsp;Zhenchao Wang","doi":"10.1016/j.bioorg.2025.108221","DOIUrl":"10.1016/j.bioorg.2025.108221","url":null,"abstract":"<div><div>The percentage of people with lung cancer remains high. Given that the majority of NSCLC patients are currently on third-generation clinical agents, the search for a class of highly effective and low-toxicity inhibitors is critical. Hence, in the present study, 24 compounds were synthesized by scaffold hopping with 2-indolone as the parent nucleus. The anti-tumor activity against two human non-small cell lung cancer cell lines (A549 and H1975) was evaluated <em>in vitro</em> using Osimertinib as a positive control drug. Results demonstrated that compound <strong>T16</strong> (IC₅₀ = 0.386 ± 0.032 μM) exhibited comparable anti-tumor activity to Osimertinib (IC₅₀ = 0.098 ± 0.006 μM). Moreover, <strong>T16</strong> showed a twofold higher selectivity than Osimertinib in normal HEK293 cells. Subsequent studies confirmed that compound <strong>T16</strong> inhibited colony formation in both H1975 and A549 cells at concentrations consistent with the initial screening assay results. Additionally, it suppressed migration of H1975 cells, and induced apoptosis while significantly reducing phosphorylation levels of EGFR and AKT proteins. <em>In vivo</em> experiments demonstrated effective tumor suppression after 20 days’ treatment with compound <strong>T16</strong> in CDX model. RNA sequencing analysis further revealed that compound <strong>T16</strong> induced expression of HMOX1 leading to ferroptosis trigger. Additionally, molecular docking results indicate that <strong>T16</strong> is chimerized into the mutant protein pocket in an ‘arch-bridge’ conformation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"156 ","pages":"Article 108221"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143197027","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":"Dehydroepiandrosterone ameliorates primary dysmenorrhea by suppressing the SP1/Hsp90ab1/COX-2 signaling pathway","authors":"Daojuan Wang ,&nbsp;Zhengquan Zhu ,&nbsp;Juan Zhao ,&nbsp;Lei Wang ,&nbsp;Yihan Wang ,&nbsp;Tingyu Wang ,&nbsp;Qiong Zhang ,&nbsp;Yu Fu ,&nbsp;Ying Huang ,&nbsp;Xiaoke Wu ,&nbsp;Yong Wang ,&nbsp;Yanting Wen ,&nbsp;Gaojian Tao","doi":"10.1016/j.bioorg.2025.108235","DOIUrl":"10.1016/j.bioorg.2025.108235","url":null,"abstract":"<div><div>Androgens play a protective role in alleviating chronic pain in women, including pelvic pain; however, their specific role and underlying mechanism in the treatment of primary dysmenorrhea (PD) remain unclear. In this study, clinical data revealed that women with PD exhibited reduced serum testosterone levels, which were inversely correlated with the severity of dysmenorrhea compared to healthy controls. Using a mouse model of PD, we observed significant upregulation of Hsp90ab1 and the PD markers COX-2 in the uterus. Treatment with dehydroepiandrosterone (DHEA), an androgen precursor, suppressed the uterine expression of Hsp90ab1 and COX-2, alleviating pain symptoms. Notably, pharmacological inhibition of Hsp90ab1 with geldanamycin reduced COX-2 expression by inactivating the p-p38 and p-JNK signaling pathways, and effectively mitigated PD. Further analysis identified specificity protein 1 (SP1) as a key driver of Hsp90ab1 transcription through its binding to the promoter region. Inhibition of SP1 using plicamycin reduced Hsp90ab1 expression, alleviated pain, and decreased uterine edema in the mouse model. Conversely, lentiviral overexpression of Hsp90ab1 reversed the therapeutic effects of DHEA, including nociception relief, reduction of uterine edema, and suppression of COX-2 expression. These findings suggest that androgen deficiency triggers SP1-mediated upregulation of Hsp90ab1 and COX-2, forming a critical regulatory loop that exacerbates menstrual cramps. Targeting this pathway represents a promising therapeutic strategy for managing PD.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"156 ","pages":"Article 108235"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143197032","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":"Nidustrin A, cysteine-retained emestrin with a unique 18-membered macrocyclic lactone from the endophytic fungus Aspergillus nidulans","authors":"Aimin Fu ,&nbsp;Qin Li ,&nbsp;Yongqi Li ,&nbsp;Yu Chen ,&nbsp;Ying Wei ,&nbsp;Jiaxin Dong ,&nbsp;Yuanyang Peng ,&nbsp;Mengyi Deng ,&nbsp;Weiguang Sun ,&nbsp;Chunmei Chen ,&nbsp;Yonghui Zhang ,&nbsp;Hucheng Zhu","doi":"10.1016/j.bioorg.2024.108105","DOIUrl":"10.1016/j.bioorg.2024.108105","url":null,"abstract":"<div><div>Nidustrin A (<strong>1</strong>), the first cysteine-retained emestrin featuring a unique sulfur-containing 18-membered macrocyclic lactone, along with four biogenetically related compounds (<strong>2</strong>–<strong>5</strong>), and one known analogue secoemestrin C (<strong>6</strong>), were isolated from the large-scale culture of <em>Aspergillus nidulans,</em> an endophytic fungus derived from the <em>Whitmania pigra</em>. Compounds <strong>2</strong> and <strong>3</strong> represent the second examples of noremestrin besides the previously reported noremestrin A, and the single crystal X-ray diffraction analysis of compound <strong>2</strong> provided solid evidence for the intriguing skeleton of noremestrin. Their structures were determined by extensive spectroscopic data, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Compounds <strong>2</strong>–<strong>4</strong> exhibited inhibitory activity against concanavalin A-induced T lymphocyte proliferation with IC₅₀ values from 2.95 to 24.5 μM, respectively. Compound <strong>4</strong> could protect the liver from hepatocyte apoptosis in ConA-induced liver injury and showed moderate cytotoxic activities with IC₅₀ values ranging from 3.26 to 15.70 μM.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108105"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925872","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":"Synthesis and potential anti-inflammatory response of indole and amide derivatives of ursolic acid in LPS-induced RAW 264.7 cells and systemic inflammation mice model: Insights into iNOS, COX2 and NF-κB","authors":"Rupali Choudhary ,&nbsp;Puneet Kumar ,&nbsp;Sanket K Shukla ,&nbsp;Asha Bhagat ,&nbsp;Jasha Momo H. Anal ,&nbsp;Gurleen Kour ,&nbsp;Zabeer Ahmed","doi":"10.1016/j.bioorg.2024.108091","DOIUrl":"10.1016/j.bioorg.2024.108091","url":null,"abstract":"<div><div>Ursolic acid (3-hydroxy-urs-12-ene-28-oic acid, UA) is a pentacyclic triterpene present in numerous plants, fruits and herbs and exhibits various pharmacological effects. However, UA has limited clinical applicability since it is classified as BCS class IV molecule, characterized by low solubility, low oral bioavailability and low permeability. In the present study, UA was isolated from the biomass marc of <em>Lavandula angustifolia</em> and was structurally modified by an induction of indole ring at the C-3 position and amide group at the C-17 position with the aim to enhance its pharmacological potential. This modification resulted in the synthesis of a series of compounds which were investigated for their anti-inflammatory potential both <em>in-vitro</em> and in animal models in comparison to UA. In RAW 264.7 cells, UA and its derivatives were non-cytotoxic up to 10 µM. The derivative UA-1 exhibited a significantly lower IC₅₀ (2.2 ± 0.4 µM) for NO inhibition compared to UA (17.5 ± 2.0 µM). Molecular docking showed strong interactions of UA-1 with TNF-α and NF-κB. UA-1 significantly reduced LPS-induced pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in RAW 264.7 macrophages with the inhibition levels of 74.2 ± 2.1 % for TNF-α, 55.9 ± 3.7 % for IL-6 and 59.7 ± 4.2 % for IL-1β at 5.0 µM, respectively and reactive oxygen species while upregulating anti-inflammatory cytokine, IL-10. It also downregulated iNOS, COX-2, p-NF-κB p65, and p-IκBα at both mRNA and protein levels. In LPS-induced systemic inflammation mice model, UA-1 significantly lowered NO, TNF-α, IL-6, IL-1β and serum biochemical parameters, reduced tissue damage, and exhibited improved aqueous solubility and moderate lipophilicity. Overall, UA-1 demonstrated superior anti-inflammatory potential, improved solubility, and better therapeutic potential compared to UA.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"155 ","pages":"Article 108091"},"PeriodicalIF":4.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925874","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}