Bioorganic & Medicinal Chemistry Letters最新文献

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Discovery of 4-((quinolin-8-ylthio)methyl)benzamide derivatives as a new class of SARS-CoV-2 nsp13 inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-25 DOI: 10.1016/j.bmcl.2025.130207

Danchen Fan , Yuanting Huang , Rui Yao , Guo Zhang , Shengyong Yang , Linli Li

Antivirals have provided important protection against COVID-19, however, the emergence of SARS-CoV-2 variants and drug-resistant mutants calls for the development of novel anti-coronavirus drugs with alternative mechanisms of action. The nonstructural protein 13 (nsp13) of SARS-CoV-2 plays a conserved role in the replication of coronaviruses and has been identified as a promising target. In this study, we report a series of 4-((quinolin-8-ylthio)methyl)benzamide derivatives as inhibitors of SARS-CoV-2 nsp13. Through structure-activity relationship (SAR) analyses, we identified compound 6r, which demonstrated potent inhibition of nsp13 with an IC₅₀ value of 0.28 ± 0.11 μM. Collectively, we discovered a new potent SARS-CoV-2 nsp13 inhibitor, which could be taken as a promising lead compound for further drug development targeting SARS-CoV-2 nsp13.

引用次数: 0

Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-25 DOI: 10.1016/j.bmcl.2025.130209

Xiaoshuang Dai , Ke Mei , Jianpeng Liu , Bin Sun , Neng Qiu

In this study, ferulic acid (FA) was conjugated with biotin via a disulfide bond to improve its anticancer activity. The resulting conjugate (FA-SS-Bio) was characterized by proton nuclear magnetic resonance (¹H NMR) and exhibited an amorphous structure, in contrast to the crystalline nature of FA. FA-SS-Bio demonstrated accelerated drug release under reductive and oxidative conditions. Biotinylation significantly increased cell uptake of the drug in biotin receptor (BR)-positive HeLa and MCF-7 cells, as confirmed by cellular uptake studies and molecular docking, which revealed strong biotin-BR interactions. Additionally, the cytotoxicity of FA-SS-Bio was significantly improved, with IC₅₀ values that were 2.94-fold and 2.95-fold lower than those of free FA against HeLa and MCF-7 cells, respectively. BR blockade with biotin reduced FA-SS-Bio cytotoxicity in a concentration-dependent manner, confirming biotin-mediated targeting. Apoptosis assays showed enhanced FA-induced apoptosis due to biotin and disulfide bonds. FA-SS-Bio demonstrated excellent blood compatibility, with a hemolysis rate below 0.5 %, compared to ∼1.5 % for FA. Additionally, FA-SS-Bio exhibited higher cell viability in MCF-10 A cells than in cancer cells, highlighting its favorable safety profile. These findings provide a novel perspective on the design of prodrug conjugates for improved cancer therapy.

{"title":"Redox-responsive ferulic acid-biotin conjugate: Design, synthesis, and enhanced anticancer efficacy","authors":"Xiaoshuang Dai , Ke Mei , Jianpeng Liu , Bin Sun , Neng Qiu","doi":"10.1016/j.bmcl.2025.130209","DOIUrl":"10.1016/j.bmcl.2025.130209","url":null,"abstract":"<div><div>In this study, ferulic acid (FA) was conjugated with biotin via a disulfide bond to improve its anticancer activity. The resulting conjugate (FA-SS-Bio) was characterized by proton nuclear magnetic resonance (<sup>1</sup>H NMR) and exhibited an amorphous structure, in contrast to the crystalline nature of FA. FA-SS-Bio demonstrated accelerated drug release under reductive and oxidative conditions. Biotinylation significantly increased cell uptake of the drug in biotin receptor (BR)-positive HeLa and MCF-7 cells, as confirmed by cellular uptake studies and molecular docking, which revealed strong biotin-BR interactions. Additionally, the cytotoxicity of FA-SS-Bio was significantly improved, with IC<sub>50</sub> values that were 2.94-fold and 2.95-fold lower than those of free FA against HeLa and MCF-7 cells, respectively. BR blockade with biotin reduced FA-SS-Bio cytotoxicity in a concentration-dependent manner, confirming biotin-mediated targeting. Apoptosis assays showed enhanced FA-induced apoptosis due to biotin and disulfide bonds. FA-SS-Bio demonstrated excellent blood compatibility, with a hemolysis rate below 0.5 %, compared to ∼1.5 % for FA. Additionally, FA-SS-Bio exhibited higher cell viability in MCF-10 A cells than in cancer cells, highlighting its favorable safety profile. These findings provide a novel perspective on the design of prodrug conjugates for improved cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130209"},"PeriodicalIF":2.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715530","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

PEG-ASO conjugates for efficient targeted delivery and migration inhibition in Cancer cell

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130208

Chunhui Zhao , Xiangjun Li , Zixin He , Chun Ye , Feng Chen , Jia Cheng

Antisense oligonucleotides (ASO) specifically bind target RNAs resulted in gene silencing, thereby inhibiting cancer cell growth. Chemical modification based on polyethylene glycol (PEG) usually improve resistance to nuclease degradation. However, the specificity and cellular uptake of PEG-conjugated ASOs for tumor cells is still a challenge. In this work, the folate (FA) and maleimide co-modified PEG was prepared and bound with thiol-modified anti-miRNA-21 ASO to form the FA-PEG-ASO conjugates by thiol-maleimide Michael addition. During the FA-PEG-ASO preparation process, removing tris-(2-carboxyethyl) phosphine hydrochloride (TCEP) is the key for the high yields. Cell imaging results showed FA-PEG-ASO internalized by the cells taken up ∼5 times higher than the control HO-PEG-ASO prepared by maleimide modified PEG and anti-miRNA-21 ASO. In addition, FA-PEG-ASO exhibited higher target cleavage and a greater reduction in tumor cell migration ability. Together, FA-PEG-ASO is a promising therapeutic platform.

引用次数: 0

Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130211

Longhao Wang, Shunshun Lei, Liyun Du, Chengyao Lai, Weijie Yang, Liqin Qiu, Rihui Cao

Tyrosinase is the key rate-limiting enzyme for melanin synthesis. The accumulation and excessive production of melanin lead to skin pigmentation. Therefore, tyrosinase is the target of tyrosinase inhibitors to control melanin synthesis. Only a few TYR inhibitors have been proven to be effective and safe to treat skin pigmentation. This highlights the importance of developing new tyrosinase inhibitors. Based on the reported tyrosinase inhibitors with phenylalanine structure, a series of novel phenylalanine derivatives were synthesized and investigated as mTYR inhibitors. The results demonstrated that most of these derivatives had more potent mTYR inhibitory activities than positive controls. Compound 3e was found to be the strongest inhibitor with an IC₅₀ value of 4.86 ± 0.026 μM. The Lineweaver-Burk plots of mTYR inhibition kinetics revealed that the selected compounds 2d and 3e were reversible and competitive inhibitors. In addition, molecular docking results of compounds 2d and 3e show they could compete with the substrate for the active center, including mTYR and hTYR. And the ADME prediction of selected derivatives assess the potential druglikeness. These results indicated that this class of compounds could be used as leads for developing new TYR inhibitors.

{"title":"Design, synthesis, molecular docking and ADME of novel phenylalanine derivatives as mushroom tyrosinase inhibitors","authors":"Longhao Wang, Shunshun Lei, Liyun Du, Chengyao Lai, Weijie Yang, Liqin Qiu, Rihui Cao","doi":"10.1016/j.bmcl.2025.130211","DOIUrl":"10.1016/j.bmcl.2025.130211","url":null,"abstract":"<div><div>Tyrosinase is the key rate-limiting enzyme for melanin synthesis. The accumulation and excessive production of melanin lead to skin pigmentation. Therefore, tyrosinase is the target of tyrosinase inhibitors to control melanin synthesis. Only a few TYR inhibitors have been proven to be effective and safe to treat skin pigmentation. This highlights the importance of developing new tyrosinase inhibitors. Based on the reported tyrosinase inhibitors with phenylalanine structure, a series of novel phenylalanine derivatives were synthesized and investigated as mTYR inhibitors. The results demonstrated that most of these derivatives had more potent mTYR inhibitory activities than positive controls. Compound <strong>3e</strong> was found to be the strongest inhibitor with an IC<sub>50</sub> value of 4.86 ± 0.026 μM. The Lineweaver-Burk plots of mTYR inhibition kinetics revealed that the selected compounds <strong>2d</strong> and <strong>3e</strong> were reversible and competitive inhibitors. In addition, molecular docking results of compounds <strong>2d</strong> and <strong>3e</strong> show they could compete with the substrate for the active center, including mTYR and hTYR. And the ADME prediction of selected derivatives assess the potential druglikeness. These results indicated that this class of compounds could be used as leads for developing new TYR inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"122 ","pages":"Article 130211"},"PeriodicalIF":2.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143725539","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

Synthesis and biological evaluation of amino-conjugated bile acid derivatives against non-alcoholic steatohepatitis

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-24 DOI: 10.1016/j.bmcl.2025.130210

Zhitao Wu , Mingge Zhang , Meng Kun Yan , Chenyue Li , Guoyu Pan , Lijiang Xuan

Non-alcoholic steatohepatitis (NASH) is emerging as a rapidly growing health concern. Bile acids (BAs) function as endocrine signaling molecules and exhibit therapeutic potential for NASH. To develop safer and more effective BA derivatives for NASH treatment, 25 amino acid-conjugated bile acid derivatives were designed and synthesized based on the pharmacological properties of the leading compound A17. The anti-lipid accumulation, anti-inflammatory and anti-fibrosis activities of these compounds were evaluated, and their structure-activity relationships were elucidated. Notably, compound C04 exhibited superior in vitro activity compared to obeticholic acid and demonstrated enhanced efficacy in improving both NASH and fibrosis in preclinical murine models via oral administration. These findings suggest that C04 is a promising candidate for NASH treatment and warrants further investigation.

引用次数: 0

Imide-based enones: A new scaffold that inhibits biofilm formation in Gram-negative pathogens

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-23 DOI: 10.1016/j.bmcl.2025.130206

J. Israel Barrera-Hernández , Jesús R. Pérez-Velázquez , Ángel Ramírez-Trinidad , Jesús Oria-Hernández , Eduardo Hernández-Vázquez

We prepared a series of enones containing different substituents as potential antibiofilm molecules. The design considered the structural features previously found in N-acylhomoserine lactones, but it replaced the labile furanone with different imides portions. After evaluation, some of the analogs inhibited 50 % or more the formation of the biofilm from P. aeruginosa or A. baumannii; moreover, substituents attached at the phenyl ring, the size of the enone as well as the type of imide seemed relevant for the selectivity against the tested pathogens. In the end, we performed a molecular docking study using the crystallized LasR to describe the main interactions of the ligand-receptor complex and propose a plausible mechanism of action.

引用次数: 0

Design, synthesis, and evaluation of a novel protein degrader FPFT-2216

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-22 DOI: 10.1016/j.bmcl.2025.130193

Yasuyuki Ueda, Takashi Ando, Yoshiteru Eikyu, Takumi Okamoto, Hironori Yokoyama, Naoshi Kunimura, Daiki Kanaoka, Shotaro Izuno, Mayumi Watanabe

For multiple myeloma (MM), various modalities of therapeutic drugs have been approved in recent years, and treatment outcomes for MM have greatly improved, but unmet medical needs still exist and new therapeutic drugs are needed. With the aim of developing a therapeutic drug for MM that has a scaffold different from the protein degrader immunomodulatory drugs (IMiDs), exploratory research was performed using the highly useful Huisgen cycloaddition reaction, and a novel lead compound 3-(4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl)piperidine-2,6-dione (FPFT-2127) was discovered. Optimization studies identified FPFT-2216, which exhibited stronger antitumor activity against MM than existing thalidomide derivatives. Furthermore, FPFT-2216 showed a synergistic combination effect with Daratumumab (Dara), a standard treatment for MM.

引用次数: 0

Tyrosine and proline conjugated trolox, hydroxy-cinnnamic acid and diclofenac hybrids as strong hypolipidemic and anti-inflammatory agents.

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-22 DOI: 10.1016/j.bmcl.2025.130194

Panagiotis Theodosis-Nobelos , Eleni A. Rekka

Oxidative stress induces the signaling of inflammatory and apoptotic pathways leading to the progression of degenerative disorders, whilst lipid increase and oxidation is an important factor for their development and propagation. L-tyrosine and L-proline amino acids and their derivatives have shown to be implicated in several of these aspects in a positive manner. In this prospect, methyl esters of these amino acids, amidated with the antioxidants trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid (hydroxylated cinnamic acid compound), as well as the classical NSAID diclofenac, were prepared and evaluated as antioxidant, anti-inflammatory and anti-hyperlipidemic agents. Almost all compounds presented high or moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and lipid peroxidation inhibitory activity, reaching up to 12 fold (in the lipid peroxidation inhibition) that of the parent antioxidant acids, such as trolox, whilst the insertion of the tyrosine moiety seemed to offer additional antioxidant potency, especially in the case of the NSAID derivative (compound 3). The majority of them displayed significant in vivo acute inflammation reduction (decrease of paw oedema, induced by carrageenan, 33–78 % at 150 μmol/kg) ability. The most active trolox-proline hybrid (compound 4) exhibited more than two fold increased inhibition in comparison to the well-established NSAIDs ibuprofen and diclofenac. They were also moderate inhibitors of soybean lipoxygenase, however active, in several cases, compared to their parent acid molecules. The most profound activity of the compounds was the reduction of the plasma lipidemic indices (Triton-induced hyperlipidemia in rats). Compound 5 was the most potent, with decrease in triglycerides, total cholesterol and low density lipoprotein, by 56 %, 87 %, and 72 %, respectively at 150 μmol/kg (i.p.), slightly better than that of simvastatin. Thus, the insertion of proline and tyrosine moieties seem to improve the anti-inflammatory activity of parent acids and NSAIDs, resulting in compounds with two or more pharmacological features (including hypolipidemic activity), which might be beneficial in cases characterized by inflammatory, oxidative, hyperlipidemic and degenerative conditions.

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引用次数: 0

Discovery of liver-selective glucokinase activators comprising N-(4-alkylthiazol-2-yl)benzamides and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamides for the treatment of metabolic disorders

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-22 DOI: 10.1016/j.bmcl.2025.130192

David S. Yoon, Shung Wu, Sean S. Chen, Rebecca A. Smirk, Robert P. Brigance, Wei Meng, Yan Shi, Shiwei Tao, Ying Wang, Hao Zhang, Arvind Mathur, Helen Grace Catanio, Stephen Kalinowski, Rachel Zebo, Jacob Zalaznick, Joseph Taylor, Bradley Zinker, Lisa M. Kopcho, Kamelia Behnia, Carrie Xu, Peter T.W. Cheng

Glucokinase (“GK”) plays a critical role in regulating glucose homeostasis within the body. Proof-of-concept animal models demonstrated that small molecule GK activation enhances glucose uptake and utilization by various tissues, including liver and pancreas. Accordingly, glucokinase activators (“GKAs”) were extensively explored as a potential therapy for carbohydrate metabolism disorders. Yet in clinical trials, mechanism-based hypoglycemia was often observed when GK was activated in both liver and pancreas. One ameliorative approach was to pursue hepatocentric GKAs. Described herein is a series of liver selective GKAs based on N-(4-alkylthiazol-2-yl)benzamide and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamide pharmacophores. Optimization efforts revealed that enhanced liver selectivity could be achieved by replacing diethylphosphonate group (compound 1) with a dimethylphosphinate (compound 3). Due to mutagenicity of a putative aminoheterocycle metabolite of 3, subsequent amines were triaged using SOS chromotest. Efforts ultimately led to identification of thiazole-based compounds 11–13, which exhibited significant glucose lowering in acute DIO (“diet-induced obese”) mouse OGTT (“oral glucose tolerance test”) studies. However, insulin secretion was observed at higher doses, and thus the desired therapeutic window between efficacy and insulin secretion was not achieved. Thiadiazole-based compounds were then explored to assess whether this modification could obviate the insulin secretion observed with the thiazole series. Several thiadiazoles were discovered with exceptionally high liver selectivity and drug liver concentrations when evaluated in mouse pharmacokinetic studies. Compounds 17–19 and 20–22 were advanced into acute DIO OGTT studies, but were inactive. Notably, a relatively higher degree of plasma protein binding was observed for the non-efficacious vs. efficacious compounds.

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引用次数: 0

Discovery of DS-1150b, a novel xanthene compound for activating GLUT4 translocation

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-21 DOI: 10.1016/j.bmcl.2025.130191

Masaki Meguro , Fuminao Doi , Tsuyoshi Soneda , Shinji Furuzono , Masahiro Konishi , Jun Harada , Jun Tanaka , Shinichi Inoue , Makoto Ono , Katsuji Kagechika

The glucose transporter 4 (GLUT4) is a high-affinity glucose transporter that is predominantly expressed in the skeletal muscle, myocardium, and adipose tissue, and is the rate-limiting transporter of insulin-stimulated glucose uptake. Compounds that enhance the process of GLUT4 translocation in skeletal muscle would provide a novel treatment for type 2 diabetes mellitus. After a high-throughput screening (HTS) campaign and medicinal chemistry efforts, we identified the xanthene compound DS-1150b (16·tBuNH₂) as a novel potent GLUT4 translocation enhancer. DS-1150b was found to promote GLUT4 translocation in L6-myotubes in rats and showed a glucose-lowering effect in an oral glucose tolerance test (oGTT) in a Zucker fatty rat model. Identification of naphthalene analog DS20060511 is also briefly described.

引用次数: 0

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