Zifan Ye, Zhouye Xu, Jianhong Ouyang, Wenzhuang Shi, Shuangyu Li, Xu Wang, Binjuan Lu, Kang Wang, Yipeng Wang
{"title":"Improving the Stability and Anti-Infective Activity of Sea Turtle AMPs Using Multiple Structural Modification Strategies","authors":"Zifan Ye, Zhouye Xu, Jianhong Ouyang, Wenzhuang Shi, Shuangyu Li, Xu Wang, Binjuan Lu, Kang Wang, Yipeng Wang","doi":"10.1021/acs.jmedchem.4c02039","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02039","url":null,"abstract":"Antimicrobial peptides (AMPs) are regarded as promising candidates for combating antimicrobial resistance. Previously we identified an AMP named <i>Cm</i>-CATH2 from the green sea turtle, which exhibited potent antibacterial activity and attractive potential in application. However, natural AMPs including <i>Cm</i>-CATH2 frequently suffer from structural instability and sensitivity to physiological conditions, limiting their effectiveness. Herein, we explored various strategies to enhance the efficacy and stability of <i>Cm</i>-CATH2, including peptide truncation, non-natural amino acid substitutions, disulfide bond-based cyclization, and stapled peptide techniques. The results demonstrated that the truncated NCM4 significantly improved the antimicrobial capability of <i>Cm</i>-CATH2 while also enhancing its anti-inflammatory and antibiofilm activities with minimal cytotoxicity. Further ornithine-substituted peptide oNCM markedly enhanced the stability of NCM4 without compromising its antimicrobial efficacy. This study successfully designed a lead peptide oNCM with significant development potential, while providing valuable insights into the advantages and limitations associated with diverse strategies for enhancing the stability of AMPs.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"32 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777049","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}
Paolo Bruno, Daniele Pala, Alessandra Micoli, Mauro Corsi, Alessandro Accetta, Laura Carzaniga, Paolo Ronchi, Claudio Fiorelli, Michele Formica, Daniela Pizzirani, Roberta Mazzucato, Sara Guariento, Serena Bertolini, Cataldo Martucci, Andrew Dennis Allen, Valentina Mileo, Silvia Capacchi, Paola Maria Gallo, Alessandro Fioni, Sergio Xanxo Fernandez, Gino Villetti, Paola Puccini, Maurizio Civelli, Matilde Guala, Michele Retini, Prisca Martinelli, Filippo Visentini, Valentina Pavoni, Matteo Daldosso, Stefano Fontana, Matteo Biagetti, Anna Maria Capelli
{"title":"Discovery of CHF-6523, an Inhaled Selective PI3Kδ Inhibitor for the Treatment of Chronic Obstructive Pulmonary Disease","authors":"Paolo Bruno, Daniele Pala, Alessandra Micoli, Mauro Corsi, Alessandro Accetta, Laura Carzaniga, Paolo Ronchi, Claudio Fiorelli, Michele Formica, Daniela Pizzirani, Roberta Mazzucato, Sara Guariento, Serena Bertolini, Cataldo Martucci, Andrew Dennis Allen, Valentina Mileo, Silvia Capacchi, Paola Maria Gallo, Alessandro Fioni, Sergio Xanxo Fernandez, Gino Villetti, Paola Puccini, Maurizio Civelli, Matilde Guala, Michele Retini, Prisca Martinelli, Filippo Visentini, Valentina Pavoni, Matteo Daldosso, Stefano Fontana, Matteo Biagetti, Anna Maria Capelli","doi":"10.1021/acs.jmedchem.4c02062","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02062","url":null,"abstract":"The design of inhaled selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitors for the treatment of inflammatory lung diseases was pursued. Knowledge-based design of a novel isocoumarin scaffold that was able to adopt a <i>propeller-shape</i> topology ensured the desired PI3Kδ selectivity. Achievement of low nanomolar cellular potencies through hinge binder group optimization, reduction of intrinsic permeability through head group optimization to extend lung retention, and screening of crystalline forms suitable for administration as dry powders culminated in the identification of compound <b>18</b>. This novel inhaled selective PI3Kδ inhibitor displayed durable anti-inflammatory activity in a disease-relevant rat model of Th-2-driven acute lung inflammation and safe <i>in vitro</i> and <i>in vivo</i> preclinical profiles. Therefore, compound <b>18</b> showed the appropriate discovery profile and was progressed to clinical trials in healthy volunteers and chronic obstructive pulmonary disease (COPD) patients as CHF-6523.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777048","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}
Chao Zhao, Wanlu Sun, Yanyan Zhu, Xiaoyan Huang, Ye Sun, Hai-Yan Wang, Yi Pan, Yi Liu
{"title":"An Activatable Heavy-Atom-Free Upconversion Photosensitizer for Targeted Imaging and Treatment of Tumors","authors":"Chao Zhao, Wanlu Sun, Yanyan Zhu, Xiaoyan Huang, Ye Sun, Hai-Yan Wang, Yi Pan, Yi Liu","doi":"10.1021/acs.jmedchem.4c02679","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02679","url":null,"abstract":"Photodynamic therapy (PDT) is an innovative and promising method for treating tumors that has attracted significant interest but still faces several challenges, such as a lack of selectivity, deep penetration of light, and efficient ROS generation. To address these challenges, we optimized and synthesized a series of photosensitizers and successfully developed a heavy-atom-free near-infrared FUCL photosensitizer NFh-NMe-2. This photosensitizer can generate singlet oxygen (<sup>1</sup>O<sub>2</sub>) and induce cellular apoptosis under 808 nm light. For the safe ablation of microtumors in vivo, an activatable FUCL photosensitizer NFh-NTR was developed based on the overexpression of nitroreductase (NTR). NFh-NTR could be activated by NTR, leading to the release of the photosensitizer NFh-NMe-2, restoring the fluorescence signal, and effectively killing tumor cells under 808 nm light irradiation. This work opens new possibilities in the chemical design of an FUCL photosensitizer for cancer treatment.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"27 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777213","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}
{"title":"Natural Products Driven Medicinal Chemistry","authors":"Sandip B. Bharate, Craig W. Lindsley","doi":"10.1021/acs.jmedchem.4c02736","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02736","url":null,"abstract":"Figure 1. Classical NPs that led to the discovery of drug molecules for therapeutic use. The year of discovery and the name of the researcher who isolated it for the first time are also mentioned. Figure 2. Anticancer leads identified through NP-driven medicinal chemistry. Figure 3. Leads for CNS diseases identified through NP-driven medicinal chemistry. Figure 4. Leads for infectious diseases identified through NP-driven medicinal chemistry. Figure 5. Anti-inflammatory lead compounds identified through NP-driven medicinal chemistry. Figure 6. Other lead compounds identified through NP-driven medicinal chemistry. Figure 7. Hits/leads identified through screening of NP-based libraries. Figure 8. Opportunities in NP-based drug discovery. This article references 18 other publications. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"64 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763752","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}
Christopher L. Carroll, Michael G. Johnson, Yanbing Ding, Zhijun Kang, R. S. K. Vijayan, Jennifer P. Bardenhagen, Cheng Fang, David Lapointe, Meng Li, Chiu-Yi Liu, Xiaobing Lv, XiaoYan Ma, Jihai Pang, Hannah E. Shepard, Catalina Suarez, Anne Ju Yau, Christopher C. Williams, Qi Wu, Robert A. Heald, Helen M. R. Robinson, Graeme C. M. Smith, Jason B. Cross, Mary K. Geck Do, Yongying Jiang, Sarah Lively, Timothy A. Yap, Virginia Giuliani, Timothy Heffernan, Philip Jones, M. Emilia Di Francesco
{"title":"Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers","authors":"Christopher L. Carroll, Michael G. Johnson, Yanbing Ding, Zhijun Kang, R. S. K. Vijayan, Jennifer P. Bardenhagen, Cheng Fang, David Lapointe, Meng Li, Chiu-Yi Liu, Xiaobing Lv, XiaoYan Ma, Jihai Pang, Hannah E. Shepard, Catalina Suarez, Anne Ju Yau, Christopher C. Williams, Qi Wu, Robert A. Heald, Helen M. R. Robinson, Graeme C. M. Smith, Jason B. Cross, Mary K. Geck Do, Yongying Jiang, Sarah Lively, Timothy A. Yap, Virginia Giuliani, Timothy Heffernan, Philip Jones, M. Emilia Di Francesco","doi":"10.1021/acs.jmedchem.4c01595","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01595","url":null,"abstract":"One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (<b>6</b>), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611). ART0380 (<b>6</b>) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"32 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777211","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}
Alice Palermiti, Amedeo De Nicolò, Alessandra Manca, Miriam Antonucci, Jacopo Mula, Martina Billi, Jessica Cusato, Alessandro Carta, Marco Pappaccogli, Lara Ponsa, Chiara Fasano, Francesco Giuseppe De Rosa, Franco Rabbia, Franco Veglio, Antonio D’Avolio
{"title":"Development and Validation of a UHPLC-MS/MS Method for the Simultaneous Quantification of Candesartan and Bisoprolol Together with Other 16 Antihypertensive Drugs in Plasma Samples","authors":"Alice Palermiti, Amedeo De Nicolò, Alessandra Manca, Miriam Antonucci, Jacopo Mula, Martina Billi, Jessica Cusato, Alessandro Carta, Marco Pappaccogli, Lara Ponsa, Chiara Fasano, Francesco Giuseppe De Rosa, Franco Rabbia, Franco Veglio, Antonio D’Avolio","doi":"10.1021/acs.jmedchem.4c02045","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02045","url":null,"abstract":"Antihypertensive pharmacological therapy is often characterized by a coadministration of different classes of drugs. Therefore, analytical methods allowing the simultaneous quantification of many drugs are needed for therapeutic drug monitoring (TDM) purposes in this context. In particular, TDM represents a useful tool to discriminate poor adherence from real cases of resistant hypertension. For this reason, the aim of this study is to validate, following the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) guidelines, an ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of 18 antihypertensive drugs in human plasma. A LX-50 coupled with a QSight 220 UHPLC-MS/MS system with electrospray ionization and multiple reaction monitoring mode was used, after a binary gradient separation (13 min) on a reverse-phase Acquity UPLC HSS T3 [1.8 μm, 2.1 mm × 150 mm] column. Method validation showed a stable and acceptable matrix effect, recovery, high accuracy, and precision, assessing the eligibility of this method for routine use in the clinical context.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"79 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777212","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}
{"title":"Natural Products Driven Medicinal Chemistry","authors":"Sandip B. Bharate*, and , Craig W. Lindsley*, ","doi":"10.1021/acs.jmedchem.4c0273610.1021/acs.jmedchem.4c02736","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02736https://doi.org/10.1021/acs.jmedchem.4c02736","url":null,"abstract":"","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"67 23","pages":"20723–20730 20723–20730"},"PeriodicalIF":6.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142850232","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}
{"title":"Correction to “New Potent RIPK2 Inhibitors as a Promising Therapeutic Avenue for Colitis Through the Blockade of NOD Inflammatory Pathways”","authors":"Morgane Rivoal, Amélie Barczyk, Perrine Six, Xavier Dezitter, Min-Jeong Cornu-Choi, Mathilde Body-Malapel, Madjid Djouina, Christophe Waxin, Laurent Dubuquoy, Régis Millet, Natascha Leleu-Chavain","doi":"10.1021/acs.jmedchem.4c02770","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02770","url":null,"abstract":"The author list has been updated to correct the spelling of Amélie Barczyk’s surname. Additionally, ref 28 in the original article should be updated (shown here as ref (1)) as the paper has now been published in <i>J. Med. Chem.</i> This article references 1 other publications. This article has not yet been cited by other publications.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"46 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763750","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}
Hong Jiang, Cong Li, Na Li, Li Sheng, Jingkai Wang, Wei-Juan Kan, Yuelei Chen, Dongmei Zhao, Dong Guo, Yu-Bo Zhou, Bing Xiong, Jia Li, Tongchao Liu
{"title":"Optimization and Biological Evaluation of Novel 1H-Pyrrolo[2,3-c]pyridin Derivatives as Potent and Reversible Lysine Specific Demethylase 1 Inhibitors for the Treatment of Acute Myelogenous Leukemia","authors":"Hong Jiang, Cong Li, Na Li, Li Sheng, Jingkai Wang, Wei-Juan Kan, Yuelei Chen, Dongmei Zhao, Dong Guo, Yu-Bo Zhou, Bing Xiong, Jia Li, Tongchao Liu","doi":"10.1021/acs.jmedchem.4c02017","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c02017","url":null,"abstract":"Lysine-specific demethylase 1 (LSD1) plays a vital role in the epigenetic regulation of various cancers, making it a promising therapeutic target for anticancer treatments. Herein, we designed and synthesized a novel series of 1<i>H</i>-pyrrolo[2,3-<i>c</i>]pyridin derivatives as potent LSD1 inhibitors. A detailed structure–activity relationship exploration was carried out to discover multiple derivatives with nanomolar enzymatic IC<sub>50</sub> values. Further biological evaluation demonstrated that these compounds acted as selective and reversible LSD1 inhibitors. The representative compounds exhibited highly potent antiproliferative activity against both AML (MV4–11 and Kasumi-1) and SCLC (NCI-H526) cell lines. Additionally, they effectively activated CD86 mRNA expression in MV4–11 cells and induced differentiation of AML cell lines. Notably, the most promising compound <b>23e</b> showed a favorable oral PK profile and effectively suppressed the tumor growth in an AML xenograft model. Overall, our medicinal chemistry efforts provide compound <b>23e</b> as a lead compound for developing LSD1 inhibitors for the treatment of AML and other advanced malignancies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"19 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142777210","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}
Fernanda Fries da Silva, Josiane Delgado Paz, Raoní Scheibler Rambo, Guilherme Arraché Gonçalves, Mauro Neves Muniz, Alexia de Matos Czeczot, Marcia Alberton Perelló, Andresa Berger, Laura Calle González, Lovaine Silva Duarte, Anelise Baptista da Silva, Carlos Alexandre Sanchez Ferreira, Sílvia Dias de Oliveira, Sidnei Moura, Cristiano Valim Bizarro, Luiz Augusto Basso, Pablo Machado
{"title":"Unveiling the Antimycobacterial Potential of Novel 4-Alkoxyquinolines: Insights into Selectivity, Mechanism of Action, and In Vivo Exposure","authors":"Fernanda Fries da Silva, Josiane Delgado Paz, Raoní Scheibler Rambo, Guilherme Arraché Gonçalves, Mauro Neves Muniz, Alexia de Matos Czeczot, Marcia Alberton Perelló, Andresa Berger, Laura Calle González, Lovaine Silva Duarte, Anelise Baptista da Silva, Carlos Alexandre Sanchez Ferreira, Sílvia Dias de Oliveira, Sidnei Moura, Cristiano Valim Bizarro, Luiz Augusto Basso, Pablo Machado","doi":"10.1021/acs.jmedchem.4c01302","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01302","url":null,"abstract":"This work presents a comprehensive investigation into the design, synthesis, and evaluation of a novel series of 4-alkoxyquinolines as potential antimycobacterial agents. The design approach, which combined molecular simplification and chain extension, resulted in compounds with potent and selective activity against both drug-susceptible and multidrug-resistant <i>Mycobacterium tuberculosis</i> strains. The lead molecule, targeting the cytochrome <i>bc</i><sub>1</sub> complex, exhibited favorable kinetic solubility and remarkable chemical stability under acidic conditions. Despite <i>in vitro</i> ADME evaluations showing low permeability and high metabolism in rat microsomes, the lead compound exhibited bacteriostatic activity in a murine macrophage model of TB infection and demonstrated promising <i>in vivo</i> exposure following gavage in mice, with an AUC<sub>0–<i>t</i></sub> of 127.5 ± 5.7 μM h. To the best of our knowledge, for the first time, a simplified structure from 2-(quinolin-4-yloxy)acetamides has shown such potential. These findings suggest a new avenue for exploring this chemical class as a source of antituberculosis drug candidates.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"262 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763755","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
