Pub Date : 2024-11-22DOI: 10.1016/j.bmcl.2024.130033
Shaoyi Sun , Sultan Chowdhury , Ivan Hemeon , Abid Hasan , Michael S. Wilson , Phillipe Bergeron , Qi Jia , Alla Y. Zenova , Mike E. Grimwood , Wei Gong , Shannon M. Decker , Paul Bichler , Jean-Christophe Andrez , Thilo Focken , Theresa Ngyuen , Jiuxiang Zhu , Andrew D. White , Girish Bankar , Sarah Howard , Elaine Chang , Christoph M. Dehnhardt
Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of NaV1.7 that showed high selectivity over NaV1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted NaV1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK.
{"title":"Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of NaV1.7","authors":"Shaoyi Sun , Sultan Chowdhury , Ivan Hemeon , Abid Hasan , Michael S. Wilson , Phillipe Bergeron , Qi Jia , Alla Y. Zenova , Mike E. Grimwood , Wei Gong , Shannon M. Decker , Paul Bichler , Jean-Christophe Andrez , Thilo Focken , Theresa Ngyuen , Jiuxiang Zhu , Andrew D. White , Girish Bankar , Sarah Howard , Elaine Chang , Christoph M. Dehnhardt","doi":"10.1016/j.bmcl.2024.130033","DOIUrl":"10.1016/j.bmcl.2024.130033","url":null,"abstract":"<div><div>Discovery efforts leading to the identification of cyclopentane carboxylic acid <strong>31</strong>, a potent inhibitor of Na<sub>V</sub>1.7 that showed high selectivity over Na<sub>V</sub>1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of <strong>31</strong> include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na<sub>V</sub>1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130033"},"PeriodicalIF":2.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694886","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}
Pub Date : 2024-11-22DOI: 10.1016/j.bmcl.2024.130036
Pengqin Chen , Pan Chen , Xiemin Wang
Acute lung injury (ALI), a common critical disease in clinical practice, has a mortality rate as high as 30–40 %, yet currently, no effective treatment methods are available. Research on ALI indicated that inhibition of overexpressed inflammatory factors might be a potential treatment for ALI. In this study, a series of cinnamic acid derivatives were obtained by introducing diverse aminothiazole fragments into the natural product cinnamic acid. Among these derivatives, compound 22 displayed excellent activity of inhibiting the release of IL-6 in J774A.1 cells. Moreover, it also ameliorated the LPS-induced ALI in mouse model by suppressing cytokine expression, reducing lung edema and macrophage infiltration. These findings indicated that compound 22 might provide a new lead structure for the development of drugs for ALI.
急性肺损伤（ALI）是临床上常见的危重病，死亡率高达 30-40%，但目前还没有有效的治疗方法。对急性肺损伤的研究表明，抑制过度表达的炎症因子可能是治疗急性肺损伤的一种潜在方法。本研究通过在天然产物肉桂酸中引入不同的氨基噻唑片段，获得了一系列肉桂酸衍生物。在这些衍生物中，化合物 22 在抑制 J774A.1 细胞中 IL-6 的释放方面表现出卓越的活性。此外，它还通过抑制细胞因子的表达、减轻肺水肿和巨噬细胞浸润，改善了 LPS 诱导的小鼠 ALI 模型。这些研究结果表明，化合物 22 可为 ALI 药物的开发提供新的先导结构。
{"title":"Design, synthesis and bioactivity evaluation of cinnamic acid derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury","authors":"Pengqin Chen , Pan Chen , Xiemin Wang","doi":"10.1016/j.bmcl.2024.130036","DOIUrl":"10.1016/j.bmcl.2024.130036","url":null,"abstract":"<div><div>Acute lung injury (ALI), a common critical disease in clinical practice, has a mortality rate as high as 30–40 %, yet currently, no effective treatment methods are available. Research on ALI indicated that inhibition of overexpressed inflammatory factors might be a potential treatment for ALI. In this study, a series of cinnamic acid derivatives were obtained by introducing diverse aminothiazole fragments into the natural product cinnamic acid. Among these derivatives, compound <strong>22</strong> displayed excellent activity of inhibiting the release of IL-6 in J774A.1 cells. Moreover, it also ameliorated the LPS-induced ALI in mouse model by suppressing cytokine expression, reducing lung edema and macrophage infiltration. These findings indicated that compound <strong>22</strong> might provide a new lead structure for the development of drugs for ALI.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130036"},"PeriodicalIF":2.5,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694972","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}
Pub Date : 2024-11-21DOI: 10.1016/j.bmcl.2024.130035
Harrison W. VanKoten , Breanna C. Pence , James R. Klinkenberg , Siddhartha Das , Steven E. Patterson
We reported earlier that oseltamivir (Osm, Tamiflu®), an anti-viral agent, inhibits the attachment of trophozoites to intestinal epithelial cells and cyst production in culture. Osm also disassembles lipid rafts (LRs) and the biogenesis of extracellular vesicles (EVs) by Giardia. In the current study, we synthesized forty-one Osm analogs with the derivatization of oseltamivir phosphate. These compounds were tested on giardial growth, and cyst production. Of these, four analogs, i.e., compounds 3b, 2c, 11i, and 11d, were found to have superior activities against trophozoites and cysts compared to the parent oseltamivir. Investigation of the mechanism(s) of action of these agents are in progress and will be reported in due course.
我们早些时候曾报道过，抗病毒药物奥司他韦（Osm，Tamiflu®）可抑制滋养体附着在肠上皮细胞上并在培养过程中产生囊肿。Osm 还能分解脂质筏（LRs）和贾第鞭毛虫胞外囊泡（EVs）的生物生成。在目前的研究中，我们利用磷酸奥司他韦衍生合成了 41 种 Osm 类似物。这些化合物对贾第鞭毛虫的生长和包囊的产生进行了测试。结果发现，与母体奥司他韦相比，其中四种类似物，即化合物 3b、2c、11i 和 11d 对滋养体和包囊具有更强的活性。对这些制剂作用机制的研究正在进行中，将在适当的时候报告。
{"title":"Synthesis and evaluation of anti-Giardia activity of oseltamivir analogs","authors":"Harrison W. VanKoten , Breanna C. Pence , James R. Klinkenberg , Siddhartha Das , Steven E. Patterson","doi":"10.1016/j.bmcl.2024.130035","DOIUrl":"10.1016/j.bmcl.2024.130035","url":null,"abstract":"<div><div>We reported earlier that oseltamivir (Osm, Tamiflu®), an anti-viral agent, inhibits the attachment of trophozoites to intestinal epithelial cells and cyst production in culture. Osm also disassembles lipid rafts (LRs) and the biogenesis of extracellular vesicles (EVs) by Giardia. In the current study, we synthesized forty-one Osm analogs with the derivatization of oseltamivir phosphate. These compounds were tested on giardial growth, and cyst production. Of these, four analogs, i.e., compounds <strong>3b</strong>, <strong>2c</strong>, <strong>11i</strong>, and <strong>11d</strong>, were found to have superior activities against trophozoites and cysts compared to the parent oseltamivir. Investigation of the mechanism(s) of action of these agents are in progress and will be reported in due course.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130035"},"PeriodicalIF":2.5,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692200","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}
Pub Date : 2024-11-20DOI: 10.1016/j.bmcl.2024.130038
Carolina Roxo, Anna Pasternak
DNA can self-assemble into G-quadruplexes and i-motifs non-canonical secondary structures that are formed by guanine-rich sequences and the cytosine-rich sequences, respectively. G-quadruplexes and i-motifs have been closely linked to cancer development since they can regulate genes expression in various promoter regions. Moreover, these structures have gained attention as viable targets for anticancer treatments because of their physicochemical properties and gene-regulatory functions. As a result, they are attractive molecular targets for innovative cancer therapies. Herein, we review the G-quadruplex and i-motif structures, their dynamic relationship in biological systems, as well as their significance in cancer biology and the potential therapeutic approaches. Furthermore, we also address the simultaneous and mutually exclusive formation of G-quadruplex and i-motif structures in cellular environment.
{"title":"Switching off cancer – An overview of G-quadruplex and i-motif functional role in oncogene expression","authors":"Carolina Roxo, Anna Pasternak","doi":"10.1016/j.bmcl.2024.130038","DOIUrl":"10.1016/j.bmcl.2024.130038","url":null,"abstract":"<div><div>DNA can self-assemble into G-quadruplexes and i-motifs non-canonical secondary structures that are formed by guanine-rich sequences and the cytosine-rich sequences, respectively. G-quadruplexes and i-motifs have been closely linked to cancer development since they can regulate genes expression in various promoter regions. Moreover, these structures have gained attention as viable targets for anticancer treatments because of their physicochemical properties and gene-regulatory functions. As a result, they are attractive molecular targets for innovative cancer therapies. Herein, we review the G-quadruplex and i-motif structures, their dynamic relationship in biological systems, as well as their significance in cancer biology and the potential therapeutic approaches. Furthermore, we also address the simultaneous and mutually exclusive formation of G-quadruplex and i-motif structures in cellular environment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130038"},"PeriodicalIF":2.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692189","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}
Pub Date : 2024-11-17DOI: 10.1016/j.bmcl.2024.130027
Marie M. Le Roy , Cassandra Métivier , Latifa Rbah-Vidal , Patricia Le Saëc , Hela Bouhsine , Michel Chérel , Alain Faivre-Chauvet , Thibault Troadec , Raphaël Tripier
Thank to their particular pharmacokinetics, the use of small organic molecules can be a very promising alternative to macromolecular targeting biomolecules (i.e. antibodies, peptides…) for specific imaging of tumours. Herein, the potential of two AMD070-like inhibitors as CXCR4-targeting units for specific imaging of cancer cells, and the influence of chromophore-grafting on their recognition properties was investigated.
{"title":"Grafting a chromophore on AMD070 analogues for CXCR4 bioimaging: Chemical synthesis and in vitro assessment of the inhibition properties of the CXCR4 receptor","authors":"Marie M. Le Roy , Cassandra Métivier , Latifa Rbah-Vidal , Patricia Le Saëc , Hela Bouhsine , Michel Chérel , Alain Faivre-Chauvet , Thibault Troadec , Raphaël Tripier","doi":"10.1016/j.bmcl.2024.130027","DOIUrl":"10.1016/j.bmcl.2024.130027","url":null,"abstract":"<div><div>Thank to their particular pharmacokinetics, the use of small organic molecules can be a very promising alternative to macromolecular targeting biomolecules (<em>i.e.</em> antibodies, peptides…) for specific imaging of tumours. Herein, the potential of two AMD070-like inhibitors as CXCR4-targeting units for specific imaging of cancer cells, and the influence of chromophore-grafting on their recognition properties was investigated.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130027"},"PeriodicalIF":2.5,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142646099","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}
Novel N-substituent diphenylamine derivatives as tubulin inhibitors targeting colchicine-binding site have been designed based on structural simplification and structural fusing strategy. Most designed compounds exhibited the moderate or potent antiproliferative activities against five cancer cell lines. Among them, compound 4k displayed the significant selectivity for osteosarcoma cells MG-63 and U2OS with the IC50 value of 0.08–0.14 μM. Further investigations verified 4k could inhibit tubulin polymerization by targeting colchicine binding site. Meanwhile, compound 4k not only effectively induced tumor cell cycle arrest at the G2/M phase, but also slightly induced cell apoptosis. These results indicated that N-substituent of diphenylamine derivatives are deserved for further development as tubulin colchicine binding site inhibitors.
{"title":"Design and evaluation of novel N-substituent diphenylamine derivatives as tubulin colchicine binding site inhibitors","authors":"Zhong Chen , Da-Wei Geng , Tang-Bo Yuan , Chen Yu , Da-Wei Cai , Yong Yin , Qiang Shen","doi":"10.1016/j.bmcl.2024.130031","DOIUrl":"10.1016/j.bmcl.2024.130031","url":null,"abstract":"<div><div>Novel <em>N</em>-substituent diphenylamine derivatives as tubulin inhibitors targeting colchicine-binding site have been designed based on structural simplification and structural fusing strategy. Most designed compounds exhibited the moderate or potent antiproliferative activities against five cancer cell lines. Among them, compound <strong>4k</strong> displayed the significant selectivity for osteosarcoma cells MG-63 and U2OS with the IC<sub>50</sub> value of 0.08–0.14 μM. Further investigations verified <strong>4k</strong> could inhibit tubulin polymerization by targeting colchicine binding site. Meanwhile, compound <strong>4k</strong> not only effectively induced tumor cell cycle arrest at the G2/M phase, but also slightly induced cell apoptosis. These results indicated that N-substituent of diphenylamine derivatives are deserved for further development as tubulin colchicine binding site inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130031"},"PeriodicalIF":2.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666306","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}
Pub Date : 2024-11-16DOI: 10.1016/j.bmcl.2024.130032
Daram Jung , Sun Hee Jin , Yeasel Jeon , Joonseo Kim , Sungjin Ahn , Minsoo Noh
PDZK1-interacting protein 1 (PDZK1IP1) has emerged as a potential therapeutic target for skin inflammatory diseases and epithelial tumors. This study investigates the modulation of PDZK1IP1 gene expression using peptide nucleic acids (PNAs), a class of oligonucleotide therapeutics known for their robust binding affinity to complementary nucleic acid sequences and their resistance to degradation by nucleases. To enhance water solubility and cellular permeability, modified PNA oligomers were synthesized by conjugating nucleobases with primary amine chains. A study using a fluorescein-labeled modified PNA oligomer demonstrated significantly enhanced cellular permeability in HaCaT cells compared to the unmodified PNA. These modified PNA oligomers effectively suppressed PDZK1IP1 gene expression and alleviated interferon γ (IFNγ)-induced inflammatory responses in normal human keratinocytes. These findings suggest the potential application of modified PNAs targeting PDZK1IP1 in the treatment of skin inflammatory diseases.
{"title":"Cell penetrable peptide nucleic acids targeting PDZK1IP1 with anti-inflammatory potential in human keratinocytes","authors":"Daram Jung , Sun Hee Jin , Yeasel Jeon , Joonseo Kim , Sungjin Ahn , Minsoo Noh","doi":"10.1016/j.bmcl.2024.130032","DOIUrl":"10.1016/j.bmcl.2024.130032","url":null,"abstract":"<div><div>PDZK1-interacting protein 1 (PDZK1IP1) has emerged as a potential therapeutic target for skin inflammatory diseases and epithelial tumors. This study investigates the modulation of PDZK1IP1 gene expression using peptide nucleic acids (PNAs), a class of oligonucleotide therapeutics known for their robust binding affinity to complementary nucleic acid sequences and their resistance to degradation by nucleases. To enhance water solubility and cellular permeability, modified PNA oligomers were synthesized by conjugating nucleobases with primary amine chains. A study using a fluorescein-labeled modified PNA oligomer demonstrated significantly enhanced cellular permeability in HaCaT cells compared to the unmodified PNA. These modified PNA oligomers effectively suppressed PDZK1IP1 gene expression and alleviated interferon γ (IFNγ)-induced inflammatory responses in normal human keratinocytes. These findings suggest the potential application of modified PNAs targeting PDZK1IP1 in the treatment of skin inflammatory diseases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130032"},"PeriodicalIF":2.5,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666356","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}
Pub Date : 2024-11-12DOI: 10.1016/j.bmcl.2024.130018
Cheng Peng , Li Sheng , Gao-Ya Xu , Xiao-Lei Qi , Yu-Bo Zhou , Jia-Li , Yong-Mei Cui
A series of novel 5-substituted thiazolyl urea derivatives were synthesized and evaluated for their efficacy as antileukemic agents against two human leukemic cell lines (THP-1 and MV-4-11). Results showed that the activities of the investigated compounds were quite sensitive to the positions and properties of the aromatic substituents. Among these compounds, compound 12k showed the highest activity with IC50 values of 29 ± 0.3 nM for THP-1 cells and 98 ± 10 nM for MV-4-11 cells.
{"title":"The synthesis and antileukemic activity of 5-substituted thiazolyl urea derivatives","authors":"Cheng Peng , Li Sheng , Gao-Ya Xu , Xiao-Lei Qi , Yu-Bo Zhou , Jia-Li , Yong-Mei Cui","doi":"10.1016/j.bmcl.2024.130018","DOIUrl":"10.1016/j.bmcl.2024.130018","url":null,"abstract":"<div><div>A series of novel 5-substituted thiazolyl urea derivatives were synthesized and evaluated for their efficacy as antileukemic agents against two human leukemic cell lines (THP-1 and MV-4-11). Results showed that the activities of the investigated compounds were quite sensitive to the positions and properties of the aromatic substituents. Among these compounds, compound <strong>12k</strong> showed the highest activity with IC<sub>50</sub> values of 29 ± 0.3 nM for THP-1 cells and 98 ± 10 nM for MV-4-11 cells.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130018"},"PeriodicalIF":2.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613402","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}
Pub Date : 2024-11-12DOI: 10.1016/j.bmcl.2024.130026
Yuebiao Zhou , Ignacio Aliagas , Shumei Wang , Chun Sing Li , Zhiguo Liu , Christine M. Bowman , Daniel J. Burdick , Kevin R. Clark , Tahnee J. Dening , John Flygare , Anjani Ganti , Hany S. Girgis , Emily J. Hanan , Seth F. Harris , Chloe Hu , Sharookh B. Kapadia , Michael F.T. Koehler , Tommy Lai , Jun Liang , Xingrong Liu , Terry D. Crawford
Tuberculosis is the leading cause of death from an infectious disease, and is caused by Mycobacterium tuberculosis (M.tb). More than 1 billion people worldwide are thought to harbor an M.tb infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant Mycobacterium tuberculosis treatment regimens are significantly longer. Inosine-5′-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in de novo guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including M.tb. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against M.tb H37Ra and H37Rv strains and have desirable safety and ADME profiles.
{"title":"Discovery of potent dihydro-oxazinoquinolinone inhibitors of GuaB for the treatment of tuberculosis","authors":"Yuebiao Zhou , Ignacio Aliagas , Shumei Wang , Chun Sing Li , Zhiguo Liu , Christine M. Bowman , Daniel J. Burdick , Kevin R. Clark , Tahnee J. Dening , John Flygare , Anjani Ganti , Hany S. Girgis , Emily J. Hanan , Seth F. Harris , Chloe Hu , Sharookh B. Kapadia , Michael F.T. Koehler , Tommy Lai , Jun Liang , Xingrong Liu , Terry D. Crawford","doi":"10.1016/j.bmcl.2024.130026","DOIUrl":"10.1016/j.bmcl.2024.130026","url":null,"abstract":"<div><div>Tuberculosis is the leading cause of death from an infectious disease, and is caused by <em>Mycobacterium tuberculosis (M.tb)</em>. More than 1 billion people worldwide are thought to harbor an <em>M.tb</em> infection. The multidrug therapy that represents the current standard of care requires a minimum of four months of dosing and drug resistant <em>Mycobacterium tuberculosis</em> treatment regimens are significantly longer. Inosine-5′-monophosphate dehydrogenase (GuaB) is the enzyme that performs the rate-limiting step in <em>de novo</em> guanine nucleotide biosynthesis that is critical for growth and viability of bacteria including <em>M.tb</em>. The development of a novel antibiotic that inhibits GuaB could combine with existing therapies in novel ways and thereby contribute to effective therapeutic regimens for the treatment of tuberculosis. Here we describe the discovery of structurally distinct small molecule GuaB inhibitors that are potent against <em>M.tb</em> H37Ra and H37Rv strains and have desirable safety and ADME profiles.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"117 ","pages":"Article 130026"},"PeriodicalIF":2.5,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613400","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}
Pub Date : 2024-11-10DOI: 10.1016/j.bmcl.2024.130025
Anastasiia A. Uspenskaia , Irina A. Doroshenko , Kseniia A. Popovicheva , Nazar V. Shmychkov , Ekaterina V. Pryakhina , Radik R. Shafikov , Dmitrii A. Skvortsov , Mikhail K. Beklemishev , Olga V. Zaborova , Tatiana A. Podrugina , Aleksei E. Machulkin , Elena K. Beloglazkina
We report a modified carbocyanine-based asymmetric fluorescent dye, suitable for the azide-alkyne cycloaddition reaction, that possesses promising photochemical properties (Φfl = 0,49). As an example of usage of the new fluorophore, it was conjugated to a ligand targeting prostate-specific membrane antigen (PSMA), one of the widely utilized prostate cancer markers.
{"title":"Pentamethine cyanine dyes with alkynyl group as perspective structure for conjugation with targeting moiety","authors":"Anastasiia A. Uspenskaia , Irina A. Doroshenko , Kseniia A. Popovicheva , Nazar V. Shmychkov , Ekaterina V. Pryakhina , Radik R. Shafikov , Dmitrii A. Skvortsov , Mikhail K. Beklemishev , Olga V. Zaborova , Tatiana A. Podrugina , Aleksei E. Machulkin , Elena K. Beloglazkina","doi":"10.1016/j.bmcl.2024.130025","DOIUrl":"10.1016/j.bmcl.2024.130025","url":null,"abstract":"<div><div>We report a modified carbocyanine-based asymmetric fluorescent dye, suitable for the azide-alkyne cycloaddition reaction, that possesses promising photochemical properties (Φ<sub>fl</sub> = 0,49). As an example of usage of the new fluorophore, it was conjugated to a ligand targeting prostate-specific membrane antigen (PSMA), one of the widely utilized prostate cancer markers.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"115 ","pages":"Article 130025"},"PeriodicalIF":2.5,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613401","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}
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