Chemical Biology & Drug Design最新文献

{"title":"Design, Synthesis, and Evaluation of Novel (−)-cis-N-Normetazocine Derivatives: In Vitro and Molecular Modeling Insights","authors":"Giuliana Costanzo,&nbsp;Alessandro Coco,&nbsp;Giuseppe Cosentino,&nbsp;Vincenzo Patamia,&nbsp;Carmela Parenti,&nbsp;Emanuele Amata,&nbsp;Agostino Marrazzo,&nbsp;Antonio Rescifina,&nbsp;Lorella Pasquinucci","doi":"10.1111/cbdd.70037","DOIUrl":"10.1111/cbdd.70037","url":null,"abstract":"<p>Suitable structural modifications of the functional groups at <i>N</i>-substituent of (−)-<i>cis</i>-<i>N</i>-normetazocine nucleus modulate the affinity and activity profile of related ligands toward opioid receptors. Our research group has developed several compounds and the most interesting ligands, <b>LP1</b> and <b>LP2</b>, exhibited a dual-target profile for mu-opioid receptor (MOR) and delta-opioid receptor (DOR). Recent structure–affinity relationship studies led to the discovery of novel <b>LP2</b> analogs (compounds <b>1</b> and <b>2</b>), which demonstrated high MOR affinity in the nanomolar range. Here, we reported the synthesis of the new (−)-<i>cis</i>-<i>N</i>-normetazocine derivatives (<b>3</b>–<b>8</b>) characterized by the absence of the phenyl ring in the <i>N</i>-substituent compared to all previous reported ligands. Compounds <b>3</b> and <b>4</b>, featuring a methyl ester functional group in the <i>N</i>-substituent, retained significant MOR affinity and exhibited similar affinity for the kappa-opioid receptor (KOR). In contrast, compounds <b>7</b> and <b>8</b>, which contain a hydroxamic acid functionality, maintained affinity exclusively toward MOR. Neither of compounds (<b>3</b>–<b>8</b>) showed DOR affinity. Molecular modeling studies confirmed a similar docking pose in the MOR binding pocket for these compounds. Additionally, the in silico ADME profile of the most interesting ligands (<b>3</b>, <b>4</b>, <b>7</b>, and <b>8</b>) was investigated revealing a favorable profile for compound <b>7</b> regarding the blood–brain barrier permeability, suggesting its potential as a peripherally restricted opioid ligand.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11671793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142900629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Activity Study of Gefitinib Derivatives Inducing Mitochondrial Apoptosis in Hela Cells","authors":"Yue Li,&nbsp;Xixi Hou,&nbsp;Shujian Liu,&nbsp;Zihao Chen,&nbsp;Qiong Wu,&nbsp;Baoyu He,&nbsp;Jingjing Guo,&nbsp;Lan Wang,&nbsp;Caihong Liu,&nbsp;Long-Fei Mao","doi":"10.1111/cbdd.70035","DOIUrl":"10.1111/cbdd.70035","url":null,"abstract":"<div>\u0000 \u0000 <p>Cervical cancer is the fourth most common cancer among women globally. Its development is closely linked to accelerated cell cycle progression and the inhibition of apoptosis in cervical cancer tissues. Gefitinib has demonstrated efficacy in inhibiting cervical cancer cells, and the 1,2,3-triazole structure is widely recognized for its role in inducing mitochondrial apoptosis in tumor cells. In this study, we employed click chemistry to modify the structure of gefitinib, leading to the synthesis of 16 derivatives containing the 1,2,3-triazole moiety. These compounds were evaluated for their in vitro activity against Hela cells. Among them, compound <b>3p</b> exhibited the most promising anticancer activity, with an IC₅₀ value of 4.09 ± 0.54 μM. Compound <b>3p</b> significantly inhibited Hela cell colony formation in a dose-dependent manner, accompanied by noticeable morphological changes. Further investigations revealed that <b>3p</b> induced apoptosis and caused G2/M phase cell cycle arrest in Hela cells. Western blot analysis showed that <b>3p</b> increased the Bax/Bcl-2 ratio and elevated the levels of cleaved caspase-3 and PARP1, indicating that apoptosis was mediated through the mitochondrial pathway. Additionally, <b>3p</b> inhibited indoleamine 2,3-dioxygenase 1 (IDO1) enzymatic activity, and molecular docking studies revealed a strong interaction between <b>3p</b> and the IDO1 active site, suggesting that IDO1 may be a potential target. In conclusion, compound <b>3p</b> shows promise as a potential therapeutic agent for cervical cancer.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico-Designed G-Quadruplex Targeting Peptide Attenuates VEGF-A Expression, Preventing Angiogenesis in Cancer Cells","authors":"Nilanjan Banerjee,&nbsp;Laboni Roy,&nbsp;Suman Panda,&nbsp;Tanaya Roychowdhury,&nbsp;Subhrangsu Chatterjee","doi":"10.1111/cbdd.70018","DOIUrl":"https://doi.org/10.1111/cbdd.70018","url":null,"abstract":"<div>\u0000 \u0000 <p>Vascular endothelial growth factor-A (VEGF-A) is a growth factor and pluripotent cytokine that promotes angiogenesis in cancer cells, transitioning to an angiogenic phenotype. The binding of VEGF-A protein to VEGF receptors (VEGFR-1 and VEGFR-2) initiates a cascade of events that stimulates angiogenesis by facilitating the migration and enhancing the permeability of endothelial cells. The proximal promoter of the VEGF gene encompasses a 36-base pair region (from −85 to −50) that can form a stable G-quadruplex (G4) structure in specific conditions. The activity of the VEGF promoter is reliant on this structure. During cancer progression, the VEGF-A G4 succumbs to cellular pressure and fails to maintain a stable structure. This shifts the balance to form a duplex structure, increasing the transcription rate. Earlier research has tried to develop small-molecule ligands to target and stabilise G4, demonstrating the possibility of suppressing VEGF expression. However, they either lack specificity or toxic. Peptides, on the other hand, are significantly less studied as G4 binders. Here, we designed a peptide that successfully binds and stabilises the VEGF-A G4 while reducing its gene expression. This further alters the expression fate of the VEGF-A signalling cascade and blocks angiogenesis in cancer cells. We employed high-resolution nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation to elucidate the chemical details of G4-peptide interaction. In addition, we used qPCR and western blot techniques to investigate the expression pattern of the molecules implicated in the VEGF-A signalling cascade. The study explores the intricate relationship between peptides and quadruplex structures, revealing valuable insights that can improve the design of pharmacophores targeting the dynamic quadruplex structure. The results of our study are encouraging, opening possibilities for advancements in, the characterisation and optimisation of peptides as G-quadruplex ligands in view of their potential therapeutic uses.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lycorine Suppresses Non-Small-Cell Lung Cancer Progression Through Activating STING Pathway and Stimulating an Antitumor Immune Response","authors":"Ze-Bo Jiang,&nbsp;Cong Xu,&nbsp;Pan Xu,&nbsp;Dong-Hui Huang,&nbsp;Li-Ping Kang","doi":"10.1111/cbdd.70036","DOIUrl":"https://doi.org/10.1111/cbdd.70036","url":null,"abstract":"<div>\u0000 \u0000 <p>Non-small-cell lung cancer (NSCLC) stands as a primary contributor to cancer-related deaths worldwide. It has been demonstrated that Lycorine (LYD), a naturally occurring active sesquiterpene present in Chinese medicinal plants, exhibits anti-cancer properties across various cancer cell lines. However, the underlying mechanisms of LYD-induced anti-tumor in NSCLC are not fully known. This study demonstrated that LYD significantly reduced the proliferation of NSCLC and induced apoptosis by increasing intracellular ROS levels. The inhibition of ROS using N-acetylcysteine (NAC) eliminated the apoptosis effects of LYD, resulting in increased cell viability. Additionally, LYD treatment significantly activated the STING pathway in NSCLC and induced the expression of CXCL10, CXCL9 and CCL5 in NSCLC cells. Mechanistically, LYD was found to significantly reduce the protein levels of P70S6K and S6K, which are key proteins involved in cell growth and survival. Notably, in vivo experiments demonstrated that LYD significantly inhibited the growth of H358 <i>xenograft</i> and LLC1 tumor, exhibiting anti-tumor activity by elevating CD8⁺ T cells in the NSCLC mouse model. Our findings suggest that LYD possesses potent anti-cancer properties in NSCLC by inducing apoptosis through ROS generation and modulating the STING pathway and key chemokines. Furthermore, LYD also exerts its antitumor effects by inhibiting crucial proteins involved in cell growth. Overall, LYD shows promise as a potential therapeutic agent for NSCLC treatment.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mollugin Derivatives as Anti-Inflammatory Agents: Design, Synthesis, and NF-κB Inhibition","authors":"Yuan-Liang Gao,&nbsp;Ming-Yue Li,&nbsp;Da-Yuan Wang,&nbsp;Shi-Ang Jin,&nbsp;Xin-Yu Ma,&nbsp;Xue-Jun Jin,&nbsp;Hu-Ri Piao","doi":"10.1111/cbdd.70024","DOIUrl":"https://doi.org/10.1111/cbdd.70024","url":null,"abstract":"<div>\u0000 \u0000 <p>Nuclear factor κB (NF-κB) is a key inducible transcription factor that controls a large number of genes involved in inflammatory and immune processes. The entire inflammation-mediated process uses NF-κB as a hub, and inflammatory gene transcription and expression can be decreased by blocking the NF-κB signaling pathway, thereby reducing inflammatory damage. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation. Here, we designed and synthesized 27 mollugin derivatives and evaluated the anti-inflammatory activity against NF-κB transcription. Most of the compounds exhibited potent anti-inflammatory activity, and compound <b>5k</b> was the most potent with 81.77% inhibition after intraperitoneal administration, which was significantly more potent than mollugin (49.72%), ibuprofen (47.51%), and mesalazine (47.24%). Investigation of the mechanism of action indicated that <b>5k</b> down-regulated NF-κB expression, possibly by suppressing LPS-induced expression of the p65 protein. ADMET prediction analysis indicated that compounds <b>5h</b> and <b>5k</b> showed good pharmacokinetic properties. The relationship between the structures of the synthesized compounds and the NF-κB inhibitory activity was rationalized using molecular docking simulation experiments. Overall, these results provide an initial basis for the development of <b>5h</b> and <b>5k</b> as potential anti-inflammatory agents.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis and Pro-Inflammatory Activity of Palmitoylated Derivatives of Thioglycolic Acid as New Immunomodulators","authors":"Samia M. Mohamed,&nbsp;Ola M. F. Abou-Ghadir,&nbsp;Mohamed A. El-Mokhtar,&nbsp;Ahmed S. Aboraia,&nbsp;Samia G. Abdel-Moty,&nbsp;Abu-Baker M. Abdel-Aal","doi":"10.1111/cbdd.70029","DOIUrl":"https://doi.org/10.1111/cbdd.70029","url":null,"abstract":"<div>\u0000 \u0000 <p>The immune system is essential for the defense against infections and is critically implicated in various disorders, including immunodeficiency, autoimmunity, inflammation and cancer. The current study includes a new design of palmitoylated derivatives of thioglycolic acids (PTGAs) capable of triggering innate immune responses. The new series were accessible through a three-step synthetic route, including <i>N</i>-palmitoylation, Claisen–Schmidt condensation and thia-Michael addition. Their structures were elucidated using different 1D and 2D NMR spectroscopic techniques and their purity was confirmed by elemental analysis. The most active PTGAs induced a 12–26-fold increase in the expression of TNF-α and IL-1β mRNA and triggered a marked release of NO in isolated macrophages. These levels were comparable to the responses elicited by heat-killed <i>E. coli</i> and <i>S. aureus</i>. The position of the palmitamide chain and aryl substitution had a significant effect on the TNF-α and IL-1β mRNA expression and NO release. Simulations of molecular dockings showed that the new PTGA derivatives occupy the same TLR2/TLR6 heterodimer active binding site of the microbial diacylated lipoproteins. The new immunomodulators may have a profound impact on various clinical disorders associated with dysfunctional innate immunity.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of Voreloxin as a Dual-Selective Stabilizer for c-Myc/Bcl-2 G-Quadruplexes in Leukemia","authors":"Jiacheng Yin,&nbsp;Pingting Jia,&nbsp;Xinxin Qu,&nbsp;Zheng Han,&nbsp;Longsheng Yao,&nbsp;Shangzhao Wang,&nbsp;Jian Gao","doi":"10.1111/cbdd.70034","DOIUrl":"10.1111/cbdd.70034","url":null,"abstract":"<div>\u0000 \u0000 <p>Overexpression of c-Myc is a key factor in the development of leukemia and other malignancies, highlighting the urgent need for novel drugs to inhibit c-Myc protein levels. DNA G-quadruplexes (G4) have emerged as potential regulatory targets for c-Myc expression. Previous studies identified trovafloxacin, a topoisomerase II inhibitor, as a novel c-Myc G4 stabilizer. In this study, virtual screening based on structural similarity led to the identification of nine derivatives of trovafloxacin, among which voreloxin exhibited potent cytotoxicity in multiple myeloma cells and showed promising therapeutic efficacy in leukemia cells. FRET assays demonstrated that voreloxin specifically stabilized the G4 structures of c-Myc and Bcl-2, with minimal effects on the G4 structures of other oncogenes. Moreover, voreloxin significantly reduced the expression levels of c-Myc and Bcl-2 in THP-1 and MOLM-13 cells. Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations further confirmed the stable binding of voreloxin to both c-Myc and Bcl-2 G4s, primarily driven by π-π stacking and hydrogen bonding interactions. These findings provide valuable insights for the development of G4-targeting drugs for cancer therapy.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tectorigenin Reduces Dabie bandavirus-Induced Cytokine Storm by Regulating Toll-Like Receptor 7/Extracellular Signal–Regulated Kinase Pathway","authors":"Qian Zhang,&nbsp;Qinqin Pu,&nbsp;Zhengyi Jiang,&nbsp;Jie Zhao,&nbsp;Yan Dai,&nbsp;Nannan Hu,&nbsp;Yaping Han,&nbsp;Nan Jiang,&nbsp;Luchen Shi,&nbsp;Jiaying Zhao,&nbsp;Ke Ouyang,&nbsp;Huaying Huang,&nbsp;Ke Jin,&nbsp;Jun Li","doi":"10.1111/cbdd.70005","DOIUrl":"10.1111/cbdd.70005","url":null,"abstract":"<div>\u0000 \u0000 <p>Severe fever with thrombocytopenia syndrome (SFTS) is a severe emerging infectious disease caused by <i>Dabie bandavirus</i> (DBV). Tectorigenin has been demonstrated to exert anti-inflammatory effect. Here, we aimed to investigate the effects of tectorigenin on DBV-induced cytokine storm. Effects of tectorigenin on cytokines in DBV-infected THP-1 cells and plasma samples of Type I interferon receptor (IFNAR)^−/− mice infected with DBV were detected. The changes in body weight and survival time of mice were recorded. The liver, spleen, kidney, and lymph node tissues were collected for hematoxylin–eosin staining. We demonstrated that tectorigenin reduced the expression levels of inflammatory cytokines in both DBV-infected THP-1 cells and plasma samples of IFNAR^−/− mice infected with DBV. Tectorigenin attenuated DBV-induced histopathological changes in mice. Mechanistically, tectorigenin attenuated DBV-induced phosphorylation of inhibitor of kappa-B kinase alpha/beta (IKKα/β) of the nuclear factor-κB (NF-κB) signaling pathway, extracellular signal–regulated kinase (ERK) of the mitogen-activated protein kinase (MAPK) signaling pathway and might function by downregulation of Toll-like receptor. The result of this study suggested that tectorigenin exerted anti-inflammatory effects in vivo and in vitro and could serve as a novel potential therapeutic strategy for SFTS.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis, and Biological Evaluation of New Benzimidazole-1,2,4-Triazole Derivatives as Potential Anticancer Agents","authors":"Ecem Kaya-Sezginer,&nbsp;Beyza Ecem Oz Bedir,&nbsp;Emine Terzi,&nbsp;Tuba Ozdemir Sanci,&nbsp;Zahra Maryam,&nbsp;Ulviye Acar Çevik","doi":"10.1111/cbdd.70033","DOIUrl":"10.1111/cbdd.70033","url":null,"abstract":"<div>\u0000 \u0000 <p>New series of benzimidazole-1,2,4-triazole derivatives were designed, synthesized, and characterized using ¹H-NMR, ¹³C-NMR, and HRMS. These compounds were evaluated for anticancer activity toward HTB-9 bladder and HT-29 colorectal cancer cell lines. Compounds <b>7h</b> and <b>7ı</b> were found to be the most active against HTB-9 cell line, with IC₅₀ 6.27 and 6.44 μM, respectively, comparable to positive control cisplatin (IC₅₀ = 11.40 μM). Additionally, in HT-29 cell line, compounds <b>7a</b> and <b>7ı</b> exhibited the lowest IC₅₀ values (20.37 and 22.71 μM, respectively), which was higher than those of cisplatin (19.79 μM). All active compounds induced apoptosis and caspase 3/7 activity and reduced the migration ability in both cell lines. Particularly, HT-29 cells treated with compound <b>7ı</b> exerted a higher apoptotic index than cisplatin-treated cells. Furthermore, compounds <b>7h</b> and <b>7ı</b> led to G1 cell cycle arrest of HTB-9, and compounds <b>7a</b> and <b>7ı</b> against HT-29 induced S and G1 cell cycle arrest, respectively. In conclusion, the antiproliferative effect of active compounds is associated with the induction of apoptosis through caspase 3/7 activation and cell cycle arrest at different phases in HTB-9 and HT-29 cell lines.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expansion of the Structure–Activity Relationship Profile of Triaminopyrimidines as Inhibitors of Caspase-1","authors":"Amanda East,&nbsp;Callista G. Polasek,&nbsp;Elizabeth A. Miller,&nbsp;Srirajkumar Ranganathan,&nbsp;Isabella D. Reda,&nbsp;Aisha Patel,&nbsp;Christopher D. Ahlers,&nbsp;Sarah K. Zingales,&nbsp;Caitlin E. Karver","doi":"10.1111/cbdd.70031","DOIUrl":"10.1111/cbdd.70031","url":null,"abstract":"<div>\u0000 \u0000 <p>Caspase-1 is a sought-after therapeutic target for inflammatory conditions due to its role in activation and release of pro-inflammatory cytokines, but there has been little success getting drugs into the clinic. We have previously shown triaminopyrimidines such as CK-1-41 are potent, reversible small molecule inhibitors of caspase-1, likely binding in an allosteric site within the enzyme. A series of analogs of CK-1-41 were synthesized and tested against caspase-1 to develop a more robust structure–activity relationship profile. In general, alkyl and aryl groups were well tolerated via an ethylene or methylene linkage to the piperazine nitrogen, with IC₅₀ values ranging from 13 to 200 nM. The most potent compounds were methylene linked o-tolyl (AE-2-21) and ethylene linked 4-trifluoromethylphenyl (AE-2-48) with IC₅₀ values of 18 and 13 nM, respectively. Derivatives with electrophilic covalent warheads linked via an amide bond to the piperazine nitrogen were synthesized and characterized. CA-1-11 and EM-1-10 were semi-reversible, non-competitive inhibitors of caspase-1 with slightly reduced potencies of 134 and 144 nM, respectively. All derivatives docked well into the allosteric site, supporting our hypothesis that this family of caspase-1 inhibitors function via an allosteric non-competitive mechanism of inhibition.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"104 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}