Bioorganic & Medicinal Chemistry Letters最新文献_第4页

Synthesis of quinazoline derivatives and their in vitro inhibition activity against MDA-MB-231 cells and A549 cells 喹唑啉衍生物的合成及其对MDA-MB-231细胞和A549细胞的体外抑制活性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-12 DOI: 10.1016/j.bmcl.2025.130308

Mengyuan Yang , Jie Xu , Mengmeng Zhao , Jiaxin Zhou , Yifan Hou , Long Zhao , Fang Liu , Yinjiu Huang

{"title":"Synthesis of quinazoline derivatives and their in vitro inhibition activity against MDA-MB-231 cells and A549 cells","authors":"Mengyuan Yang , Jie Xu , Mengmeng Zhao , Jiaxin Zhou , Yifan Hou , Long Zhao , Fang Liu , Yinjiu Huang","doi":"10.1016/j.bmcl.2025.130308","DOIUrl":"10.1016/j.bmcl.2025.130308","url":null,"abstract":"<div><div>A series of novel 4-aniline quinazoline derivatives (Y1-Y26) were synthesised from 2-amino-6-nitrobenzoic acid based on the quinazoline parent nucleus via trifluoroacetylation, ring-closing and chlorination; The CCK-8 method was used to assess the in vitro inhibitory activities of the resulting compounds against two distinct cell lines: breast cancer cells (MDA-MB-231) and non-small cell lung cancer (A549). The results demonstrated that most of the compounds exhibited in vitro proliferation inhibitory activity against both MDA-MB-231 and A549 cells. Among these, compound Y22 exhibited the strongest inhibitory effect on MDA-MB-231 cells (IC50 = 4.53 μM); As the concentration of Y22 increased, the inhibition of cell proliferation was enhanced, and the cells gradually shrank and underwent morphological changes consistent with apoptosis; Transwell assay demonstrated that the compound Y22 exhibited a substantial inhibitory effect on cell migration; Flow cytometry revealed a substantial augmentation in apoptosis with elevated compound concentrations; Western blot analysis indicated that Y22 may exert in vitro antitumour activity by decreasing the expression of the anti-apoptotic protein Bcl-2 while increasing the expression of the pro-apoptotic protein Bax. The findings of these studies suggest that Y22 can potentially plays a significant role in the design and synthesis of antitumour drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130308"},"PeriodicalIF":2.5,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293043","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, synthesis and antitumor evaluation of a novel nectin-4 targeting bicyclic toxin conjugate 新型靶向双环毒素偶联物nectin-4的设计、合成及抗肿瘤评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-10 DOI: 10.1016/j.bmcl.2025.130306

Jia-Ning Gu , Feng Liu , Yun-Song Song , Hai-Feng Ding , Xiang-Yang Feng , Xian-Li Ma , Yang-Qing Huang , Ye Zhang

{"title":"Design, synthesis and antitumor evaluation of a novel nectin-4 targeting bicyclic toxin conjugate","authors":"Jia-Ning Gu , Feng Liu , Yun-Song Song , Hai-Feng Ding , Xiang-Yang Feng , Xian-Li Ma , Yang-Qing Huang , Ye Zhang","doi":"10.1016/j.bmcl.2025.130306","DOIUrl":"10.1016/j.bmcl.2025.130306","url":null,"abstract":"<div><div>A Nectin-4 targeting bicyclic toxin conjugate (BTC) BGC1614 was designed, synthesized and evaluated as an antitumor agent. Fluorescence-activated cell sorting (FACS) assay results indicated that BGC1614 exhibited selective and strong binding to Nectin-4-expressing cells in comparison with the clinical drug BT8009. Surface plasmon resonance (SPR) test showed that the equilibrium dissociation constants (KD) for BT8009 and BGC1614 were 3.219 ± 0.412 × 10−7 M and 3.859 ± 0.287 × 10−7 M, respectively, indicating that BGC1614 exhibited similar target engagement capability with Nectin-4 compared to BT8009. In vivo antiproliferative activity assay results showed that BGC1614 (0.12 μM/kg) exhibited better antiproliferative activity than BT8009 (0.12 μM/kg, inhibition rate (IR) 87.6 %) in PC-3 (human prostate cancer cell) model with IR of 96.3 %, while BGC1614 (0.36 μM/kg) displayed similar inhibition with BT8009 (0.36 μM/kg, IR 72.7 %) in N87 (human gastric cancer cell) model with IR of 70.1 %, demonstrating that BGC1614 exhibited better antitumor effect in the same molar concentration in PC-3 model. In addition, BGC1614 was well-tolerated in efficacious doses in the nude model assays, while the pharmacokinetic (PK) parameters of BGC1614 were comparable to that of BT8009.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130306"},"PeriodicalIF":2.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281855","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

Fighting Alzheimer's naturally: Peptides as multitarget drug leads 自然对抗阿尔茨海默病：多肽作为多靶点药物的先导。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-08 DOI: 10.1016/j.bmcl.2025.130305

Roque Spinelli , Ivan Sanchís , Alvaro Siano

{"title":"Fighting Alzheimer's naturally: Peptides as multitarget drug leads","authors":"Roque Spinelli , Ivan Sanchís , Alvaro Siano","doi":"10.1016/j.bmcl.2025.130305","DOIUrl":"10.1016/j.bmcl.2025.130305","url":null,"abstract":"<div><div>In this review, we provide a comprehensive analysis of the role of natural peptides—particularly those derived from amphibian skin secretions—as multitarget-directed ligands (MTDLs) in the context of Alzheimer's disease (AD). Given the multifactorial nature of AD, where cholinergic dysfunction intersects with amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, metal ion imbalance, and monoamine oxidase dysregulation, therapeutic strategies capable of modulating several pathological pathways simultaneously are urgently needed. We begin by revisiting the cholinergic hypothesis and its molecular and structural underpinnings, emphasizing the relevance of key binding sites such as the catalytic active site (CAS) and the peripheral anionic site (PAS) of cholinesterases. The central axis of this review lies in the exploration of naturally occurring peptides that have demonstrated dual or multiple activities against AD-related targets. We highlight our group's pioneering work on amphibian-derived peptides such as Hp-1971, Hp-1935, and BcI-1003, which exhibit non-competitive inhibition of AChE and BChE, MAO-B modulation, and antioxidant properties. Furthermore, we describe additional peptide-rich extracts and bioactive sequences from various amphibians and other animal or plant sources, expanding the landscape of natural molecules with neuroprotective potential. We also delve into peptide modification strategies—such as amino acid substitution, cyclization, D-amino acid incorporation, and terminal/side-chain functionalization—that have been employed to enhance peptide stability, blood-brain barrier permeability, and target affinity. These strategies not only improve the pharmacokinetic profiles of native peptides but also open the door for the rational design of next-generation peptide therapeutics. Overall, this review underscores the vast potential of natural peptides as scaffolds for the development of multifunctional agents capable of intervening in the complex cascade of Alzheimer's pathology.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"127 ","pages":"Article 130305"},"PeriodicalIF":2.5,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264981","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

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