Pub Date : 2026-01-27DOI: 10.1021/acs.jmedchem.5c02817
Alan Bao, Xue Gong, Shuang Lin, Chi Gao, Hao Wang, Dongxiao Wang, Wanghaoran Sun, Chunmei Chen, Qin Li, Ying Ye, Weiguang Sun, Yonghui Zhang, Hucheng Zhu
Through genome mining, we discovered a 5/8/5 fusicoccane-type diterpenoid gene cluster (named Thm) from the biocontrol fungus Trichoderma harzianum, representing the first report of such a cluster in the genus Trichoderma. Heterologous expression of Thm in Aspergillus oryzae NSAR1 led to the isolation of 33 fusicoccane-type diterpenoids (including 30 new compounds 1–30). Structurally, compounds 1–14 were tetracyclic diterpenoids, with 1 and 2 being a class of rare fusicoccane-alkaloid hybrids. Mechanistic profiling revealed that compound 6 acts as a selective GPVI pathway antagonist, potently inhibiting Syk and PLCγ2 phosphorylation and subsequent platelet activation. In contrast, compound 31 exerts its antiplatelet effect via a distinct ROCK1-dependent pathway, suppressing cytoskeletal reorganization by reducing myosin light chain (MLC) phosphorylation and key regulator expression. Critically, both compounds demonstrate a groundbreaking therapeutic dissociation, providing robust protection against arterial and venous thrombosis without impairing normal hemostasis, thereby presenting a promising strategy for safe antithrombotic therapy.
{"title":"Efficient Mining for Structurally Diverse Fusicoccane-Type Diterpenoids as Novel Antithrombotic Agents and Their Divergent Mechanisms on Platelet Inhibition","authors":"Alan Bao, Xue Gong, Shuang Lin, Chi Gao, Hao Wang, Dongxiao Wang, Wanghaoran Sun, Chunmei Chen, Qin Li, Ying Ye, Weiguang Sun, Yonghui Zhang, Hucheng Zhu","doi":"10.1021/acs.jmedchem.5c02817","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02817","url":null,"abstract":"Through genome mining, we discovered a 5/8/5 fusicoccane-type diterpenoid gene cluster (named <i>Thm</i>) from the biocontrol fungus <i>Trichoderma harzianum</i>, representing the first report of such a cluster in the genus <i>Trichoderma</i>. Heterologous expression of <i>Thm</i> in <i>Aspergillus oryzae</i> NSAR1 led to the isolation of 33 fusicoccane-type diterpenoids (including 30 new compounds <b>1</b>–<b>30</b>). Structurally, compounds <b>1</b>–<b>14</b> were tetracyclic diterpenoids, with <b>1</b> and <b>2</b> being a class of rare fusicoccane-alkaloid hybrids. Mechanistic profiling revealed that compound <b>6</b> acts as a selective GPVI pathway antagonist, potently inhibiting Syk and PLCγ2 phosphorylation and subsequent platelet activation. In contrast, compound <b>31</b> exerts its antiplatelet effect via a distinct ROCK1-dependent pathway, suppressing cytoskeletal reorganization by reducing myosin light chain (MLC) phosphorylation and key regulator expression. Critically, both compounds demonstrate a groundbreaking therapeutic dissociation, providing robust protection against arterial and venous thrombosis without impairing normal hemostasis, thereby presenting a promising strategy for safe antithrombotic therapy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1021/acs.jmedchem.5c02763
Zeping Yang, Yuanqing Wu, Feizhi Kong, Yue Zhang, Lijun Jia, Chu Tang, Fu Wang
Histone deacetylase 6 (HDAC6) is a pivotal epigenetic regulator and is involved in the tumorigenesis and progression. Our previous study revealed that HDAC6 is overactivated in hepatocellular carcinoma (HCC), and identified SelSA as a novel HDAC6 inhibitor (HDAC6i) for HCC therapy. In this work, we optimized this inhibitor and discovered 14a as a novel HDAC6i with better efficacy against HDAC6 and HepG2 cells than SelSA through structure–activity relationship (SAR) studies. The flow cytometry indicated that 14a markedly induced apoptosis and cell cycle arrest at the S phase in HepG2 cells. Mechanistic studies demonstrated that 14a effectively downregulated the levels of HDAC6 and the phosphorylation of ERK1/2, and attenuated the migration, invasion, and clonogenicity of HepG2 cells. More crucially, 14a possessed more potency to suppress tumor growth in HepG2 xenograft models compared to SelSA, without obvious toxicity. In summary, 14a represents a novel HDAC6i with anti-HCC effects.
{"title":"Discovery of Novel Selenocyanate Derivatives as Histone Deacetylase 6 Inhibitors for the Treatment of Hepatocellular Carcinoma","authors":"Zeping Yang, Yuanqing Wu, Feizhi Kong, Yue Zhang, Lijun Jia, Chu Tang, Fu Wang","doi":"10.1021/acs.jmedchem.5c02763","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02763","url":null,"abstract":"Histone deacetylase 6 (HDAC6) is a pivotal epigenetic regulator and is involved in the tumorigenesis and progression. Our previous study revealed that HDAC6 is overactivated in hepatocellular carcinoma (HCC), and identified <b>SelSA</b> as a novel HDAC6 inhibitor (HDAC6i) for HCC therapy. In this work, we optimized this inhibitor and discovered <b>14a</b> as a novel HDAC6i with better efficacy against HDAC6 and HepG2 cells than SelSA through structure–activity relationship (SAR) studies. The flow cytometry indicated that <b>14a</b> markedly induced apoptosis and cell cycle arrest at the S phase in HepG2 cells. Mechanistic studies demonstrated that <b>14a</b> effectively downregulated the levels of HDAC6 and the phosphorylation of ERK1/2, and attenuated the migration, invasion, and clonogenicity of HepG2 cells. More crucially, <b>14a</b> possessed more potency to suppress tumor growth in HepG2 xenograft models compared to SelSA, without obvious toxicity. In summary, <b>14a</b> represents a novel HDAC6i with anti-HCC effects.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"7 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ salvage synthesis, represents an attractive target for gastric cancer therapy. Loss of nicotinic acid phosphoribosyltransferase (NAPRT) has been associated with an increased vulnerability to NAMPT inhibition in specific metabolic contexts. Here, we report the design and synthesis of o-aminobenzamide NAMPT inhibitors, among which compound N16 exhibited potent enzymatic selectivity and inhibition (IC50 = 17.4 nM) and pronounced activity against NAPRT-deficient HGC-27 cells (IC50 = 1.3 nM). N16 depleted NAD+ and ATP, disrupted mitochondrial potential, and suppressed self-renewal, proliferation, invasion, and migration while inducing cell-cycle arrest and apoptosis. Compared with lead compound 1, N16 displayed improved pharmacokinetics and in vivo antitumor efficacy. Notably, nicotinic acid coadministration enhanced tolerability without compromising antitumor activity in vivo. Collectively, these findings identify N16 as a promising NAMPT inhibitor with translational potential for treating metabolically vulnerable gastric cancer, particularly NAPRT-deficient subtypes.
{"title":"Discovery of Potent o-Aminobenzoamide-Based NAMPT Inhibitors for Targeting NAPRT-Deficient Gastric Cancer.","authors":"Heng Yang,Zhiyi Li,Huiqian Peng,Lixian Shen,Zhen Li,Lejing Zhu,Rifan Ding,Yiting Shi,Yuting Liu,Miao Zhang,Linsheng Zhuo,Meiling Yang,Zhen Wang,Weifan Jiang","doi":"10.1021/acs.jmedchem.5c02564","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02564","url":null,"abstract":"Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ salvage synthesis, represents an attractive target for gastric cancer therapy. Loss of nicotinic acid phosphoribosyltransferase (NAPRT) has been associated with an increased vulnerability to NAMPT inhibition in specific metabolic contexts. Here, we report the design and synthesis of o-aminobenzamide NAMPT inhibitors, among which compound N16 exhibited potent enzymatic selectivity and inhibition (IC50 = 17.4 nM) and pronounced activity against NAPRT-deficient HGC-27 cells (IC50 = 1.3 nM). N16 depleted NAD+ and ATP, disrupted mitochondrial potential, and suppressed self-renewal, proliferation, invasion, and migration while inducing cell-cycle arrest and apoptosis. Compared with lead compound 1, N16 displayed improved pharmacokinetics and in vivo antitumor efficacy. Notably, nicotinic acid coadministration enhanced tolerability without compromising antitumor activity in vivo. Collectively, these findings identify N16 as a promising NAMPT inhibitor with translational potential for treating metabolically vulnerable gastric cancer, particularly NAPRT-deficient subtypes.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"293 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1021/acs.jmedchem.5c02409
Katherine Valderrama, Oliver Horlacher, Gabriel Publicola, Patrick Eisenring, Maryline Kienle, Samira Boarbi, Mehdi Kiass, Jana Korduláková, Jonathan Chatagnon, Catherine Piveteau, Florence Leroux, Karin Savková, Monika Záhorszká, Francois-Xavier Cantrelle, Christian Lherbet, Lionel Mourey, Katarína Mikušová, Vanessa Mathys, Reiner Aichholz, Laurent Maveyraud, Karl-Heinz Altmann, Ruben C. Hartkoorn
Pyridomycin is a natural product with potent activity against Mycobacterium tuberculosis (Mtb), acting through direct inhibition of the fatty acid synthesis enzyme InhA. As a direct inhibitor, pyridomycin maintains activity on Mtb strains resistant to the InhA targeting prodrugs isoniazid and ethionamide. Evaluation of the drug-like properties of pyridomycin, however, found it to have poor in vitro metabolic stability, thus limiting its drug development potential. To address this limitation, semisynthetic derivatives were generated by replacing the metabolically labile hydroxypicolinic acid group with alternative (hetero)aromatic moieties, identifying several derivatives with improved in vitro metabolic stability and with comparable or even enhanced antibacterial activity. Pharmacokinetic studies in mice, however, revealed that these gains did not reduce systemic clearance in vivo, and neither pyridomycin nor its derivatives were effective in a murine pulmonary tuberculosis model. Overall, semisynthesis yielded more potent, P450-stable analogs, but the improvements were insufficient to provide measurable in vivo efficacy.
{"title":"Optimizing the Antibiotic Potency and Metabolic Stability of Pyridomycin Using a Semisynthetic Approach","authors":"Katherine Valderrama, Oliver Horlacher, Gabriel Publicola, Patrick Eisenring, Maryline Kienle, Samira Boarbi, Mehdi Kiass, Jana Korduláková, Jonathan Chatagnon, Catherine Piveteau, Florence Leroux, Karin Savková, Monika Záhorszká, Francois-Xavier Cantrelle, Christian Lherbet, Lionel Mourey, Katarína Mikušová, Vanessa Mathys, Reiner Aichholz, Laurent Maveyraud, Karl-Heinz Altmann, Ruben C. Hartkoorn","doi":"10.1021/acs.jmedchem.5c02409","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02409","url":null,"abstract":"Pyridomycin is a natural product with potent activity against <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), acting through direct inhibition of the fatty acid synthesis enzyme InhA. As a direct inhibitor, pyridomycin maintains activity on <i>Mtb</i> strains resistant to the InhA targeting prodrugs isoniazid and ethionamide. Evaluation of the drug-like properties of pyridomycin, however, found it to have poor <i>in vitro</i> metabolic stability, thus limiting its drug development potential. To address this limitation, semisynthetic derivatives were generated by replacing the metabolically labile hydroxypicolinic acid group with alternative (hetero)aromatic moieties, identifying several derivatives with improved <i>in vitro</i> metabolic stability and with comparable or even enhanced antibacterial activity. Pharmacokinetic studies in mice, however, revealed that these gains did not reduce systemic clearance <i>in vivo</i>, and neither pyridomycin nor its derivatives were effective in a murine pulmonary tuberculosis model. Overall, semisynthesis yielded more potent, P450-stable analogs, but the improvements were insufficient to provide measurable <i>in vivo</i> efficacy.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"44 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Phosphoinositide 3-kinase (PI3K) dysregulation drives tumorigenesis through regulation of cell cycle progression and survival. Several small molecular inhibitors targeting PI3K have been approved for tumor treatment. However, these inhibitors exposed unexpected severe off-tumor toxicity, leading to poor patient prognosis. Radiopharmaceuticals based on radiolabeled PI3K inhibitors for targeted internal radionuclide therapy offer a revitalized therapeutic approach to reduced pharmacological toxicity. Herein, we rationally designed and synthesized four bifunctional radiolabeled small-molecule chimeras based on the PI3K inhibitor IMM-H012, denoted as [68Ga]Ga/[177Lu]Lu-P(1-4). Among them, radiolabeled P4 demonstrated superior pharmacodynamic and pharmacokinetic profiles in multiple tumor models. Moreover, [177Lu]Lu-P4 substantially suppressed subcutaneous melanoma tumor growth with an acceptable safety profile. Additionally, [177Lu]Lu-P4 combined with IMM-H012 showed synergistic antitumor effects. The mechanistic study suggested a novel radiosensitization mechanism of 177Lu to PI3K inhibitors by downregulating fatty acid oxidase expression. These findings reposition PI3K as a versatile theranostic target while providing an effective repurposing strategy for PI3K inhibitors.
{"title":"Revitalizing PI3K Inhibitors for PET/CT Imaging and Radionuclide Therapy of Multiple Cancers.","authors":"Hongyi Huang,Shouguo Peng,Quan Zuo,Siqi Zhang,Jiang Wu,Yumeng Zhang,Xueyao Chen,Qingshuang Lu,Qichen Hu,Shuo Jiang,Jieting Shen,Jie Yan,Jiaqi Hu,Junlong Lu,Feng Wang,Rui Wang,Heng Xu,Kuan Hu","doi":"10.1021/acs.jmedchem.5c03583","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03583","url":null,"abstract":"Phosphoinositide 3-kinase (PI3K) dysregulation drives tumorigenesis through regulation of cell cycle progression and survival. Several small molecular inhibitors targeting PI3K have been approved for tumor treatment. However, these inhibitors exposed unexpected severe off-tumor toxicity, leading to poor patient prognosis. Radiopharmaceuticals based on radiolabeled PI3K inhibitors for targeted internal radionuclide therapy offer a revitalized therapeutic approach to reduced pharmacological toxicity. Herein, we rationally designed and synthesized four bifunctional radiolabeled small-molecule chimeras based on the PI3K inhibitor IMM-H012, denoted as [68Ga]Ga/[177Lu]Lu-P(1-4). Among them, radiolabeled P4 demonstrated superior pharmacodynamic and pharmacokinetic profiles in multiple tumor models. Moreover, [177Lu]Lu-P4 substantially suppressed subcutaneous melanoma tumor growth with an acceptable safety profile. Additionally, [177Lu]Lu-P4 combined with IMM-H012 showed synergistic antitumor effects. The mechanistic study suggested a novel radiosensitization mechanism of 177Lu to PI3K inhibitors by downregulating fatty acid oxidase expression. These findings reposition PI3K as a versatile theranostic target while providing an effective repurposing strategy for PI3K inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"42 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146056401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1021/acs.jmedchem.5c02795
Xi Gao, Yimin Chen, Zehua Li, Xiaojun Zhang, Yuying Li, Hualong Fu, Jinming Zhang, Mengchao Cui
Quinoline-based fibroblast activation protein inhibitors (FAPIs) have shown great potential for tumor diagnosis and therapy. To address the instability and limited applicability of [18F]AlF coordination chemistry, we designed nine fluorinated FAPIs incorporating the UAMC-1110 pharmacophore, enabling 18F-labeling through the formation of stable C–18F covalent bonds. All compounds exhibited high fibroblast activation protein affinities (Ki = 0.092–1.22 nM). Among them, [18F]54, synthesized via copper-catalyzed click chemistry, demonstrated excellent in vivo performance, achieving a high tumor-to-muscle ratio (TMR = 11 ± 3.1) at 60 min postinjection (p.i.) and sustained tumor retention, with only a 19% decrease from 30 to 120 min p.i. These findings support [18F]54 as a promising candidate for FAP-targeted imaging and highlight C–18F bond formation as a compelling alternative to [18F]AlF methods for developing next-generation FAP-targeted positron emission tomography tracers.
{"title":"Exploring Covalent C–18F Bonding Strategies in the Design of FAP-Targeted Radiotracers","authors":"Xi Gao, Yimin Chen, Zehua Li, Xiaojun Zhang, Yuying Li, Hualong Fu, Jinming Zhang, Mengchao Cui","doi":"10.1021/acs.jmedchem.5c02795","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02795","url":null,"abstract":"Quinoline-based fibroblast activation protein inhibitors (FAPIs) have shown great potential for tumor diagnosis and therapy. To address the instability and limited applicability of [<sup>18</sup>F]AlF coordination chemistry, we designed nine fluorinated FAPIs incorporating the <b>UAMC-1110</b> pharmacophore, enabling <sup>18</sup>F-labeling through the formation of stable C–<sup>18</sup>F covalent bonds. All compounds exhibited high fibroblast activation protein affinities (<i>K</i><sub>i</sub> = 0.092–1.22 nM). Among them, [<sup>18</sup>F]<b>54</b>, synthesized via copper-catalyzed click chemistry, demonstrated excellent <i>in vivo</i> performance, achieving a high tumor-to-muscle ratio (TMR = 11 ± 3.1) at 60 min postinjection (p.i.) and sustained tumor retention, with only a 19% decrease from 30 to 120 min p.i. These findings support [<sup>18</sup>F]<b>54</b> as a promising candidate for FAP-targeted imaging and highlight C–<sup>18</sup>F bond formation as a compelling alternative to [<sup>18</sup>F]AlF methods for developing next-generation FAP-targeted positron emission tomography tracers.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-27DOI: 10.1021/acs.jmedchem.5c02355
Julia H. Bormio Nunes, Christina Hacker, Monika Caban, Daniel Valcanover, Patrick A. Yassemipour, Sebastian Türck, Ingo Ott, Lukas Skos, Andrea Bileck, Christopher Gerner, Samuel M. Meier-Menches, Thomas Mohr, Walter Berger, Christian R. Kowol, Petra Heffeter
Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum resistance posing a major therapeutic challenge. To explore alternatives, we synthesized silver- and gold-based N-heterocyclic carbene (NHC) complexes differing only in their central metal ion and evaluated their activity in platinum-resistant OC. Structure–activity relationships revealed distinct metal-dependent behaviors. Silver complexes showed little variation with ligand modifications, whereas gold complexes displayed pronounced differences. Two bis-NHC–gold compounds were of particular interest: In an isogenic OC resistance model (A2780 and A2780/cis), [(NHC2)2Au]Br showed cross-resistance, while [(NHC1)2Au]Br induced collateral sensitivity. These effects were independent of intracellular accumulation, apoptosis induction, or TrxR inhibition. Instead, proteomic and metabolic analyses demonstrated that [(NHC1)2Au]Br inhibited oxidative phosphorylation, forcing a metabolic shift to aerobic glycolysis. As A2780/cis cells already rely on maximal glycolysis, [(NHC1)2Au]Br caused an energy collapse. These findings highlight a metabolic vulnerability in cisplatin-resistant OC that may be exploited for the development of novel therapeutic candidates.
{"title":"Structure–Activity Relationships of Silver(I)- and Gold(I)–NHC Complexes Reveal Distinctly Different Responses of Cisplatin-Resistant Ovarian Cancer to Bis-NHC–Gold(I) Derivatives","authors":"Julia H. Bormio Nunes, Christina Hacker, Monika Caban, Daniel Valcanover, Patrick A. Yassemipour, Sebastian Türck, Ingo Ott, Lukas Skos, Andrea Bileck, Christopher Gerner, Samuel M. Meier-Menches, Thomas Mohr, Walter Berger, Christian R. Kowol, Petra Heffeter","doi":"10.1021/acs.jmedchem.5c02355","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c02355","url":null,"abstract":"Ovarian cancer (OC) is the most lethal gynecological malignancy, with platinum resistance posing a major therapeutic challenge. To explore alternatives, we synthesized silver- and gold-based <i>N</i>-heterocyclic carbene (NHC) complexes differing only in their central metal ion and evaluated their activity in platinum-resistant OC. Structure–activity relationships revealed distinct metal-dependent behaviors. Silver complexes showed little variation with ligand modifications, whereas gold complexes displayed pronounced differences. Two bis-NHC–gold compounds were of particular interest: In an isogenic OC resistance model (A2780 and A2780/cis), [(NHC<sub>2</sub>)<sub>2</sub>Au]Br showed cross-resistance, while [(NHC<sub>1</sub>)<sub>2</sub>Au]Br induced collateral sensitivity. These effects were independent of intracellular accumulation, apoptosis induction, or TrxR inhibition. Instead, proteomic and metabolic analyses demonstrated that [(NHC<sub>1</sub>)<sub>2</sub>Au]Br inhibited oxidative phosphorylation, forcing a metabolic shift to aerobic glycolysis. As A2780/cis cells already rely on maximal glycolysis, [(NHC<sub>1</sub>)<sub>2</sub>Au]Br caused an energy collapse. These findings highlight a metabolic vulnerability in cisplatin-resistant OC that may be exploited for the development of novel therapeutic candidates.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"87 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146048695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c01797
Marco Banzato, Martina Colognesi, Lorena Lucatello, Stefano Comai, Gianfranco Pasut, Francesca Capolongo, Laura Orian, Lucia Biasutto, Anna Signor, Daniela Gabbia, Paolo L. Manfredi, Sara De Martin, Andrea Mattarei
Psilocybin, the phosphorylated prodrug of psilocin, holds therapeutic promise across a range of neuropsychiatric conditions, yet its clinical utility is constrained by acute psychoactive effects. Here, we report the rational design, synthesis, and evaluation of a focused library of fluorinated reversible N-alkyl carbamate derivatives of psilocin aimed at reducing acute psilocin exposure and thereby limiting hallucinogenic-like effects. Carbamate bond stability was systematically modulated by varying the number and positioning of fluorine atoms on the alkyl promoiety. The resulting compounds exhibited finely tuned hydrolysis under physiological conditions. A selected lead compound (4e) showed favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. Notably, 4e displayed intrinsic serotonergic activity at 5-HT2A and 5-HT2C receptors but induced attenuated psychotropic effects relative to psilocybin. Overall, these findings highlight fluorinated carbamate chemistry as a versatile platform to control psilocin exposure and serotonergic signaling, rather than the development of a classical pharmacologically inert prodrug.
{"title":"Design, Synthesis, and Pharmacokinetic Profiling of Fluorinated Reversible N-Alkyl Carbamate Derivatives of Psilocin for Sub-Hallucinogenic Brain Exposure","authors":"Marco Banzato, Martina Colognesi, Lorena Lucatello, Stefano Comai, Gianfranco Pasut, Francesca Capolongo, Laura Orian, Lucia Biasutto, Anna Signor, Daniela Gabbia, Paolo L. Manfredi, Sara De Martin, Andrea Mattarei","doi":"10.1021/acs.jmedchem.5c01797","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c01797","url":null,"abstract":"Psilocybin, the phosphorylated prodrug of psilocin, holds therapeutic promise across a range of neuropsychiatric conditions, yet its clinical utility is constrained by acute psychoactive effects. Here, we report the rational design, synthesis, and evaluation of a focused library of fluorinated reversible <i>N</i>-alkyl carbamate derivatives of psilocin aimed at reducing acute psilocin exposure and thereby limiting hallucinogenic-like effects. Carbamate bond stability was systematically modulated by varying the number and positioning of fluorine atoms on the alkyl promoiety. The resulting compounds exhibited finely tuned hydrolysis under physiological conditions. A selected lead compound (4e) showed favorable oral bioavailability and efficient brain penetration while undergoing partial bioconversion to psilocin. Notably, 4e displayed intrinsic serotonergic activity at 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors but induced attenuated psychotropic effects relative to psilocybin. Overall, these findings highlight fluorinated carbamate chemistry as a versatile platform to control psilocin exposure and serotonergic signaling, rather than the development of a classical pharmacologically inert prodrug.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"1 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c03109
Jeeyeon Kim, Kyeongwon Moon, Jihun Kim, Sung-Jun Park, Nari Kim, Yonggyu Jung, Yoonsuk Lee, Kyoungmin Lee, Wokchul Yoo, Jong Hoon Kim, Byeong-Won Kim, Daseul Kim, Hyun-Ju Park, Jaeheon Lee, Pargat Singh, In Su Kim
Capping is a natural and distinctive modification that occurs at the 5′-end of eukaryotic messenger RNA (mRNA), which regulates biological functions for gene expression events. Recently, the synthetic variation of a 5′-cap element has attracted considerable attention for improving the transcriptional efficiency and stability of mRNA. Herein, we describe the synthesis and biological evaluation of trinucleotide 5′-capping agents with 2′- and 3′-ribose modifications. The 3′-O-mesylated m7GpppAmG 43 demonstrated a high capping efficiency of 97.1%, comparable to the commercial CleanCapAG(3′OMe) 9. Furthermore, compound 43 exhibited a potent translational ability in the dual luciferase reporter assay, which was 1.8-fold higher than that of compound 9. Moreover, compound 43 was resistant against decapping enzymes (DcpS and hDcp2), thereby revealing its stability under biological conditions. In vivo translational studies demonstrated that lipid nanoparticle 43a, formulated from compound 43 with firefly luciferase mRNA, exhibited intense bioluminescence, supporting its translational competence.
{"title":"Synthesis and Translational Assessment of Trinucleotide 5′-Cap Analogs for Messenger Ribonucleic Acid-Based Therapeutics","authors":"Jeeyeon Kim, Kyeongwon Moon, Jihun Kim, Sung-Jun Park, Nari Kim, Yonggyu Jung, Yoonsuk Lee, Kyoungmin Lee, Wokchul Yoo, Jong Hoon Kim, Byeong-Won Kim, Daseul Kim, Hyun-Ju Park, Jaeheon Lee, Pargat Singh, In Su Kim","doi":"10.1021/acs.jmedchem.5c03109","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03109","url":null,"abstract":"Capping is a natural and distinctive modification that occurs at the 5′-end of eukaryotic messenger RNA (mRNA), which regulates biological functions for gene expression events. Recently, the synthetic variation of a 5′-cap element has attracted considerable attention for improving the transcriptional efficiency and stability of mRNA. Herein, we describe the synthesis and biological evaluation of trinucleotide 5′-capping agents with 2′- and 3′-ribose modifications. The 3′-<i>O</i>-mesylated m<sup>7</sup>GpppA<sub>m</sub>G <b>43</b> demonstrated a high capping efficiency of 97.1%, comparable to the commercial CleanCapAG(3′OMe) <b>9</b>. Furthermore, compound <b>43</b> exhibited a potent translational ability in the dual luciferase reporter assay, which was 1.8-fold higher than that of compound <b>9</b>. Moreover, compound <b>43</b> was resistant against decapping enzymes (DcpS and hDcp2), thereby revealing its stability under biological conditions. <i>In vivo</i> translational studies demonstrated that lipid nanoparticle <b>43a</b>, formulated from compound <b>43</b> with firefly luciferase mRNA, exhibited intense bioluminescence, supporting its translational competence.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"100 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-26DOI: 10.1021/acs.jmedchem.5c03037
Eslam Roshdy,Eva Řezníčková,Mostafa M. Elbadawi,Ismail Celik,Simone Giovannuzzi,Denisa Veselá,Veronika Vojáčková,Petra Krňávková,Alessio Nocentini,Claudiu T. Supuran,Vladimír Kryštof,Wagdy M. Eldehna,Manabu Abe
Leukemia remains a challenging hematological malignancy, with limited therapeutic options. To address this unmet need, we report quinoline–sulfonamide hybrids as first-in-class dual inhibitors of platelet-derived growth factor receptor (PDGFR) and carbonic anhydrase (CA) IX/XII. Structure–activity relationship studies identified compound 9d as a potent lead, exhibiting strong inhibition of PDGFRA (IC50 = 20 nM) and CA IX/XII (KI = 93.3 and 80.0 nM, respectively), along with exceptional antiproliferative activity in FIP1L1–PDGFRA-driven EOL-1 cells (GI50 = 2 nM), comparable to clinical agents. Mechanistic analyses revealed that 9d effectively abrogates PDGFRA signaling, induces G0/G1 cell-cycle arrest, and triggers apoptosis. Molecular docking and 200 ns molecular dynamics simulations supported stable dual binding of 9d within the ATP-binding pocket of PDGFR and the catalytic cleft of CA IX. By simultaneously targeting oncogenic PDGFRA signaling and hypoxia-driven pH regulation (CA IX/XII), 9d represents a promising lead for preclinical development in PDGFR/CA IX/XII-driven leukemias.
{"title":"First-in-Class Dual PDGFR/Carbonic Anhydrase IX/XII Inhibitors: 6,7-Dimethoxyquinoline-Sulfonamides as Promising Antileukemic Agents","authors":"Eslam Roshdy,Eva Řezníčková,Mostafa M. Elbadawi,Ismail Celik,Simone Giovannuzzi,Denisa Veselá,Veronika Vojáčková,Petra Krňávková,Alessio Nocentini,Claudiu T. Supuran,Vladimír Kryštof,Wagdy M. Eldehna,Manabu Abe","doi":"10.1021/acs.jmedchem.5c03037","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.5c03037","url":null,"abstract":"Leukemia remains a challenging hematological malignancy, with limited therapeutic options. To address this unmet need, we report quinoline–sulfonamide hybrids as first-in-class dual inhibitors of platelet-derived growth factor receptor (PDGFR) and carbonic anhydrase (CA) IX/XII. Structure–activity relationship studies identified compound 9d as a potent lead, exhibiting strong inhibition of PDGFRA (IC50 = 20 nM) and CA IX/XII (KI = 93.3 and 80.0 nM, respectively), along with exceptional antiproliferative activity in FIP1L1–PDGFRA-driven EOL-1 cells (GI50 = 2 nM), comparable to clinical agents. Mechanistic analyses revealed that 9d effectively abrogates PDGFRA signaling, induces G0/G1 cell-cycle arrest, and triggers apoptosis. Molecular docking and 200 ns molecular dynamics simulations supported stable dual binding of 9d within the ATP-binding pocket of PDGFR and the catalytic cleft of CA IX. By simultaneously targeting oncogenic PDGFRA signaling and hypoxia-driven pH regulation (CA IX/XII), 9d represents a promising lead for preclinical development in PDGFR/CA IX/XII-driven leukemias.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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