Bioorganic Chemistry最新文献

{"title":"Exploring Trisubstituted adenine derivatives as adenosine A1 receptor ligands with antagonist activity: Synthesis, biological evaluation and molecular modelling","authors":"Laura B. Córdoba-Gómez ,&nbsp;Álvaro Lorente-Macías ,&nbsp;María Isabel Loza ,&nbsp;José Brea ,&nbsp;Antón Leandro Martínez ,&nbsp;Jonathon Mok ,&nbsp;Ben King ,&nbsp;Francisco Franco-Montalban ,&nbsp;Antonio González García ,&nbsp;Juan José Guardia-Monteagudo ,&nbsp;Maria J. Matos ,&nbsp;Asier Unciti-Broceta ,&nbsp;Juan José Díaz-Mochón ,&nbsp;Maria Jose Pineda de Las Infantas","doi":"10.1016/j.bioorg.2025.108395","DOIUrl":"10.1016/j.bioorg.2025.108395","url":null,"abstract":"<div><div>The therapeutic potential of adenosine receptor (AR) ligands is becoming increasingly important as our understanding of the physio-pathological functions of ARs advances. This study presents the synthesis and biological screening of six novel trisubstituted adenine analogues, expanding a previously reported series. The AR binding affinity and antiproliferative activity were evaluated for both the new and previously reported compounds, leading to the discovery of derivatives that displaying selective binding affinity towards <em>h</em>A₁AR. Compounds were synthesized using a cyclization approach by combining 4,6-bisalkylamino-5-aminopyrimidines with three different trialkyl/arylorthoesters, thereby generating adenines featuring three different substituents at the 8 position: H, methyl or phenyl. Most promising derivatives presented a phenyl ring at such position and displayed selective antagonistic activity against <em>h</em>A₁AR. <em>N</em>^<em>6</em>,9-diisopropyl-8-phenyl-9<em>H</em>-purin-6-amine (<strong>14c</strong>) was identified as the most potent compound with a K_i of 2 nM, motivating the synthesis of new derivatives including <em>N</em>^<em>6</em>,9-dicyclopentyl-8-phenyl-9<em>H</em>-purin-6-amine (<strong>19c</strong>). Docking modelling predicted key interactions between the lead compounds and <em>h</em>A₁AR. Determination of their anti-proliferative activity on six cancer cell lines found <strong>19c</strong> to be the most potent derivative with low micromolar EC₅₀ values. Our findings support further exploration around the adenine scaffold for cancer research and AR drug development.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108395"},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704563","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":"Acetylshikonin induces cell necroptosis via mediating mitochondrial function and oxidative stress-regulated signaling in human Oral Cancer cells","authors":"Kung-Yu Shao ,&nbsp;Sheng-Dean Luo ,&nbsp;Eng-Yen Huang ,&nbsp;Tsung-Ming Chang ,&nbsp;Lavanya Botcha ,&nbsp;Misbah Sehar ,&nbsp;Ju-Fang Liu ,&nbsp;Po-Kai Chuang","doi":"10.1016/j.bioorg.2025.108396","DOIUrl":"10.1016/j.bioorg.2025.108396","url":null,"abstract":"<div><div>Human oral squamous cell carcinoma (OSCC) represents a significant global health challenge, with conventional treatments showing limited efficacy in improving patient survival rates. To investigate the therapeutic potential of acetylshikonin on OSCC, we conducted comprehensive analyses including cell viability assays, flow cytometry, and molecular pathway investigations. Our findings demonstrate that acetylshikonin significantly inhibits OSCC cell proliferation with IC50 values of 3.81 μM and 5.87 μM in HSC3 and SCC4 cells respectively. Flow cytometry analysis revealed that acetylshikonin treatment significantly increased reactive oxygen species (ROS) production and decreased mitochondrial membrane potential in OSCC cells. Additionally, Western blot analysis showed enhanced phosphorylation of RIPK1, RIPK3, and MLKL proteins, indicating activation of the necroptotic pathway. The critical role of necroptosis was further confirmed using specific inhibitors (GSK872, Necrostatin-1, and 7-CL-O Nec-1), which significantly attenuated acetylshikonin-induced cell death. Transmission electron microscopy revealed distinct ultrastructural changes in cellular organelles, while decreased GPX4 expression suggested potential cross-activation of ferroptotic pathways. These data demonstrate that acetylshikonin suppresses OSCC growth through selective activation of oxidative stress-mediated necroptosis and mitochondrial dysfunction, identifying it as a promising natural compound for OSCC therapy through its ability to activate alternative cell death pathways and overcome traditional therapy limitations.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108396"},"PeriodicalIF":4.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747184","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":"A novel MMP-9 inhibitor exhibits selective inhibition in non-small-cell lung cancer harboring EGFR T790M mutation by blocking EGFR/STAT3 signaling pathway","authors":"Liangping Li ,&nbsp;Minghan Lu ,&nbsp;Hui Wang ,&nbsp;Xuesong Ma ,&nbsp;Wenqing Du ,&nbsp;Yufei Zhao ,&nbsp;Shulan Zeng ,&nbsp;Yan Peng ,&nbsp;Guohai Zhang","doi":"10.1016/j.bioorg.2025.108393","DOIUrl":"10.1016/j.bioorg.2025.108393","url":null,"abstract":"<div><div>The T790M secondary mutation in EGFR confers therapeutic resistance to EGFR-TKIs, leading to poor outcomes. Non-small-cell lung cancer (NSCLC) harboring EGFR T790M mutation is incurable and there is an urgent need for improved therapeutics. Here we report the identification of a small compound, <strong>MG-3C</strong>, that kills NSCLC cells with T790M mutation while sparing lung cancer cells without T790M mutation. We found that <strong>MG-3C</strong> activity targets EGFR-STAT3 signaling pathway in NSCLC through direct inhibition of matrix metalloproteinase 9 (MMP-9), ultimately leading to G2/M phase arrest, growth inhibition and apoptosis. Compared with the reported MMP-9 inhibitor Ilomastat, <strong>MG-3C</strong> shows high anticancer activity and affinity for targets. <strong>MG-3C</strong> forms hydrogen bonds with the ASP-113, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of −9.04 kcal/mol, while Ilomastat forms hydrogen bonds with the GLN-169, ASP-201 and HIS-203 amino acid residues of MMP-9 with a docking fraction of −5.98 kcal/mol. The spatial structure composed of ASP-113, ASP-201, and HIS-203 of MMP-9 provides a new coordinate for the design of MMP-9 inhibitors. Most importantly, subcutaneous and oral administration of <strong>MG-3C</strong> elicit dramatic regression of NSCLC xenograft tumors harboring T790M mutation as well as favorable biosafety profile in vivo, suggesting that <strong>MG-3C</strong> may be a potential candidate for NSCLC harboring T790M mutation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108393"},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687696","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":"Six isomers of diphenylheptane dimers from Zingiber officinale peel exert renal protection activities through anti-fibrosis and anti-inflammatory effects","authors":"Ying-Ying Si ,&nbsp;Ge-Ge Xia ,&nbsp;Hui-Ying Niu ,&nbsp;Hong-Bin Fang ,&nbsp;Yong-Xian Cheng ,&nbsp;Yan-Zhi Wang","doi":"10.1016/j.bioorg.2025.108394","DOIUrl":"10.1016/j.bioorg.2025.108394","url":null,"abstract":"<div><div>As the symbolic compounds in Zingiberaceae, most of diphenylheptane are exist in plants in the form of aglycones, and relatively rare dimers and glycosides of them have been found. A particular phytochemical investigation of <em>Zingiber officinale</em> peel led to the finding of six novel diphenylheptane dimers, including five aglycone isomers (<strong>1</strong>–<strong>5</strong>) and one new glycoside (<strong>6</strong>). Various spectroscopic and computational methods combined with acid hydrolysis were applied in their structurally elucidation. Biological evaluations of anti-inflammatory and anti-renal fibrosis activities of these compounds were carried out in vitro. Compounds <strong>1</strong>–<strong>5</strong> displayed effective anti-inflammatory activity in LPS induced RAW264.7 cells, especially that <strong>2</strong>, <strong>3</strong> and <strong>5</strong> reduced the production of iNOS at a low concentration of 0.625 μM. Compound <strong>3</strong> could significantly inhibit the expression of fibronectin, collagen I and <em>α</em>-SMA in TGF-<em>β</em>1 induced NRK-52e cells at 5 μM. The stereoscopic configurations of the diphenylheptane isomers can markedly influence the biological activities, and compound <strong>3</strong> is a potential molecule for kidney protection via inhibiting inflammation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108394"},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687695","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 biological evaluation of novel Trifluoromethylated Arylidene-hydrazinyl-thiazoles as neuroprotective agents","authors":"Ranjana Aggarwal ,&nbsp;Prince Kumar ,&nbsp;Suresh Kumar ,&nbsp;Saurabh Tiwari ,&nbsp;Rajnish Kumar Chaturvedi","doi":"10.1016/j.bioorg.2025.108390","DOIUrl":"10.1016/j.bioorg.2025.108390","url":null,"abstract":"<div><div>Neurodegenerative diseases, a substantial global health challenge affecting millions, underscore the pressing need for novel and effective pharmacotherapeutic drugs to address these disorders. In this concern, a library of novel trifluoromethylated arylidene-hydrazinyl-thiazoles has been synthesized and assessed for their anti-neurodegenerative potential. Multicomponent regioselective chemical transformation has been carried out utilizing thiosemicarbazide, trifluoromethylated 1,3-diketones and heteroaryl aldehydes in the presence of N-bromosuccinimide (NBS) in refluxing ethanol. The regioisomeric structure of the synthesized products was unambiguously characterized by employing heteronuclear 2D NMR spectroscopic studies. All the synthesized derivatives were evaluated for their anti-neurodegenerative properties on rat brain hippocampus-derived Neural Stem Cells (NSCs), examining their impact on survival, proliferation and neuronal differentiation <em>in vitro</em>. Among the tested thiazole derivatives, compounds <strong>4a</strong>, <strong>4b</strong>, <strong>4c</strong>, <strong>4f</strong>, <strong>4</strong> <strong>g</strong>, <strong>4b’</strong> and <strong>4i’</strong> demonstrated a remarkable increase in the number of neuronal cells as compared to the control group within the NSC culture and also exhibited the ability to promote NSC differentiation towards the neuronal lineage. Additionally, the selected compounds showed protection against amyloid beta (Aβ)-induced neurotoxicity in NSCs culture. Incorporating the trifluoromethyl group into the thiazole scaffold is a pivotal factor in augmenting biopotency, resulting in a marked increase in the count of neuronal cells compared to their non-fluorinated thiazole counterparts.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108390"},"PeriodicalIF":4.5,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697206","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 new marine-derived terphenyllin derivatives as potential antifoulants through structural optimization","authors":"Cui-Fang Wang ,&nbsp;Jie Hu ,&nbsp;Xiao-Ying Liu ,&nbsp;Yue-Xuan Qi ,&nbsp;Xi-Zhen Cao ,&nbsp;Wen-Jing Sun ,&nbsp;Ya-Jie Cheng ,&nbsp;Mei-Yan Wei ,&nbsp;Ji-Yong Zheng ,&nbsp;Chang-Lun Shao","doi":"10.1016/j.bioorg.2025.108389","DOIUrl":"10.1016/j.bioorg.2025.108389","url":null,"abstract":"<div><div>Marine biofouling remains a global problem, harming the maritime industries and ocean's ecosystem. Toxic antifoulants caused serious environmental pollution, which may enter human body through the food chain and affect human health. We searched for antifouling active compounds from the marine compound library, and a natural <em>p</em>-terphenyl metabolite, terphenyllin (<strong>1</strong>) and its derivatives (<strong>2</strong>–<strong>8</strong>) attracted our attention. Two 2′ or 4″ hydroxy group etherified derivatives (<strong>4</strong> and <strong>5</strong>) of terphenyllin showed antialgal activity. To improve its activity, twenty-four new terphenyllin derivatives (<strong>9</strong>–<strong>21</strong>, <strong>23</strong>–<strong>27</strong>, and <strong>29</strong>–<strong>34</strong>), along with two know derivatives (<strong>22</strong> and <strong>28</strong>), were designed and semisynthesized by halogenation, etherification, and acylation reactions. All the compounds were evaluated for their antifouling activity against diatoms <em>Navicula Exigua</em>, <em>N. Leavissima</em>, <em>Amphora Ovalis</em>, <em>Skeletonema Costatum</em>, and <em>Nitzschia closterium f. minutissima</em>. Twelve compounds (<strong>9</strong>–<strong>11</strong>, <strong>19</strong>, <strong>22</strong>–<strong>25</strong>, <strong>28</strong>, <strong>30</strong>–<strong>31</strong>, and <strong>34</strong>) displayed antialgal activities with EC₅₀ values from 1.2 to 9.8 μg/mL. Especially, compounds <strong>10</strong>, <strong>11</strong>, and <strong>25</strong> exhibited promising broad-spectrum antifouling activity (EC₅₀ = 1.2–3.6 μg/mL) with lower ecotoxicity (LC₅₀ &gt; 150 μg/mL), which were approximately equivalent to the commercial antifouling agent Econea (EC₅₀ = 0.5–1.1 μg/mL). It was worth noting that compound <strong>9</strong> (EC₅₀ = 2.0 μg/mL, LC₅₀ &gt; 150 μg/mL) showed potential antifouling activity against the settlement of the macrofouling species Mussel <em>Mytilus edulis</em>. The preliminary structure−activity relationships of these compounds were also discussed. In conclusion, this study provided promising antifouling compounds, which were poised for further development as new environmentally friendly antifoulants.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108389"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687694","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":"Targeting anti-apoptotic mechanisms in tumour cells: Strategies for enhancing Cancer therapy","authors":"Benu Chaudhary ,&nbsp;Preeti Arya ,&nbsp;Vikas Sharma ,&nbsp;Parveen Kumar ,&nbsp;Deepak Singla ,&nbsp;Ajmer Singh Grewal","doi":"10.1016/j.bioorg.2025.108388","DOIUrl":"10.1016/j.bioorg.2025.108388","url":null,"abstract":"<div><div>Anti-cancer drug's cytotoxicity is determined by their ability to induce predetermined cell demise, commonly called apoptosis. The cancer-causing cells are able to evade cell death, which has been affiliated with both malignancy as well as resistance to cancer treatments. In order to avoid cell death, cancerous tumour cells often produce an abundance of anti-apoptotic proteins, becoming “dependent” on them. Consequently, protein inhibitors of cell death may prove to be beneficial as pharmacological targets for the future creation of cancer therapies. This article examines the molecular routes of apoptosis, its clinical manifestations, anti-cancer therapy options that target the intrinsic mechanism of apoptosis, proteins that prevent cell death, and members of the B-lymphoma-2 subset. In addition, novel approaches to cell death are highlighted, including how curcumin mitigates chemotherapy-induced apoptosis in healthy tissues and the various ways melatonin modifies apoptosis to improve cancer treatment efficacy, particularly through the TNF superfamily. Cancer treatment-induced increases in anti-apoptotic proteins lead to drug resistance; yet, ligands that trigger cell death by inhibiting these proteins are expected to improve chemotherapy's efficacy. The potential of frequency-modulated dietary phytochemicals as a cancer therapeutic pathway, including autophagy and apoptosis, is also explored. This approach may be more efficient than inhibition alone in overcoming drug resistance. Consequently, this method has the potential to allow for lower medication concentrations, reducing cytotoxicity and unwanted side effects.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108388"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643794","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":"New pyrrolo[3,4-d] isoxazolidines hybrid with furan as antitumor agents and multi-target enzyme inhibitors: Synthesis and in silico study","authors":"Awad I. Said ,&nbsp;Wafaa A. Ewes ,&nbsp;Abdelrahman Hamdi ,&nbsp;Ahmed A. El-Rashedy ,&nbsp;Mostafa Ahmed","doi":"10.1016/j.bioorg.2025.108377","DOIUrl":"10.1016/j.bioorg.2025.108377","url":null,"abstract":"<div><div>Herein, new Pyrrolo[3,4-<em>d</em>] isoxazolidines hybrid with furan were synthesized by 1,3-dipolar cycloaddition reaction of nitrone <strong>2</strong> with N-substituted maleimides <strong>3a-j</strong>. The synthesized compounds were screened <em>in vitro</em> cytotoxic assay against four cancer cell lines namely, HeLa, HEPG-2, HCT-116 and MCF-7 using doxorubicin (DOX) as a reference using MTT assay. The results demonstrated that compounds <strong>4b</strong> and <strong>4j</strong> exhibited the highest antitumor activity with IC₅₀ =6.22–16.44  μM in comparable to DOX (IC₅₀ = 4.17–5.57μM). The most active hybrids <strong>4b</strong> and <strong>4j</strong> were further subjected to multi-targeting assays against EGFR, VEGFR-2, and Topo II. They showed good to moderate inhibitory activities. In addition, flow cytometric analysis of <strong>4b</strong> and <strong>4j</strong> inhibited cell population of MCF-7 cells in the S phase. Compound <strong>4b</strong>, and <strong>4j</strong> were further evaluated using molecular docking and dynamics simulations (20 ns) and the EGFR, TOPII, or VEGFR-2 receptor protein. All the data sets accurately predict the strongest binding affinity for the selected compounds, as evidenced by the highest free binding energy from MM/GBSA calculations and significant amino acid steric interactions. Furthermore, the RMS/RMSF/Rg/SASA dynamics parameters show the formed complexes demonstrate satisfactory stability. The ADMET properties indicate that the selected new ligands have shown a promising drug-like profile and can be considered potential candidates for future anti-cancer therapies, with perspective validating their anticancer activity by <em>in vitro</em> studies.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108377"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143687774","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":"The use of the white biotechnology toolkit to edit natural purines for studying their anticancer activity via mTOR pathway","authors":"Ahmed M. Younis ,&nbsp;Ghada Attia ,&nbsp;Mohamed M. Saleh ,&nbsp;Mahmoud A.A. Ibrahim ,&nbsp;Mohamed-Elamir F. Hegazy ,&nbsp;Paul W. Paré ,&nbsp;Mohamed A. El-Tayeb ,&nbsp;Peter A. Sidhom ,&nbsp;Amal Kabbash ,&nbsp;Abdel-Rahim S. Ibrahim","doi":"10.1016/j.bioorg.2025.108391","DOIUrl":"10.1016/j.bioorg.2025.108391","url":null,"abstract":"<div><div>Purine alkaloids were proven to have significant cytotoxic activity against different cancer cell lines via modulating several cellular pathways, leading to inhibition of cell proliferation and increasing cell death. The search for new potential cytotoxic compounds produced by natural eco-friendly means is of great importance. The microbial transformation of natural purine alkaloids, caffeine (Cf), theophylline (Tp), theobromine (Tb), and theacrine (Tc) via filamentous fungi was explored using <em>Aspergillus versicolor</em> (AUMC 4807), <em>Aspergillus niger</em> (NRRL 328), <em>Cunninghamella echinulata</em> (ATCC 1382), and <em>Penicillium chrysogeneum</em> (ATCC 9480). Nine metabolites were isolated via demethylation, and oxidation reactions, namely; 1.3.7-trimethyl uric acid (<strong>M1</strong>), theacrine (<strong>M2</strong>), theobromine (<strong>M3</strong>), paraxanthine (<strong>M4</strong>), theophylline (<strong>M5</strong>), 3-methylxanthine (<strong>M6</strong>), caffeine (<strong>M7</strong>), 7-methylxanthine (<strong>M8</strong>) and 3,7,9-trimethyl uric acid (<strong>M9</strong>). The structure elucidation of the metabolites was based primarily on 1D, 2D-NMR analyses and HRMS. <em>In vitro</em> cytotoxic activity of metabolites was evaluated against CNS (SNB-75) and melanoma (MDA-MB-435) cancer cell lines. Based on the pharmacophore and structural similarity, mTOR enzyme inhibition assay was carried out, and results were confirmed by molecular docking and molecular dynamic studies using mTOR as the target enzyme. Furthermore, the binding mode of <strong>M9</strong> with mTOR was investigated using docking computations. The steadiness and binding affinities of compound <strong>M9</strong> in complex with mTOR were estimated and compared to caffeine (<strong>M7</strong>) over the 100 ns MD course. Results confirmed that <strong>M9</strong> has great potential as a cytotoxic agent with experimentally proved safety that can be produced by biotransformation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"159 ","pages":"Article 108391"},"PeriodicalIF":4.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143704564","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)00263-9","DOIUrl":"10.1016/S0045-2068(25)00263-9","url":null,"abstract":"","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"158 ","pages":"Article 108383"},"PeriodicalIF":4.5,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}