Two novel alkaloids, pegaharmolinones A and B (1–2), featuring an unprecedented 6/6/5/5 tetracyclic skeleton based on a 1,4-dihydro-6H-pyrrolo[2′,3′:3,4]pyrrolo[2,1-b]quinazolin-6-one core, and nineteen undescribed alkaloids, including luotonins G–L (3–7, 11) and pegaharmnolines A–K (18–22, 26, 29–30, 33–35), as well as fourteen known analogs, were isolated from the aerial parts of Peganum harmala. Their structures and absolute configurations were determined through analysis of NMR, HR-ESI-MS spectroscopic data, and ECD calculations, supported by a strategy of CASE-DFT. A plausible biosynthetic pathway for 1 and 2 was proposed. The anticancer activity in vitro was evaluated using the CCK-8 method, revealing that compound 22 exhibited potent efficacy and high selectivity, with an IC50 value of 6.49 μM and a selectivity index greater than 10. A series of bioassay suggested that 22 significantly suppressed the proliferation and migration of Hep G2 cells, and induced mitochondria-mediated apoptosis through both intrinsic and extrinsic pathways. Moreover, the SAR analysis of the tested active compounds provides structural modification strategies for the natural lead candidates 2 and 22.
{"title":"Identification of quinazolinone and quinoline alkaloids from Peganum harmala L. inducing mitochondria-mediated apoptosis in liver cancer","authors":"Qin Zhang, Jin-Zheng Yu, Chun-Lei Yuan, Fan-Zhu Meng, Meng-Yue Yang, Han-Gao Yang, Fang-Shen Liu, Sheng-Ge Li, Ying Zhang, Yi-Yang Liu, Yan-Hui Zan, Da-Hong Li, Hui-Ming Hua","doi":"10.1016/j.bioorg.2026.109528","DOIUrl":"10.1016/j.bioorg.2026.109528","url":null,"abstract":"<div><div>Two novel alkaloids, pegaharmolinones A and B (<strong>1–2</strong>), featuring an unprecedented 6/6/5/5 tetracyclic skeleton based on a 1,4-dihydro-6<em>H</em>-pyrrolo[2′,3′:3,4]pyrrolo[2,1-<em>b</em>]quinazolin-6-one core, and nineteen undescribed alkaloids, including luotonins G–L (<strong>3–7</strong>, <strong>11</strong>) and pegaharmnolines A–K (<strong>18–22</strong>, <strong>26</strong>, <strong>29–30</strong>, <strong>33–35</strong>), as well as fourteen known analogs, were isolated from the aerial parts of <em>Peganum harmala</em>. Their structures and absolute configurations were determined through analysis of NMR, HR-ESI-MS spectroscopic data, and ECD calculations, supported by a strategy of CASE-DFT. A plausible biosynthetic pathway for <strong>1</strong> and <strong>2</strong> was proposed. The anticancer activity in vitro was evaluated using the CCK-8 method, revealing that compound <strong>22</strong> exhibited potent efficacy and high selectivity, with an IC<sub>50</sub> value of 6.49 μM and a selectivity index greater than 10. A series of bioassay suggested that <strong>22</strong> significantly suppressed the proliferation and migration of Hep G2 cells, and induced mitochondria-mediated apoptosis through both intrinsic and extrinsic pathways. Moreover, the SAR analysis of the tested active compounds provides structural modification strategies for the natural lead candidates <strong>2</strong> and <strong>22</strong>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"171 ","pages":"Article 109528"},"PeriodicalIF":4.7,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146076914","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}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109527
Yuxiao Xia , Jianpeng Cao , Dongkun Xu , Xue Jiang , Qian Liu , Lina Liu , Wenling Tu , Ying Huang , Quanyu Zhou , Yuhong Shi , Hua Pang
Objective
Prolonging the systemic half-life of fibroblast-activation-protein inhibitors (FAPIs) through an albumin-binding module is an attractive strategy to amplify intratumoral dose delivery. We report a head-to-head comparison of the identical scaffold FAPI-X5 labeled with 68Ga, 177Lu and the emerging 47Sc.
Methods
FAPI-X5 was designed by in-silico docking, synthesized, and radiolabeled with 68Ga, 177Lu or 47Sc. Radiochemical purity, stability, lipophilicity, albumin binding, cellular uptake, biodistribution, micro-PET/SPECT imaging and single-dose radiotherapy (18.5–55.5 MBq) were evaluated in U87MG-FAP tumor-bearing mice.
Results
All conjugates showed >95% radiochemical purity and > 40% albumin binding. 68Ga-FAPI-X5 achieved rapid tumor uptake (23.6%ID/g at 2 h) and a tumor-to-liver SUVmean ratio of 1.3, enabling high-contrast PET imaging. 177Lu- and 47Sc-FAPI-X5 exhibited prolonged tumor retention but prominent hepatic accumulation (34%ID/g for 47Sc at 2 h), yielding tumor-to-liver SUVmean ≤0.28 and simplified hepatic absorbed doses >30 Gy. 47Sc-FAPI-X5 additionally displayed elevated bone uptake (17%ID/g) and marrow doses 35–60% higher than the 177Lu analogue. Therapy studies showed only cytostatic effects (T/C 36–43%) accompanied by dose-dependent hepatogastrointestinal toxicity.
Conclusion
While 68Ga-FAPI-X5 is a promising PET tracer, the unfavorable tumor-to-liver and tumor-to-bone ratios of 47Sc-FAPI-X5 preclude its clinical translation. Future 47Sc-FAPI development must prioritize scandium-optimized chelators and nephrophilic scaffold redesign.
{"title":"Comparative study of 47Sc and 177Lu-labeled albumin binder-conjugated FAPI radiopharmaceuticals","authors":"Yuxiao Xia , Jianpeng Cao , Dongkun Xu , Xue Jiang , Qian Liu , Lina Liu , Wenling Tu , Ying Huang , Quanyu Zhou , Yuhong Shi , Hua Pang","doi":"10.1016/j.bioorg.2026.109527","DOIUrl":"10.1016/j.bioorg.2026.109527","url":null,"abstract":"<div><h3>Objective</h3><div>Prolonging the systemic half-life of fibroblast-activation-protein inhibitors (FAPIs) through an albumin-binding module is an attractive strategy to amplify intratumoral dose delivery. We report a head-to-head comparison of the identical scaffold FAPI-X5 labeled with <sup>68</sup>Ga, <sup>177</sup>Lu and the emerging <sup>47</sup>Sc.</div></div><div><h3>Methods</h3><div>FAPI-X5 was designed by in-silico docking, synthesized, and radiolabeled with <sup>68</sup>Ga, <sup>177</sup>Lu or <sup>47</sup>Sc. Radiochemical purity, stability, lipophilicity, albumin binding, cellular uptake, biodistribution, micro-PET/SPECT imaging and single-dose radiotherapy (18.5–55.5 MBq) were evaluated in U87MG-FAP tumor-bearing mice.</div></div><div><h3>Results</h3><div>All conjugates showed >95% radiochemical purity and > 40% albumin binding. <sup>68</sup>Ga-FAPI-X5 achieved rapid tumor uptake (23.6%ID/g at 2 h) and a tumor-to-liver SUVmean ratio of 1.3, enabling high-contrast PET imaging. <sup>177</sup>Lu- and <sup>47</sup>Sc-FAPI-X5 exhibited prolonged tumor retention but prominent hepatic accumulation (34%ID/g for <sup>47</sup>Sc at 2 h), yielding tumor-to-liver SUVmean ≤0.28 and simplified hepatic absorbed doses >30 Gy. <sup>47</sup>Sc-FAPI-X5 additionally displayed elevated bone uptake (17%ID/g) and marrow doses 35–60% higher than the <sup>177</sup>Lu analogue. Therapy studies showed only cytostatic effects (T/C 36–43%) accompanied by dose-dependent hepatogastrointestinal toxicity.</div></div><div><h3>Conclusion</h3><div>While <sup>68</sup>Ga-FAPI-X5 is a promising PET tracer, the unfavorable tumor-to-liver and tumor-to-bone ratios of <sup>47</sup>Sc-FAPI-X5 preclude its clinical translation. Future <sup>47</sup>Sc-FAPI development must prioritize scandium-optimized chelators and nephrophilic scaffold redesign.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109527"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016708","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}
The development of new antitubercular drugs is critically hindered by the persistent and adaptive nature of Mycobacterium tuberculosis (Mtb), underscoring an urgent need for innovative therapeutic strategies. In this work, a series of structurally varied 2-aminothiophene and 2-aminothiazole derivatives was designed, synthesized, and characterized using FT-IR, NMR, HRMS, and single-crystal X-ray techniques. The thiophene analogues were prepared via the Gewald reaction, while thiazole derivatives were obtained through Hantzsch synthesis, with structural diversity achieved by modifying alkyl, ester, and fused ring groups. Several compounds exhibited potent antitubercular activity against Mtb H37Rv, with 4h, 4k, and 4l showing MIC values of 0.78 μg/mL, comparable to the standard drug Ethambutol. SAR studies revealed that linear alkyl chains enhanced activity, whereas aryl and fused rings were less favourable. Additionally, compounds 4q, 4s, 7g, 7o, and 9e emerged as moderate antibacterial leads against both Gram-positive and Gram-negative bacteria. Cytotoxicity assays for the potent compounds were performed in Vero cells and THP-1 cells, supporting a favourable safety profile and selective activity against Mtb. Furthermore, target prediction, molecular docking, along with DFT and ADMET analyses, provided valuable insights into their putative molecular targets, binding modes, and the drug-like and electronic properties that influence bioactivity. Collectively, these results identify compound 4k as a promising lead candidate against Mtb, underscoring the potential of the 2-aminothiophene scaffold as a valuable framework for antitubercular drug discovery. These findings encourage further exploration of 2-aminothiophene and 2-aminothiazole scaffolds by medicinal chemists for the development of novel, potent, and selective antitubercular and antibacterial drug candidates.
{"title":"2-Aminothiophene and 2-aminothiazole scaffolds as potent antimicrobial agents: Design, synthesis, biological evaluation, and computational insights","authors":"Munugala Chandrakanth , Jyothi Kumari , Paramita Pakhira , Dharmarajan Sriram , Siddhardha Busi , Sampathkumar Ranganathan , Chandni Kumari , Sonam Bisla , Mukesh Pasupuleti , Ramesh Gondru , Jesu Arockiaraj , Janardhan Banothu","doi":"10.1016/j.bioorg.2026.109511","DOIUrl":"10.1016/j.bioorg.2026.109511","url":null,"abstract":"<div><div>The development of new antitubercular drugs is critically hindered by the persistent and adaptive nature of <em>Mycobacterium tuberculosis (Mtb)</em>, underscoring an urgent need for innovative therapeutic strategies. In this work, a series of structurally varied 2-aminothiophene and 2-aminothiazole derivatives was designed, synthesized, and characterized using FT-IR, NMR, HRMS, and single-crystal X-ray techniques. The thiophene analogues were prepared <em>via</em> the Gewald reaction, while thiazole derivatives were obtained through Hantzsch synthesis, with structural diversity achieved by modifying alkyl, ester, and fused ring groups. Several compounds exhibited potent antitubercular activity against <em>Mtb H37Rv</em>, with <strong>4</strong><strong>h</strong>, <strong>4</strong><strong>k</strong>, and <strong>4</strong><strong>l</strong> showing MIC values of 0.78 μg/mL, comparable to the standard drug Ethambutol. SAR studies revealed that linear alkyl chains enhanced activity, whereas aryl and fused rings were less favourable. Additionally, compounds <strong>4q</strong>, <strong>4</strong><strong>s</strong>, <strong>7</strong><strong>g, 7o</strong>, and <strong>9e</strong> emerged as moderate antibacterial leads against both Gram-positive and Gram-negative bacteria. Cytotoxicity assays for the potent compounds were performed in Vero cells and THP-1 cells, supporting a favourable safety profile and selective activity against <em>Mtb</em>. Furthermore, target prediction, molecular docking, along with DFT and ADMET analyses, provided valuable insights into their putative molecular targets, binding modes, and the drug-like and electronic properties that influence bioactivity. Collectively, these results identify compound <strong>4</strong><strong>k</strong> as a promising lead candidate against <em>Mtb</em>, underscoring the potential of the 2-aminothiophene scaffold as a valuable framework for antitubercular drug discovery. These findings encourage further exploration of 2-aminothiophene and 2-aminothiazole scaffolds by medicinal chemists for the development of novel, potent, and selective antitubercular and antibacterial drug candidates.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109511"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035019","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}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109525
Xinmo Gui , Jie Wang , Xian Wang , Min Xie , Guangyuan Yin , Liangkai Shao , Liqing Zheng , Peixin Han , Jiong Zhang
Carbonic anhydrase represents a highly promising target in drug discovery, as the dysregulation or overexpression of its various isoforms in humans is closely associated with a range of diseases. Carbonic anhydrase inhibitors can modulate the activity of human carbonic anhydrases, thereby exerting diuretic, anti-glaucoma, antiepileptic, analgesic, antitumor, and anti-obesity effects. In this study, to obtain structurally diverse human carbonic anhydrase inhibitors, we employed a modular click chemistry library strategy to construct 401 para-aryl sulfonamide-triazoles in 96-well plates. Through this diversity-oriented clicking approach followed by enzymatic activity screening, we identified 16 hit compounds that exhibit potent inhibitory activity against hCA II with considerable structural diversity. Among them, compounds 3o and 3h showed excellent inhibitory activity against hCA II, with Ki values of 1.65 nM and 2.26 nM, respectively, while compounds such as 3e also demonstrated certain selectivity among different hCA isoforms. Furthermore, these compounds displayed favorable predicted drug-like properties.
{"title":"Diversity-oriented synthesis of Para-aryl Sulfonamides as potent human carbonic anhydrase inhibitors via modular click chemistry","authors":"Xinmo Gui , Jie Wang , Xian Wang , Min Xie , Guangyuan Yin , Liangkai Shao , Liqing Zheng , Peixin Han , Jiong Zhang","doi":"10.1016/j.bioorg.2026.109525","DOIUrl":"10.1016/j.bioorg.2026.109525","url":null,"abstract":"<div><div>Carbonic anhydrase represents a highly promising target in drug discovery, as the dysregulation or overexpression of its various isoforms in humans is closely associated with a range of diseases. Carbonic anhydrase inhibitors can modulate the activity of human carbonic anhydrases, thereby exerting diuretic, anti-glaucoma, antiepileptic, analgesic, antitumor, and anti-obesity effects. In this study, to obtain structurally diverse human carbonic anhydrase inhibitors, we employed a modular click chemistry library strategy to construct 401 <em>para</em>-aryl sulfonamide-triazoles in 96-well plates. Through this diversity-oriented clicking approach followed by enzymatic activity screening, we identified 16 hit compounds that exhibit potent inhibitory activity against hCA II with considerable structural diversity. Among them, compounds <strong>3o</strong> and <strong>3h</strong> showed excellent inhibitory activity against hCA II, with K<sub>i</sub> values of 1.65 nM and 2.26 nM, respectively, while compounds such as <strong>3e</strong> also demonstrated certain selectivity among different hCA isoforms. Furthermore, these compounds displayed favorable predicted drug-like properties.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109525"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034947","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}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109494
Ghada M. Sadiq , Mohamed A. Mawhoup , Mai M.M. Tawfik , Mahmoud Mostafa , Amany Abdelaziz , Ramadan Yahia , Rehab Mahmoud Abd El-Baky , Mohamed Abdel-Aziz , Gamal El-Din A. Abuo-Rahma , Aliaa M. Mohassab
A series of novel phenylpiperazine-based carbodithioate derivatives (3a–j) were designed, synthesized, formulated as PEG-Niosomes and evaluated for their potential hydrogen sulphide (H2S) donating properties and their antifungal activities. Structural modifications were inspired by the antifungal drug tolnaftate, incorporating a dithiocarbamate moiety to enhance biological activity and target engagement. H2S-releasing capacity was quantified via the methylene blue assay. Compound 3j (S-phenacyl p-chloro derivative) exhibiting the highest release (89.71%), followed by compounds 3a and 3i. Antifungal efficacy against Candida albicans was determined using the microbroth dilution method, where compounds 3a, 3b, 3f, 3i and 3j demonstrated potent inhibitory activity (MIC = 4.68 μg/mL), exceeding that of fluconazole. Further investigations revealed that these compounds also effectively suppressed hyphal formation and biofilm development, two major virulence factors of C. albicans. Notably, compound 3j exhibited superior performance across all assays. In a preliminary safety evaluation, compound 3j displayed low cytotoxicity toward mammalian fibroblasts (WS-1) (IC₅₀ = 65.73 ± 4.20 μg/mL) compared to doxorubicin (IC₅₀ = 26.72 ± 2.20 μg/mL), providing an 14-fold selectivity index relative to its antifungal MIC (4.68 μg/mL). Molecular docking studies corroborated these findings by showing favorable binding of compound 3j to the lanosterol 14α-demethylase enzyme (CYP51), highlighting π–sulfur and hydrophobic interactions critical for binding affinity. Additionally, compound 3j directly inhibited CYP51 in vitro (IC₅₀ = 0.331 ± 0.025 μM), showing stronger inhibition than the reference azole fluconazole (IC₅₀ = 1.388 ± 0.099 μM. H₂S release was also verified by scavenger reversal. In the presence of MgO (1.5 mg/mL), the antifungal activity of compound 3j decreased, with the MIC rising to 32 μg/mL. These results underscore the potential of phenylpiperazine dithioates, particularly compound 3j, as promising antifungal agent with multi-target activity. Additionally, the PEG-Niosomes of compound 3j represent a promising delivery system for enhancing the dissolution and potential bioavailability of compound 3j.
{"title":"Phenylpiperazine/dithioates as novel H2S donors: design, synthesis, H2S release, formulation as PEG-niosomes and antifungal activity against Candida albicans","authors":"Ghada M. Sadiq , Mohamed A. Mawhoup , Mai M.M. Tawfik , Mahmoud Mostafa , Amany Abdelaziz , Ramadan Yahia , Rehab Mahmoud Abd El-Baky , Mohamed Abdel-Aziz , Gamal El-Din A. Abuo-Rahma , Aliaa M. Mohassab","doi":"10.1016/j.bioorg.2026.109494","DOIUrl":"10.1016/j.bioorg.2026.109494","url":null,"abstract":"<div><div>A series of novel phenylpiperazine-based carbodithioate derivatives <strong>(3a–j)</strong> were designed, synthesized, formulated as PEG-Niosomes and evaluated for their potential hydrogen sulphide (H<sub>2</sub>S) donating properties and their antifungal activities. Structural modifications were inspired by the antifungal drug tolnaftate, incorporating a dithiocarbamate moiety to enhance biological activity and target engagement. H<sub>2</sub>S-releasing capacity was quantified <em>via</em> the methylene blue assay. Compound <strong>3j</strong> (S-phenacyl p-chloro derivative) exhibiting the highest release (89.71%), followed by compounds <strong>3a</strong> and <strong>3i</strong>. Antifungal efficacy against <em>Candida albicans</em> was determined using the microbroth dilution method, where compounds <strong>3a, 3b, 3f, 3i</strong> and <strong>3j</strong> demonstrated potent inhibitory activity (MIC = 4.68 μg/mL), exceeding that of fluconazole. Further investigations revealed that these compounds also effectively suppressed hyphal formation and biofilm development, two major virulence factors of <em>C. albicans</em>. Notably, compound <strong>3j</strong> exhibited superior performance across all assays. In a preliminary safety evaluation, compound <strong>3j</strong> displayed low cytotoxicity toward mammalian fibroblasts (WS-1) (IC₅₀ = 65.73 ± 4.20 μg/mL) compared to doxorubicin (IC₅₀ = 26.72 ± 2.20 μg/mL), providing an 14-fold selectivity index relative to its antifungal MIC (4.68 μg/mL). Molecular docking studies corroborated these findings by showing favorable binding of compound <strong>3j</strong> to the lanosterol 14α-demethylase enzyme (CYP51), highlighting π–sulfur and hydrophobic interactions critical for binding affinity. Additionally, compound <strong>3j</strong> directly inhibited CYP51 <em>in vitro</em> (IC₅₀ = 0.331 ± 0.025 μM), showing stronger inhibition than the reference azole fluconazole (IC₅₀ = 1.388 ± 0.099 μM. H₂S release was also verified by scavenger reversal. In the presence of MgO (1.5 mg/mL), the antifungal activity of compound <strong>3j</strong> decreased, with the MIC rising to 32 μg/mL. These results underscore the potential of phenylpiperazine dithioates, particularly compound <strong>3j</strong>, as promising antifungal agent with multi-target activity. Additionally, the PEG-Niosomes of compound <strong>3j</strong> represent a promising delivery system for enhancing the dissolution and potential bioavailability of compound <strong>3j</strong>.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109494"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035021","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}
Pub Date : 2026-01-19DOI: 10.1016/j.bioorg.2026.109521
Bo Cui , Yulin Song , Xueran Wang , Yuxuan Wang , Xinyuan Chen , Shuai Yu , Deao Man , Haidan Yuan, Guangchun Piao, Yushun Tian
Despite significant advances in cancer treatment in recent years, existing therapies still exhibit notable limitations. Consequently, the continuous development of novel anticancer agents remains paramount. Natural products remain the major source for discovering highly effective and low-toxicity anticancer drug leads. Isoalantolactone, a natural product, demonstrates diverse pharmacological activities, including anti-inflammatory and anticancer effects, but suffers from drawbacks such as poor water solubility, necessitating structural modifications. The enzyme Poly (ADP-ribose) polymerase 1 (PARP1) is a key therapeutic target in breast cancer and its inhibition represents a vital advancement in cancer treatment. In this study, in silico molecular docking was employed to identify binding sites between isoalantolactone and the PARP1 protein. Subsequently, thirty-four of isoalantolactone-benzylamine derivatives were synthesized. Among them, compound 3-(((3,4,5-trimethoxybenzyl)amino) methyl)-3-demethylene isoalantolactone (3f) exhibited potent inhibitory activity against MCF-7 cells (IC50 = 3.67 μM), which represented a ∼ 7-fold improvement over isoalantolactone itself and demonstrated markedly enhanced solubility. And, MCF-7 cancer cells take up 3 f from the culture environment much more efficiently than L-02 normal cells. The molecular docking results showed that 3 f binds to PARP1 through multiple interactions, exhibiting significantly more interaction bonds than isoalantolactone, and ELISA assays confirmed that 3 f potently inhibits intracellular PARP1 of MCF-7 cancer cells. Moreover, 3 f suppresses the enzymatic function of PARP1 and inhibits the PARP1-mediated DNA damage repair pathway by elevating γH2AX expression levels. In vitro, compound 3 f exhibited significant dose-dependent anti-cancer activity, inhibiting MCF-7 cancer cell migration, invasion, COL1 protein expression and colony formation. It also significantly elevated intracellular reactive oxygen species (ROS) levels in MCF-7 cancer cells. Additionally, 3 f markedly decreased the mitochondrial membrane potential of MCF-7 cells, which may have led to their apoptosis and death. These findings suggest that 3 f acts as a novel PARP1 inhibitor and holds considerable promise for future breast cancer therapy.
{"title":"Design, synthesis and biological evaluation of novel isoalantolactone-benzylamine derivatives leading to the discovery of a PARP1 inhibitor with selective cytotoxicity against MCF-7 breast cancer cells","authors":"Bo Cui , Yulin Song , Xueran Wang , Yuxuan Wang , Xinyuan Chen , Shuai Yu , Deao Man , Haidan Yuan, Guangchun Piao, Yushun Tian","doi":"10.1016/j.bioorg.2026.109521","DOIUrl":"10.1016/j.bioorg.2026.109521","url":null,"abstract":"<div><div>Despite significant advances in cancer treatment in recent years, existing therapies still exhibit notable limitations. Consequently, the continuous development of novel anticancer agents remains paramount. Natural products remain the major source for discovering highly effective and low-toxicity anticancer drug leads. Isoalantolactone, a natural product, demonstrates diverse pharmacological activities, including anti-inflammatory and anticancer effects, but suffers from drawbacks such as poor water solubility, necessitating structural modifications. The enzyme Poly (ADP-ribose) polymerase 1 (PARP1) is a key therapeutic target in breast cancer and its inhibition represents a vital advancement in cancer treatment. In this study, in silico molecular docking was employed to identify binding sites between isoalantolactone and the PARP1 protein. Subsequently, thirty-four of isoalantolactone-benzylamine derivatives were synthesized. Among them, compound 3-(((3,4,5-trimethoxybenzyl)amino) methyl)-3-demethylene isoalantolactone (<strong>3f</strong>) exhibited potent inhibitory activity against MCF-7 cells (IC<sub>50</sub> = 3.67 μM), which represented a ∼ 7-fold improvement over isoalantolactone itself and demonstrated markedly enhanced solubility. And, MCF-7 cancer cells take up <strong>3 f</strong> from the culture environment much more efficiently than L-02 normal cells. The molecular docking results showed that <strong>3 f</strong> binds to PARP1 through multiple interactions, exhibiting significantly more interaction bonds than isoalantolactone, and ELISA assays confirmed that <strong>3 f</strong> potently inhibits intracellular PARP1 of MCF-7 cancer cells. Moreover, <strong>3 f</strong> suppresses the enzymatic function of PARP1 and inhibits the PARP1-mediated DNA damage repair pathway by elevating γH2AX expression levels. In vitro, compound <strong>3 f</strong> exhibited significant dose-dependent anti-cancer activity, inhibiting MCF-7 cancer cell migration, invasion, COL1 protein expression and colony formation. It also significantly elevated intracellular reactive oxygen species (ROS) levels in MCF-7 cancer cells. Additionally, <strong>3 f</strong> markedly decreased the mitochondrial membrane potential of MCF-7 cells, which may have led to their apoptosis and death. These findings suggest that <strong>3 f</strong> acts as a novel PARP1 inhibitor and holds considerable promise for future breast cancer therapy.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109521"},"PeriodicalIF":4.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027911","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}
Pub Date : 2026-01-18DOI: 10.1016/j.bioorg.2026.109522
Alexandra K. Kennedy , Miguel Angel Herrera-Rueda , Reese Wilby , Frank Wuest , Paul LaPointe
Radiotheragnostics is a promising but still developing approach for cancer diagnosis and treatment, limited by the availability of high-affinity, targetable proteins. One such target is the 90 kDa heat shock protein (Hsp90), a chaperone essential for protein folding and stabilization. Cancer cells rely heavily on Hsp90, and its inhibitors show tumor-selective retention. Onalespib (AT13387), a potent Hsp90 inhibitor in phase III clinical trials, was used as a reference for the design of new compounds harbouring atoms with potential for radiotheragnostics. We synthesized 10 Onalespib analogues, modifying the isopropyl group on the resorcinol moiety with bulky atoms like bromine and iodine to mimic its steric effects. The piperazine ring was also substituted with chiral scaffolds using R/S quinuclidine and R/S piperidine to assess the influence of stereochemistry on biological activity. Binding assays showed that non-chiral compounds 12 and 17 had the lowest affinity for Hsp90, while R-stereochemistry analogues 16 and 21 had the highest. Brominated analogues 17, 20, and 21 exhibited strong disruption of Hsp90 client signaling in cell-based assays. Microscopy confirmed that the new compounds did not alter Hsp90 localization. Our preliminary Structure-Activity Relationship (SAR) study, indicates the following. First, the substitution of the isopropyl group with iodine or bromine preserves Hsp90 inhibitory function. Second, R-stereochemistry in these compounds plays a key role in the affinity for Hsp90. Finally, less bulky substituents (i.e. bromine) have stronger Hsp90 inhibition properties than more bulky ones (i.e. iodine). Compound 21, in particular, emerged as a lead compound and will be radiolabeled with 76/77Br as a radiotheragnostic agent for PET imaging (76Br) and Meitner-Auger electron therapy (77Br).
{"title":"Novel Hsp90 inhibitors as leads for the development of radiotheragnostics for Meitner-Auger electron therapy","authors":"Alexandra K. Kennedy , Miguel Angel Herrera-Rueda , Reese Wilby , Frank Wuest , Paul LaPointe","doi":"10.1016/j.bioorg.2026.109522","DOIUrl":"10.1016/j.bioorg.2026.109522","url":null,"abstract":"<div><div>Radiotheragnostics is a promising but still developing approach for cancer diagnosis and treatment, limited by the availability of high-affinity, targetable proteins. One such target is the 90 kDa heat shock protein (Hsp90), a chaperone essential for protein folding and stabilization. Cancer cells rely heavily on Hsp90, and its inhibitors show tumor-selective retention. Onalespib (AT13387), a potent Hsp90 inhibitor in phase III clinical trials, was used as a reference for the design of new compounds harbouring atoms with potential for radiotheragnostics. We synthesized 10 Onalespib analogues, modifying the isopropyl group on the resorcinol moiety with bulky atoms like bromine and iodine to mimic its steric effects. The piperazine ring was also substituted with chiral scaffolds using R/S quinuclidine and R/S piperidine to assess the influence of stereochemistry on biological activity. Binding assays showed that non-chiral compounds <strong>12</strong> and <strong>17</strong> had the lowest affinity for Hsp90, while R-stereochemistry analogues <strong>16</strong> and <strong>21</strong> had the highest. Brominated analogues <strong>17</strong>, <strong>20</strong>, and <strong>21</strong> exhibited strong disruption of Hsp90 client signaling in cell-based assays. Microscopy confirmed that the new compounds did not alter Hsp90 localization. Our preliminary Structure-Activity Relationship (SAR) study, indicates the following. First, the substitution of the isopropyl group with iodine or bromine preserves Hsp90 inhibitory function. Second, R-stereochemistry in these compounds plays a key role in the affinity for Hsp90. Finally, less bulky substituents (<em>i.e.</em> bromine) have stronger Hsp90 inhibition properties than more bulky ones (<em>i.e.</em> iodine). Compound <strong>21</strong>, in particular, emerged as a lead compound and will be radiolabeled with <sup>76/77</sup>Br as a radiotheragnostic agent for PET imaging (<sup>76</sup>Br) and Meitner-Auger electron therapy (<sup>77</sup>Br).</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109522"},"PeriodicalIF":4.7,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035022","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}
Pub Date : 2026-01-18DOI: 10.1016/j.bioorg.2026.109513
Yanguo Shang , Zherui Hu , Wenjuan Fei , Miaomiao Pang , Boxuan Chen , Tingting Zhou , Tao Shen
Multitarget natural product–platinum conjugates represent a promising strategy to overcome the limitations of Pt(IV) drugs, including severe side effects and drug resistance. In this study, a series of platinum-based hybrids incorporating glycyrrhetinic acid (GA) as axial ligands were designed, synthesized, and evaluated for their antitumor activity against various cancer cell lines. The lead complex GABP (glycyrrhetinic acid-carboplatin conjugate) demonstrated superior cytotoxicity compared to carboplatin, along with enhanced anti-liver cancer activity and low toxicity toward THLE-2 normal liver cells. Moreover, GABP significantly reversed cisplatin resistance in A549/CDDP cells. Mechanistic studies revealed that GABP induces DNA damage and ROS generation, leading to G2/M phase arrest, inhibition of migration and invasion, and apoptosis in HepG-2 cells via the Bcl-2/Bax/Caspase-3 pathway. Pharmacokinetic analysis indicated favorable plasma stability and liver tissue distribution for GABP. In a zebrafish model, GABP exhibited reduced hepatotoxicity and cardiotoxicity relative to carboplatin. In vivo, GABP achieved a tumor inhibition rate of 71.5% in HepG-2 xenograft mice, significantly outperforming carboplatin (48.3%) and the carboplatin/GA combination (55.2%), with no observable toxicity. By leveraging the hepatoselective accumulation of glycyrrhetinic acid, this study validates the GA-Pt(IV) prodrug conjugate as a “two-birds-one-stone” strategy that simultaneously enhances tissue targeting, overcomes resistance, and improves the safety profile of platinum-based anticancer agents.
{"title":"Design and evaluation of glycyrrhetinic acid-Pt(IV) hybrids for targeted therapy of liver cancer with reduced systemic toxicity","authors":"Yanguo Shang , Zherui Hu , Wenjuan Fei , Miaomiao Pang , Boxuan Chen , Tingting Zhou , Tao Shen","doi":"10.1016/j.bioorg.2026.109513","DOIUrl":"10.1016/j.bioorg.2026.109513","url":null,"abstract":"<div><div>Multitarget natural product–platinum conjugates represent a promising strategy to overcome the limitations of Pt(IV) drugs, including severe side effects and drug resistance. In this study, a series of platinum-based hybrids incorporating glycyrrhetinic acid (GA) as axial ligands were designed, synthesized, and evaluated for their antitumor activity against various cancer cell lines. The lead complex GABP (glycyrrhetinic acid-carboplatin conjugate) demonstrated superior cytotoxicity compared to carboplatin, along with enhanced anti-liver cancer activity and low toxicity toward THLE-2 normal liver cells. Moreover, GABP significantly reversed cisplatin resistance in A549/CDDP cells. Mechanistic studies revealed that GABP induces DNA damage and ROS generation, leading to G2/M phase arrest, inhibition of migration and invasion, and apoptosis in HepG-2 cells via the Bcl-2/Bax/Caspase-3 pathway. Pharmacokinetic analysis indicated favorable plasma stability and liver tissue distribution for GABP. In a zebrafish model, GABP exhibited reduced hepatotoxicity and cardiotoxicity relative to carboplatin. In vivo, GABP achieved a tumor inhibition rate of 71.5% in HepG-2 xenograft mice, significantly outperforming carboplatin (48.3%) and the carboplatin/GA combination (55.2%), with no observable toxicity. By leveraging the hepatoselective accumulation of glycyrrhetinic acid, this study validates the GA-Pt(IV) prodrug conjugate as a “two-birds-one-stone” strategy that simultaneously enhances tissue targeting, overcomes resistance, and improves the safety profile of platinum-based anticancer agents.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109513"},"PeriodicalIF":4.7,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035020","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}
Pub Date : 2026-01-18DOI: 10.1016/j.bioorg.2026.109507
Jiaqian Li , Yang Cui , Mengyu Xiong , Liying Zhang , Shuo Mu , Ziqi He , Hongcheng Zhu , Kaiyin Yang , Qidi Zhong
Given its critical role in mediating the DNA damage response and repair, Poly (ADP-ribose) polymerase-1 (PARP1) has been established as a significant therapeutic target for cancer and a multitude of other human diseases. In this study, a novel series of hydrophobic tagging (HyT) derivatives were developed through design, synthesis, and evaluation to induce the degradation of PARP1. Leading compound 11e demonstrated significant efficacy in the triple-negative breast cancer cell line MDA-MB-231, potently degrading PARP1 in a concentration- and time-dependent manner, thereby effectively inhibiting cancer cell proliferation and migration. Moreover, a degradation of PARP1 was induced by 11e in various BRCA1/2-proficient carcinoma-derived lines, with potency observed at low compound levels. In conclusion, compound 11e, a novel and highly effective PARP1 degrading agent, displays superior degradation capability and holds considerable promise for future clinical applications.
{"title":"Design, synthesis, and biological evaluation of hydrophobic-tagged poly (ADP-ribose) polymerase 1 (PARP1) degraders","authors":"Jiaqian Li , Yang Cui , Mengyu Xiong , Liying Zhang , Shuo Mu , Ziqi He , Hongcheng Zhu , Kaiyin Yang , Qidi Zhong","doi":"10.1016/j.bioorg.2026.109507","DOIUrl":"10.1016/j.bioorg.2026.109507","url":null,"abstract":"<div><div>Given its critical role in mediating the DNA damage response and repair, Poly (ADP-ribose) polymerase-1 (PARP1) has been established as a significant therapeutic target for cancer and a multitude of other human diseases. In this study, a novel series of hydrophobic tagging (HyT) derivatives were developed through design, synthesis, and evaluation to induce the degradation of PARP1. Leading compound <strong>11e</strong> demonstrated significant efficacy in the triple-negative breast cancer cell line MDA-MB-231, potently degrading PARP1 in a concentration- and time-dependent manner, thereby effectively inhibiting cancer cell proliferation and migration. Moreover, a degradation of PARP1 was induced by <strong>11e</strong> in various BRCA1/2-proficient carcinoma-derived lines, with potency observed at low compound levels. In conclusion, compound <strong>11e</strong>, a novel and highly effective PARP1 degrading agent, displays superior degradation capability and holds considerable promise for future clinical applications.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109507"},"PeriodicalIF":4.7,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016774","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}
Pub Date : 2026-01-17DOI: 10.1016/j.bioorg.2026.109518
Jinnian Wang , Haoming Zhao , Shijun Tong , Xingjian Zhang , Shuyu Ding , Han Zhang , Zhong-Hua Yang
The industrial production of pyridoxal 5′-phosphate (PLP)—an indispensable enzymatic cofactor—is hampered by inefficient multistep chemical syntheses and the economic infeasibility of ATP-dependent biocatalytic routes. To address these challenges, we report an ATP-autonomous biocatalytic cascade that couples pyridoxal kinase (PLK) with polyphosphate kinase (PPK) for sustainable PLP synthesis. This system harnesses inexpensive sodium hexametaphosphate (SHMP) as a phosphoryl donor to drive continuous ATP regeneration, thereby enabling efficient phosphorylation of pyridoxal to PLP without exogenous ATP input. Recombinant PLK and PPK were co-expressed in E. coli BL21(DE3), yielding specific activities of 50 and 145 U/gcell, respectively. The whole-cell biocatalyst achieved only about 25% conversion yield due to mass transfer limitations and intracellular PLP degradation. Notably, while the optimized cell-free system (45 °C, pH 6.5, PLK:PPK = 1:3, 25 mM SHMP) attained a remarkable 95% PLP yield. This 3.8-fold enhancement demonstrates the critical advantage of eliminating cellular barriers in complex multi-enzyme cascades. Our work establishes a robust, ATP-independent platform for high-efficiency PLP biosynthesis that seamlessly integrates cofactor regeneration with cascade catalysis, offering a scalable and economically viable route for industrial biomanufacturing. Moreover, it demonstrates the broader utility of polyphosphate-driven energy recycling in sustainable biocatalysis.
吡哆醛5'-磷酸（PLP）是一种不可或缺的酶促因子，其工业生产受到多步化学合成效率低下和依赖atp的生物催化途径在经济上不可行的阻碍。为了解决这些挑战，我们报道了一个atp自主的生物催化级联，将吡哆醛激酶（PLK）与多磷酸激酶（PPK）偶联，以实现可持续的PLP合成。该系统利用廉价的六正磷酸钠（SHMP）作为磷酸基供体来驱动连续的ATP再生，从而在没有外源ATP输入的情况下实现吡多醛高效磷酸化为PLP。重组PLK和PPK在大肠杆菌BL21（DE3）中共表达，比活性分别为50和145 U/gcell。由于传质限制和细胞内PLP降解，全细胞生物催化剂的转化率仅为25%左右。值得注意的是，优化后的无细胞体系（45°C, pH 6.5, PLK:PPK = 1:3, 25 mM SHMP）获得了95%的PLP产率。这3.8倍的增强证明了在复杂的多酶级联反应中消除细胞屏障的关键优势。我们的工作建立了一个强大的、不依赖于atp的高效PLP生物合成平台，将辅助因子再生与级联催化无缝集成，为工业生物制造提供了一条可扩展且经济可行的途径。此外，它证明了多磷酸盐驱动的能源回收在可持续生物催化中的广泛应用。
{"title":"Cascade biocatalysis for pyridoxal 5′-phosphate synthesis with ATP autonomy via polyphosphate kinase","authors":"Jinnian Wang , Haoming Zhao , Shijun Tong , Xingjian Zhang , Shuyu Ding , Han Zhang , Zhong-Hua Yang","doi":"10.1016/j.bioorg.2026.109518","DOIUrl":"10.1016/j.bioorg.2026.109518","url":null,"abstract":"<div><div>The industrial production of pyridoxal 5′-phosphate (PLP)—an indispensable enzymatic cofactor—is hampered by inefficient multistep chemical syntheses and the economic infeasibility of ATP-dependent biocatalytic routes. To address these challenges, we report an ATP-autonomous biocatalytic cascade that couples pyridoxal kinase (PLK) with polyphosphate kinase (PPK) for sustainable PLP synthesis. This system harnesses inexpensive sodium hexametaphosphate (SHMP) as a phosphoryl donor to drive continuous ATP regeneration, thereby enabling efficient phosphorylation of pyridoxal to PLP without exogenous ATP input. Recombinant PLK and PPK were co-expressed in <em>E. coli</em> BL21(DE3), yielding specific activities of 50 and 145 U/g<sub>cell</sub>, respectively. The whole-cell biocatalyst achieved only about 25% conversion yield due to mass transfer limitations and intracellular PLP degradation. Notably, while the optimized cell-free system (45 °C, pH 6.5, PLK:PPK = 1:3, 25 mM SHMP) attained a remarkable 95% PLP yield. This 3.8-fold enhancement demonstrates the critical advantage of eliminating cellular barriers in complex multi-enzyme cascades. Our work establishes a robust, ATP-independent platform for high-efficiency PLP biosynthesis that seamlessly integrates cofactor regeneration with cascade catalysis, offering a scalable and economically viable route for industrial biomanufacturing. Moreover, it demonstrates the broader utility of polyphosphate-driven energy recycling in sustainable biocatalysis.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"170 ","pages":"Article 109518"},"PeriodicalIF":4.7,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016739","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}
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