Bioorganic & Medicinal Chemistry Letters最新文献

Potential of fat-soluble vitamins as a platform for antiviral drug development 脂溶性维生素作为抗病毒药物开发平台的潜力

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-06 DOI: 10.1016/j.bmcl.2025.130292

Yoshihisa Hirota , Mika Okamoto , Masanori Baba , Yoshitomo Suhara

引用次数: 0

Discovery of 3-phenyl-1H-5-pyrazolylamides as PLpro inhibitors through virtual screening and structure optimization 通过虚拟筛选和结构优化发现3-苯基- 1h -5吡唑酰胺作为PLpro抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-03 DOI: 10.1016/j.bmcl.2025.130293

Chengwei Wu , Mengdie Ou , Bo Qin , Shuo Wang , Peng Li , Sheng Cui , Haihong Huang , Gang Li

{"title":"Discovery of 3-phenyl-1H-5-pyrazolylamides as PLpro inhibitors through virtual screening and structure optimization","authors":"Chengwei Wu , Mengdie Ou , Bo Qin , Shuo Wang , Peng Li , Sheng Cui , Haihong Huang , Gang Li","doi":"10.1016/j.bmcl.2025.130293","DOIUrl":"10.1016/j.bmcl.2025.130293","url":null,"abstract":"<div><div>The papain-like protease (PLpro) of SARS-CoV-2 has been identified as a pivotal enzyme in viral replication, indicating it a promising target for drug discovery. Utilizing a virtual screening strategy, compound 1 with the N-(3-(5-amino-1H-pyrazol-3-yl)phenyl) benzenesulfonamide scaffold was discovered as a hit targeting PLpro. Structural modification from virtually screened hit 1 led to the development of a series of substituted 3-phenyl-1H-5-pyrazolylamide derivatives. Notably, compounds 14h and 14e exhibited improved PLpro inhibitory activity (IC50 = 14.2 μM and 12.0 μM, respectively) and low cytotoxicity. Further biological evaluation revealed that compound 14e with a thiophene aldehyde group displayed potent binding activity (KD = 1.86 μM). This 3-phenyl-1H-5-pyrazolylamide scaffold offers significant potential for further development as a novel class of PLpro inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130293"},"PeriodicalIF":2.5,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232817","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}

引用次数: 0

Discovery of a novel CD39 inhibitor by DNA-encoded library screening 通过dna编码文库筛选发现一种新的CD39抑制剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-02 DOI: 10.1016/j.bmcl.2025.130294

Simin Wang , Jiannan Zhao , Takashi Nakai , Suyi Chen , Yongtao Duan , Ruijun Li , Chuanjun Song , Yongfang Yao

{"title":"Discovery of a novel CD39 inhibitor by DNA-encoded library screening","authors":"Simin Wang , Jiannan Zhao , Takashi Nakai , Suyi Chen , Yongtao Duan , Ruijun Li , Chuanjun Song , Yongfang Yao","doi":"10.1016/j.bmcl.2025.130294","DOIUrl":"10.1016/j.bmcl.2025.130294","url":null,"abstract":"<div><div>The ATP-adenosine pathway, as a key regulator of adaptive immunity, can regulate tumor growth and proliferation, which is an important direction of anti-tumor immunity research. As a rate-limiting extracellular nucleotidase in eATP hydrolysis, CD39 is a promising target for anticancer therapy. In this study, we discovered a novel CD39 small molecule inhibitor (compound 338) by DNA-encoded library (DEL) technology. Subsequently, compound 338 was synthesized and tested with promising inhibitory effect which IC50 value was 68.7 nM against CD39. It also showed moderate anti-proliferative effects on tumor cells and low toxicity on normal cell lines. Meanwhile, molecular docking and SPR results demonstrated that 338 had a robust binding interaction with CD39. The druggability of 338 was predicted. In conclusion, the novel compound 338 showed strong CD39 inhibitory activity and good druggability, which can be used as a potential anti-tumor therapeutic agent and can be optimized in further studies.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130294"},"PeriodicalIF":2.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221760","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}

引用次数: 0

Asymmetric synthesis of potent and orally bioavailable thiophene-based EZH2 inhibitors 有效的口服噻吩基EZH2抑制剂的不对称合成。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-30 DOI: 10.1016/j.bmcl.2025.130291

Xinrong Tian, Ken Newlander, Louis LaFrance, James Mack, James Brackley, Charles McHugh, Yanan He, Neil Johnson, Maggie Truong, Melissa B. Pappalardi, Michael T. McCabe, Steven D. Knight

引用次数: 0

Design and synthesis of hydroxychloroquine-sugar conjugates as promising antimalarial agents 羟氯喹-糖偶联物抗疟药物的设计与合成

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-29 DOI: 10.1016/j.bmcl.2025.130289

Emil Salim , Hilkatul Ilmi , Aty Widyawaruyanti , Natsuhisa Oka

引用次数: 0

Synthesis of substrate peptides incorporating non-natural amino acids and screening study using BACE1 含非天然氨基酸的底物肽的合成及BACE1筛选研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-28 DOI: 10.1016/j.bmcl.2025.130290

Shinji Katsuoka, Ryo Watanabe, Yuma Uchida, Masaki Midorikawa, Reo Yamada, Taeko Kakizawa

引用次数: 0

Design, synthesis, and activity evaluation of Asiatic acid derivatives as Survivin inhibitors 亚洲酸衍生物作为Survivin抑制剂的设计、合成和活性评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-23 DOI: 10.1016/j.bmcl.2025.130288

Heng Wu , Liangfeng Zhang , Xuehao Lu , Yuting Han , Zan Wang , Yanqiu Meng

{"title":"Design, synthesis, and activity evaluation of Asiatic acid derivatives as Survivin inhibitors","authors":"Heng Wu , Liangfeng Zhang , Xuehao Lu , Yuting Han , Zan Wang , Yanqiu Meng","doi":"10.1016/j.bmcl.2025.130288","DOIUrl":"10.1016/j.bmcl.2025.130288","url":null,"abstract":"<div><div>Asiatic acid, a triterpenoid isolated from Centella asiatica, putatively functions through inhibition of Survivin—a member of the Inhibitor of Apoptosis Protein (IAP) family that modulates tumor survival. Taking GDP366 and LQZ-7I, two Survivin inhibitors of preclinical stage, as reference compounds, two classes of novel Asiatic acid derivatives (24 compounds in total) were designed and synthesized. These compounds demonstrated favorable docking capabilities and binding modes with the three-dimensional crystal structure of Survivin. The MTT assay demonstrated that these compounds exhibited anti-proliferative effects against A549 and MCF-7 cell lines, with compounds I3, I9, II3, II5, and II12 showing potency comparable to the positive control drug. Furthermore, Western blot analysis revealed that compound II3 dose-dependently reduced Survivin protein levels. Compound II3 provides a valuable reference for further research on Survivin inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130288"},"PeriodicalIF":2.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141019","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}

引用次数: 0

Discovery of nonpungent Transient Receptor Potential Vanilloid (TRPV1) agonist antedrugs for treatment of dysphagia 发现非刺激性瞬时受体电位香草样蛋白（TRPV1）激动剂治疗吞咽困难

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI: 10.1016/j.bmcl.2025.130287

Hiroyuki Kitano , Yuki Mizukami, Masanori Miyauchi, Itaru Natsutani, Kozo Yoshida

{"title":"Discovery of nonpungent Transient Receptor Potential Vanilloid (TRPV1) agonist antedrugs for treatment of dysphagia","authors":"Hiroyuki Kitano , Yuki Mizukami, Masanori Miyauchi, Itaru Natsutani, Kozo Yoshida","doi":"10.1016/j.bmcl.2025.130287","DOIUrl":"10.1016/j.bmcl.2025.130287","url":null,"abstract":"<div><div>Transient Receptor Potential Vanilloid 1 (TRPV1) is a ligand-gated nonselective cation channel that functions as a cellular sensor for heat and chemical stimuli, such as vanilloids. In recent years, TRPV1 has gained attention as a therapeutic target for treating dysphagia, with both preclinical and clinical trials utilizing capsaicin, a member of the vanilloid family. However, TRPV1 agonists often have pronounced irritant properties and may potentially induce hypothermia upon systemic exposure. Here, we describe the synthesis and characterization of a series of nonpungent TRPV1 agonists with antedrug properties. The discovered compounds exhibit similar agonistic properties to capsaicin, while demonstrating low irritancy in animal models and showing no systemic exposure when administered orally. As these compounds selectively act within the oral cavity without causing a sensation of spiciness, they offer a useful alternative to address the challenges associated with TRPV1 agonists as therapeutic agents for improving dysphagia.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130287"},"PeriodicalIF":2.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134186","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}

引用次数: 0

Telomerase reverse transcriptase degradation via a rationally designed covalent proteolysis targeting chimera 端粒酶逆转录酶降解通过合理设计的共价蛋白水解靶向嵌合体。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI: 10.1016/j.bmcl.2025.130286

Grant B. Frost , Yue Liu , Stephen J. Kron , Karl A. Scheidt

{"title":"Telomerase reverse transcriptase degradation via a rationally designed covalent proteolysis targeting chimera","authors":"Grant B. Frost , Yue Liu , Stephen J. Kron , Karl A. Scheidt","doi":"10.1016/j.bmcl.2025.130286","DOIUrl":"10.1016/j.bmcl.2025.130286","url":null,"abstract":"<div><div>Expression of telomerase reverse transcriptase (TERT) is a hallmark of cancer, maintaining telomere integrity to enable replicative immortality. However, TERT also serves multiple enzyme-dependent and -independent functions to support cancer growth and survival, including enhanced DNA damage response. Agents that inhibit TERT reverse transcriptase activity prevent telomere elongation but may fail to limit other TERT functions that mediate cancer therapy resistance. Thus, we applied structure-based design, modular synthesis, and biochemical assays towards developing a proteolysis targeting chimera (PROTAC) to drive proteasomal degradation of TERT in cancer cells. This yielded NU-PRO-1, a PROTAC linking the TERT active site-targeted covalent inhibitor NU-1 to the VHL E3-ligase ligand (S,R,S)-AHPC. Applied to cancer cells, NU-PRO-1 induced transient VHL- and proteasome-dependent TERT degradation. NU-PRO-1 did not induce DNA damage on its own but acted to further delay DNA repair after irradiation compared to NU-1. TERT-degrading PROTACs provide novel chemical probes of TERT's non-catalytic functions and may overcome the limitations of current telomerase inhibitors as cancer therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130286"},"PeriodicalIF":2.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141024","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}

引用次数: 0

Design and characterization of N-oxide cinnamanilide derivative PX5–9: Improved solubility and BDNF upregulation n -氧化物肉桂苯胺衍生物PX5-9的设计和表征：改善溶解度和上调BDNF

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-05-22 DOI: 10.1016/j.bmcl.2025.130266

Zhixian Zhang , Qianhui Shen , Yanping Chen , Zhi Liang , Yuan Liu , Yu Ren , Cailv Wei , Kang Jia , Chao Ding , Shisong Wang , Rongbiao Pi

{"title":"Design and characterization of N-oxide cinnamanilide derivative PX5–9: Improved solubility and BDNF upregulation","authors":"Zhixian Zhang , Qianhui Shen , Yanping Chen , Zhi Liang , Yuan Liu , Yu Ren , Cailv Wei , Kang Jia , Chao Ding , Shisong Wang , Rongbiao Pi","doi":"10.1016/j.bmcl.2025.130266","DOIUrl":"10.1016/j.bmcl.2025.130266","url":null,"abstract":"<div><div>Compound 5, a cinnamanilide derivative, upregulates brain derivated neurotrophic factor (BDNF) expression but with low soluablity. In this study, PX5–9, a N-oxide derivative of 5, demonstrated significant protective effects in the HT22 glutamate-induced toxicity model and showed no significant toxicity at 30 μM. Western blot analysis confirmed that PX5–9 increased BDNF levels similar to 5. Solubility tests revealed a significant improvement in PX5–9 (37.10 ± 0.33 μg/mL) compared to 5 (< 15 ng/mL). Pharmacokinetic studies of PX5–9 revealed favorable properties, fast absorption and also can be transformated into parent compound 5, suggesting it is a potential candidate for these diseases involving with BDNF. The N-oxide modification might be a good prodrug design to enhance solubility while preserving biological activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"125 ","pages":"Article 130266"},"PeriodicalIF":2.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144125083","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}

引用次数: 0