Pub Date : 2024-10-31DOI: 10.1016/j.bmc.2024.117983
Qian Yu , Lixin Gao , Linhao Xu , Yubing Han , Yu Cao , Jianjun Xi , Yigang Zhong , Linjie Li , Liteng Shen , Jinxin Che , Xiaowu Dong , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Yizhou Xu , Jia Li , Yubo Zhou , Jiankang Zhang
Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016–8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion.
{"title":"Exploration of novel 20S proteasome activators featuring anthraquinone structures and their application in hypoxic cardiomyocyte protection","authors":"Qian Yu , Lixin Gao , Linhao Xu , Yubing Han , Yu Cao , Jianjun Xi , Yigang Zhong , Linjie Li , Liteng Shen , Jinxin Che , Xiaowu Dong , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Yizhou Xu , Jia Li , Yubo Zhou , Jiankang Zhang","doi":"10.1016/j.bmc.2024.117983","DOIUrl":"10.1016/j.bmc.2024.117983","url":null,"abstract":"<div><div>Under hypoxic conditions, the accumulation of misfolded proteins primarily relies on the autonomous activity of 20S proteasome for degradation. The buildup of toxic proteins in cardiomyocyte contribute to various cardiovascular diseases. Therefore, enhancing the 20S proteasome degradation capacity and restoring protein homeostasis in myocardial cells with small molecule activators represent a promising therapeutic strategy for the treatment of ischemic cardiomyopathy. In this study, the lead compound 8016–8398 was identified through virtual screening, and subsequent structure optimization resulted in a series of highly potent 20S proteasome activators. Intracellular protein degradation assessment revealed that these compounds possessed abilities to alleviate endoplasmic reticulum stress, as demonstrated by the luciferase reporter system. Additionally, selected compound B-03 significantly enhanced the survival rate of hypoxic-damaged cardiomyocytes. Mechanistic investigations verified B-03 rescued hypoxic damaged cardiomyocyte through apoptosis inhibition and proliferation promotion.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117983"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.bmc.2024.117982
Hao Yang , Haoran Xu , Xinxin Lin , Zengxuan Cai , Yong Xia , Yu Wang , Zejie Chen , Koutian Zhang , Yanling Wu , Jianwei Wang , Annoor Awadasseid , Wen Zhang
Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including VPOT64 and VPOT76, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, VPOT76 effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC50 of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that VPOT76 increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that VPOT76 inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that VPOT76 reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of VPOT76, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes VPOT76 as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.
{"title":"Design, synthesis and biological evaluation of novel TMPRSS2-PROTACs with florosubstituted 4-guanidino-N-phenylbenzamide derivative ligands","authors":"Hao Yang , Haoran Xu , Xinxin Lin , Zengxuan Cai , Yong Xia , Yu Wang , Zejie Chen , Koutian Zhang , Yanling Wu , Jianwei Wang , Annoor Awadasseid , Wen Zhang","doi":"10.1016/j.bmc.2024.117982","DOIUrl":"10.1016/j.bmc.2024.117982","url":null,"abstract":"<div><div>Transmembrane Serine Protease 2 (TMPRSS2) plays a critical role in tumorigenesis and progression, making its degradation a promising therapeutic strategy. In this study, we designed and synthesized TMPRSS2-PROTACs, including <strong>VPOT64</strong> and <strong>VPOT76</strong>, based on camostat. Both compounds exhibited superior inhibitory effects on HT-29 colorectal and Calu-3 lung cancer cells compared to paclitaxel. Notably, <strong>VPOT76</strong> effectively degraded TMPRSS2, significantly inhibiting the proliferation of TMPRSS2-positive HT-29 cells and inducing apoptosis with an IC<sub>50</sub> of 0.39 ± 0.01 μM. Flow cytometry analysis demonstrated that <strong>VPOT76</strong> increased early apoptotic cells in a dose-dependent manner and caused G2 phase arrest at 0.8 μM. Colony formation assays showed that <strong>VPOT76</strong> inhibited HT-29 colony formation, even at low concentrations, further confirming its anti-proliferative effect. Additionally, wound healing assays indicated that <strong>VPOT76</strong> reduced the migration of HT-29 cells after 48 h, suggesting its potential to impair tumor cell invasion and metastasis. These findings highlight the multifaceted anticancer activities of <strong>VPOT76</strong>, including apoptosis induction, cell cycle arrest, colony formation inhibition, and migration suppression. Overall, this study establishes <strong>VPOT76</strong> as a potent TMPRSS2-degrading PROTAC with strong therapeutic potential, laying the groundwork for further development of TMPRSS2-targeting treatments for colorectal and other cancers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 117982"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.bmc.2024.117968
Haonan Li , Qingyinglu Ma , Yufeng Jia , Chao Wang , Jianfei Wu , Siyuan Wang , Huiming Hua , Jincai Lu , Dahong Li
Activating programmed cell death by delivering hydrogen sulfide (H2S) has emerged as a promising strategy for tumor therapy. Oridonin serves as a lead compound for drug development due to its unique scaffold and wide-ranging biological effects, especially its antitumor properties. Based on the previous structure–activity relationship studies, 33 novel 1-O/14-O H2S-releasing oridonin derivatives were synthesized. Particularly, 11a exhibited the most potent antiproliferative activity, effectively inhibiting colony formation, migration and invasion in both MCF-7 and MIA-PaCa-2 cells. It also inhibited the PI3K/AKT pathway to regulate the expression of Bax and Bcl-2, thereby initiating the Caspase cascade to activate mitochondrial mediated apoptosis. Furthermore, 11a suppressed tumor growth in breast cancer syngeneic models with no apparent toxicity.
{"title":"H2S-releasing oridonin derivatives with improved antitumor activity by inhibiting the PI3K/AKT pathway","authors":"Haonan Li , Qingyinglu Ma , Yufeng Jia , Chao Wang , Jianfei Wu , Siyuan Wang , Huiming Hua , Jincai Lu , Dahong Li","doi":"10.1016/j.bmc.2024.117968","DOIUrl":"10.1016/j.bmc.2024.117968","url":null,"abstract":"<div><div>Activating programmed cell death by delivering hydrogen sulfide (H<sub>2</sub>S) has emerged as a promising strategy for tumor therapy. Oridonin serves as a lead compound for drug development due to its unique scaffold and wide-ranging biological effects, especially its antitumor properties. Based on the previous structure–activity relationship studies, 33 novel 1-<em>O</em>/14-<em>O</em> H<sub>2</sub>S-releasing oridonin derivatives were synthesized. Particularly, <strong>11a</strong> exhibited the most potent antiproliferative activity, effectively inhibiting colony formation, migration and invasion in both MCF-7 and MIA-PaCa-2 cells. It also inhibited the PI3K/AKT pathway to regulate the expression of Bax and Bcl-2, thereby initiating the Caspase cascade to activate mitochondrial mediated apoptosis. Furthermore, <strong>11a</strong> suppressed tumor growth in breast cancer syngeneic models with no apparent toxicity.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117968"},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1016/j.bmc.2024.117970
Chunlan Pu , Yuanyuan Liu , Suke Lan , Hengrui Fan , Lvye Liu , Jianyu Liu , Yuanbiao Guo
Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Repression of bromodomain-containing protein 4 (BRD4) can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound, which induces PARP1 degradation, was employed in combination with the BRD4 inhibitor JQ1, confirming their synergistic effect in HR-proficient pancreatic cancer through various methods. Moreover, compared to the JQ1 and PARPi olaparib combination, PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.
{"title":"Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor","authors":"Chunlan Pu , Yuanyuan Liu , Suke Lan , Hengrui Fan , Lvye Liu , Jianyu Liu , Yuanbiao Guo","doi":"10.1016/j.bmc.2024.117970","DOIUrl":"10.1016/j.bmc.2024.117970","url":null,"abstract":"<div><div>Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Repression of bromodomain-containing protein 4 (BRD4) can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound, which induces PARP1 degradation, was employed in combination with the BRD4 inhibitor JQ1, confirming their synergistic effect in HR-proficient pancreatic cancer through various methods. Moreover, compared to the JQ1 and PARPi olaparib combination, PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117970"},"PeriodicalIF":3.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142542450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1016/j.bmc.2024.117969
Xiaoyan Shen , Honglan Zhai , Wei Tian , Linfang Lai , Tuo Ma , Xuyang Chen , Chunmiao Wang , Huaxin Hou
This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound KA-MO-g showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound KA-MO-g simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload, then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because KA-MO-g showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study.
{"title":"Discovery and optimization of anthraquinone derivatives containing substituted bisbenzyloxy groups as a novel scaffold damaged endoplasmic reticulum and against hepatocellular carcinoma cells","authors":"Xiaoyan Shen , Honglan Zhai , Wei Tian , Linfang Lai , Tuo Ma , Xuyang Chen , Chunmiao Wang , Huaxin Hou","doi":"10.1016/j.bmc.2024.117969","DOIUrl":"10.1016/j.bmc.2024.117969","url":null,"abstract":"<div><div>This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound <strong>KA-MO-g</strong> showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound <strong>KA-MO-g</strong> simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload, then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because <strong>KA-MO-g</strong> showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117969"},"PeriodicalIF":3.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1016/j.bmc.2024.117967
Chao Zhang , Xiuyun Sun , Peilu Song , Yu Rao
Immune-inflammatory diseases are a class of conditions with high prevalence that severely impact the quality of life. Current treatment strategies include immunosuppressants, glucocorticoids, and monoclonal antibodies. However, these approaches have certain limitations, such as poor membrane permeability, immunogenicity, and the requirement for injection in large molecule drugs. Small molecule compounds, on the other hand, suffer from issues like poor selectivity, inability to inhibit non-enzymatic functions, and biological compensation. These factors constrain the effectiveness of current therapeutic strategies in immune-inflammatory diseases. As a novel small molecule drug development technology, proteolysis-targeting chimeras (PROTACs) regulate protein levels by inducing interactions between target proteins and E3 ubiquitin ligases, leading to the selective degradation of target proteins. This technology has already shown promising therapeutic effects in the treatment of immune-inflammatory diseases. This review aims to comprehensively summarize the application of PROTAC technology in the field of immune inflammation and provide insights into its potential in treating immune-inflammatory diseases.
{"title":"The application of PROTACs in immune-inflammation diseases","authors":"Chao Zhang , Xiuyun Sun , Peilu Song , Yu Rao","doi":"10.1016/j.bmc.2024.117967","DOIUrl":"10.1016/j.bmc.2024.117967","url":null,"abstract":"<div><div>Immune-inflammatory diseases are a class of conditions with high prevalence that severely impact the quality of life. Current treatment strategies include immunosuppressants, glucocorticoids, and monoclonal antibodies. However, these approaches have certain limitations, such as poor membrane permeability, immunogenicity, and the requirement for injection in large molecule drugs. Small molecule compounds, on the other hand, suffer from issues like poor selectivity, inability to inhibit non-enzymatic functions, and biological compensation. These factors constrain the effectiveness of current therapeutic strategies in immune-inflammatory diseases. As a novel small molecule drug development technology, proteolysis-targeting chimeras (PROTACs) regulate protein levels by inducing interactions between target proteins and E3 ubiquitin ligases, leading to the selective degradation of target proteins. This technology has already shown promising therapeutic effects in the treatment of immune-inflammatory diseases. This review aims to comprehensively summarize the application of PROTAC technology in the field of immune inflammation and provide insights into its potential in treating immune-inflammatory diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117967"},"PeriodicalIF":3.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22DOI: 10.1016/j.bmc.2024.117963
Duc V.H. Tran, Ha T.N. Nguyen, Hee-Chul Ahn, Young-Woo Kim
The 310-helix is a crucial secondary structure in proteins, playing an essential role in various protein–protein interactions, yet stabilizing it in biologically relevant peptides remains challenging. In this study, we investigated the potential of 4-atom hydrocarbon staples to stabilize 310-helices in peptides. Using ring-closing metathesis, we demonstrated that the staple’s configuration is critical for both the stabilization and screw sense control of 310-helices. Circular dichroism spectroscopy revealed that the Ri,i+3S(4) staple—a 4-atom cross-link with (R)-configuration at the i position, (S)-configuration at the i + 3 position, and flanked by methyl groups—strongly induces right-handed 310-helices, especially in sequences with proteinogenic l-amino acids. Furthermore, multiple staples effectively stabilized longer peptides, underscoring the versatility of this approach for applications in peptide therapeutics and biomolecular engineering.
310 螺旋是蛋白质中一种重要的二级结构，在各种蛋白质-蛋白质相互作用中发挥着至关重要的作用，然而在具有生物相关性的肽中稳定这种结构仍然具有挑战性。在本研究中，我们研究了 4 原子碳氢化合物主链稳定肽中 310 螺旋的潜力。通过闭环偏析，我们证明了主链的构型对于 310-helices的稳定和螺杆感控制至关重要。环二色性光谱显示，Ri,i+3S(4) 主链--一种在 i 位具有 (R) 构型、在 i + 3 位具有 (S) 构型、两侧有甲基的 4 原子交联--能强烈诱导右旋 310 螺旋，尤其是在含有蛋白质源 l- 氨基酸的序列中。此外，多重主链还能有效稳定较长的肽段，突出了这种方法在肽治疗和生物分子工程中应用的多样性。
{"title":"310-Helix stabilization and screw sense control via stereochemically configured 4-atom hydrocarbon staples","authors":"Duc V.H. Tran, Ha T.N. Nguyen, Hee-Chul Ahn, Young-Woo Kim","doi":"10.1016/j.bmc.2024.117963","DOIUrl":"10.1016/j.bmc.2024.117963","url":null,"abstract":"<div><div>The 3<sub>10</sub>-helix is a crucial secondary structure in proteins, playing an essential role in various protein–protein interactions, yet stabilizing it in biologically relevant peptides remains challenging. In this study, we investigated the potential of 4-atom hydrocarbon staples to stabilize 3<sub>10</sub>-helices in peptides. Using ring-closing metathesis, we demonstrated that the staple’s configuration is critical for both the stabilization and screw sense control of 3<sub>10</sub>-helices. Circular dichroism spectroscopy revealed that the <strong><em>R<sub>i</sub></em><sub>,</sub><em><sub>i</sub></em><sub>+3</sub><em>S</em>(4)</strong> staple—a 4-atom cross-link with (<em>R</em>)-configuration at the <em>i</em> position, (<em>S</em>)-configuration at the <em>i</em> + 3 position, and flanked by methyl groups—strongly induces right-handed 3<sub>10</sub>-helices, especially in sequences with proteinogenic <span>l</span>-amino acids. Furthermore, multiple staples effectively stabilized longer peptides, underscoring the versatility of this approach for applications in peptide therapeutics and biomolecular engineering.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117963"},"PeriodicalIF":3.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vascular endothelial growth factors (VEGFs) are a class of homodimeric ligands that bind to their receptors (VEGFRs) to carryout physiological and pathological angiogenesis essential for regulating homeostasis of body. Overexpression of VEGF results in metastasis of benign tumor into malignant tumor. An active role of VEGFR-2 in cancer angiogenesis makes it a major target for cancer therapy. FDA approved VEGFR-2 inhibitors like sorafenib, vemurafenib and dabrafenib, and monoclonal antibodies such as bevacizumab and ramucirumab are available in market but possess side effects like hypertension, CVS disorders, liver damage and adverse effects like Iatrogenicity. Several research groups across the globe have designed and reported varied small molecules from different heteronuclei like quinazoline, pyrimidine, coumarin, pyrazole, indoline, benzimidazole, benzoxazole, etc. as VEGFR-2 inhibitors based on the information available on active site of the receptor, and pharmacophoric features of FDA approved drugs. The present review compiles the information available on benzo-fused heteronuclear compounds including benzimidazole, benzoxazole and benzothiazole in recent years, with emphasis on their design, activity, structure–activity relationship (SAR) and docking analysis for understanding binding interactions in the active site of VEGFR-2. In addition to this, a topological similarity analysis of these compounds is performed taking sorafenib as template, and a comprehensive SAR is proposed for researchers to further explore the anticancer potential of these pharmacophore.
血管内皮生长因子（VEGFs）是一类同源二聚体配体，可与其受体（VEGFRs）结合，进行生理性和病理性血管生成，对调节体内平衡至关重要。血管内皮生长因子的过度表达会导致良性肿瘤转移为恶性肿瘤。VEGFR-2 在癌症血管生成中的积极作用使其成为癌症治疗的主要靶点。美国 FDA 批准的 VEGFR-2 抑制剂如索拉非尼（sorafenib）、维莫非尼（vemurafenib）和达拉菲尼（dabrafenib），以及单克隆抗体如贝伐珠单抗（bevacizumab）和雷莫单抗（ramucirumab）已在市场上销售，但它们都有副作用，如高血压、CVS 紊乱、肝损伤和先天性不良反应等。全球已有多个研究小组根据受体活性位点的信息和美国 FDA 批准药物的药效学特征，设计并报道了不同杂核（如喹唑啉、嘧啶、香豆素、吡唑、吲哚啉、苯并咪唑、苯并恶唑等）的各种小分子作为 VEGFR-2 抑制剂。本综述汇编了近年来有关苯并咪唑、苯并恶唑和苯并噻唑等苯并杂核化合物的信息，重点介绍了这些化合物的设计、活性、结构-活性关系（SAR）和对接分析，以了解 VEGFR-2 活性位点的结合相互作用。此外，还以索拉非尼为模板，对这些化合物进行了拓扑相似性分析，并提出了全面的 SAR，供研究人员进一步探索这些药源的抗癌潜力。
{"title":"A critical analysis of design, binding pattern and SAR of benzo-fused heteronuclear compounds as VEGFR-2 inhibitors","authors":"Mayank Kashyap, Saurabh Gupta, Yogita Bansal, Gulshan Bansal","doi":"10.1016/j.bmc.2024.117966","DOIUrl":"10.1016/j.bmc.2024.117966","url":null,"abstract":"<div><div>Vascular endothelial growth factors (VEGFs) are a class of homodimeric ligands that bind to their receptors (VEGFRs) to carryout physiological and pathological angiogenesis essential for regulating homeostasis of body. Overexpression of VEGF results in metastasis of benign tumor into malignant tumor. An active role of VEGFR-2 in cancer angiogenesis makes it a major target for cancer therapy. FDA approved VEGFR-2 inhibitors like sorafenib, vemurafenib and dabrafenib, and monoclonal antibodies such as bevacizumab and ramucirumab are available in market but possess side effects like hypertension, CVS disorders, liver damage and adverse effects like Iatrogenicity. Several research groups across the globe have designed and reported varied small molecules from different heteronuclei like quinazoline, pyrimidine, coumarin, pyrazole, indoline, benzimidazole, benzoxazole, etc. as VEGFR-2 inhibitors based on the information available on active site of the receptor, and pharmacophoric features of FDA approved drugs. The present review compiles the information available on benzo-fused heteronuclear compounds including benzimidazole, benzoxazole and benzothiazole in recent years, with emphasis on their design, activity, structure–activity relationship (SAR) and docking analysis for understanding binding interactions in the active site of VEGFR-2. In addition to this, a topological similarity analysis of these compounds is performed taking sorafenib as template, and a comprehensive SAR is proposed for researchers to further explore the anticancer potential of these pharmacophore.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"115 ","pages":"Article 117966"},"PeriodicalIF":3.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.bmc.2024.117964
Aneta Vrzalová , Radim Vrzal , Petr Nádvorník , Marek Šebela , Zdeněk Dvořák
The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.
{"title":"Modulation of aryl hydrocarbon receptor activity by halogenated indoles","authors":"Aneta Vrzalová , Radim Vrzal , Petr Nádvorník , Marek Šebela , Zdeněk Dvořák","doi":"10.1016/j.bmc.2024.117964","DOIUrl":"10.1016/j.bmc.2024.117964","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117964"},"PeriodicalIF":3.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-19DOI: 10.1016/j.bmc.2024.117965
Jinmin Miao , Jianping Lin , Jiajun Dong , Ovini Amarasinghe , Emily R. Mason , Shaoyou Chu , Zihan Qu , Clayton C. Cullers , Karson S. Putt , Zhong-Yin Zhang
Src Homology 2-containing Inositol 5′-Phosphatase-1 (SHIP-1), encoded by INPP5D, has been identified as an Alzheimer’s disease (AD) risk-associated gene through recent genetic and epigenetic studies. SHIP-1 confers AD risk by inhibiting the TREM2 cascade and reducing beneficial microglial cellular processes, including phagocytosis. While several small molecules have been reported to modulate SHIP-1 activity, their limited selectivity and efficacy in advanced models restricted their potential as therapeutic agents or probes for biological studies. Herein, we validated and implemented a high-throughput screening platform to explore new chemotypes that can modulate the phosphatase activity of SHIP-1. We screened 49,260 central nervous system (CNS)-penetrate compounds sourced from commercial vendors using the malachite green-based assay for anti-SHIP-1 activity. Through analysis, prioritization, and validation of the screening hits, we identified three novel types of scaffolds that inhibit the SHIP-1 phosphatase activity with IC50s as low as 46.6 µM. To improve the inhibitory activity of these promising hits, we carried out structure–activity relationship (SAR) studies, resulting in a lead molecule SP3-12 that inhibits SHIP-1 with an IC50 value of 6.1 μM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a Ki value of 3.2 µM for SHIP-1 and a 7-fold selectivity over SHIP-2. Furthermore, results from testing in a microglial phagocytosis/cell health high content assay indicated that SP3-12 could effectively activate phagocytosis in human microglial clone 3 (HMC3) cells, with an EC50 of 2.0 µM, without cytotoxicity in the dose range. Given its potency, selectivity, and cellular activity, SP3-12 emerges as a promising small molecule inhibitor with potential for investigating the biological functions of SHIP-1.
{"title":"Discovery and evaluation of novel SHIP-1 inhibitors","authors":"Jinmin Miao , Jianping Lin , Jiajun Dong , Ovini Amarasinghe , Emily R. Mason , Shaoyou Chu , Zihan Qu , Clayton C. Cullers , Karson S. Putt , Zhong-Yin Zhang","doi":"10.1016/j.bmc.2024.117965","DOIUrl":"10.1016/j.bmc.2024.117965","url":null,"abstract":"<div><div>Src Homology 2-containing Inositol 5′-Phosphatase-1 (SHIP-1), encoded by <em>INPP5D</em>, has been identified as an Alzheimer’s disease (AD) risk-associated gene through recent genetic and epigenetic studies. SHIP-1 confers AD risk by inhibiting the TREM2 cascade and reducing beneficial microglial cellular processes, including phagocytosis. While several small molecules have been reported to modulate SHIP-1 activity, their limited selectivity and efficacy in advanced models restricted their potential as therapeutic agents or probes for biological studies. Herein, we validated and implemented a high-throughput screening platform to explore new chemotypes that can modulate the phosphatase activity of SHIP-1. We screened 49,260 central nervous system (CNS)-penetrate compounds sourced from commercial vendors using the malachite green-based assay for anti-SHIP-1 activity. Through analysis, prioritization, and validation of the screening hits, we identified three novel types of scaffolds that inhibit the SHIP-1 phosphatase activity with IC<sub>50</sub>s as low as 46.6 µM. To improve the inhibitory activity of these promising hits, we carried out structure–activity relationship (SAR) studies, resulting in a lead molecule SP3-12 that inhibits SHIP-1 with an IC<sub>50</sub> value of 6.1 μM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a <em>K</em><sub>i</sub> value of 3.2 µM for SHIP-1 and a 7-fold selectivity over SHIP-2. Furthermore, results from testing in a microglial phagocytosis/cell health high content assay indicated that SP3-12 could effectively activate phagocytosis in human microglial clone 3 (HMC3) cells, with an EC<sub>50</sub> of 2.0 µM, without cytotoxicity in the dose range. Given its potency, selectivity, and cellular activity, SP3-12 emerges as a promising small molecule inhibitor with potential for investigating the biological functions of SHIP-1.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"114 ","pages":"Article 117965"},"PeriodicalIF":3.3,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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