Bioorganic & Medicinal Chemistry Letters最新文献

英文中文

Discovery of farnesoid X receptor antagonists from Salvia miltiorrhiza based on virtual screening and activity verification

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-06 DOI: 10.1016/j.bmcl.2025.130222

Jiaojiao Tu , Wa Cheng , Zhenghu Ban, Jiayi Ning, Xiangduan Tan

The farnesoid X receptor (FXR) is a promising therapeutic target for the treatment of non-alcoholic fatty liver disease (NAFLD). Salvia miltiorrhiza, a traditional Chinese medicine, has demonstrated significant efficacy in the prevention and treatment of liver diseases. Consequently, investigating the potential effects of Salvia miltiorrhiza on FXR could provide new insights for NAFLD treatment. This study explores whether active ingredients from Salvia miltiorrhiza can target FXR and serve as therapeutic agents for treating NAFLD. The findings revealed that cynaroside and lithospermic acid displayed strong FXR antagonistic activity, with IC₅₀ values of 5.41 ± 1.08 μM and 16.92 ± 2.68 μM, respectively. Salvianolic acid A also showed moderate activity (IC₅₀ = 56.35 ± 4.54 μM). MTT assays demonstrated that these three compounds were non-toxic to HepG2 and LO2 cells at a concentration of 200 μM. Molecular dynamics simulations were conducted to elucidate the interaction mechanisms of cynaroside and lithospermic acid with FXR. These results suggest that cynaroside and lithospermic acid from Salvia miltiorrhiza may be potential candidates for targeting FXR in treating NAFLD.

{"title":"Discovery of farnesoid X receptor antagonists from Salvia miltiorrhiza based on virtual screening and activity verification","authors":"Jiaojiao Tu , Wa Cheng , Zhenghu Ban, Jiayi Ning, Xiangduan Tan","doi":"10.1016/j.bmcl.2025.130222","DOIUrl":"10.1016/j.bmcl.2025.130222","url":null,"abstract":"<div><div>The farnesoid X receptor (FXR) is a promising therapeutic target for the treatment of non-alcoholic fatty liver disease (NAFLD). <em>Salvia miltiorrhiza</em>, a traditional Chinese medicine, has demonstrated significant efficacy in the prevention and treatment of liver diseases. Consequently, investigating the potential effects of <em>Salvia miltiorrhiza</em> on FXR could provide new insights for NAFLD treatment. This study explores whether active ingredients from <em>Salvia miltiorrhiza</em> can target FXR and serve as therapeutic agents for treating NAFLD. The findings revealed that cynaroside and lithospermic acid displayed strong FXR antagonistic activity, with IC<sub>50</sub> values of 5.41 ± 1.08 μM and 16.92 ± 2.68 μM, respectively. Salvianolic acid A also showed moderate activity (IC<sub>50</sub> = 56.35 ± 4.54 μM). MTT assays demonstrated that these three compounds were non-toxic to HepG2 and LO2 cells at a concentration of 200 μM. Molecular dynamics simulations were conducted to elucidate the interaction mechanisms of cynaroside and lithospermic acid with FXR. These results suggest that cynaroside and lithospermic acid from <em>Salvia miltiorrhiza</em> may be potential candidates for targeting FXR in treating NAFLD.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130222"},"PeriodicalIF":2.5,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810235","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 novel Ebola entry inhibitors with 1,2,3,4-tetrahydroisoquinoline-3-carboxamide based on (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-06 DOI: 10.1016/j.bmcl.2025.130230

Junzhen Lin , Fuling Xiao , Sheng Han , Youhong Hu , Jianping Zuo , Xiankun Tong , Wuhong Chen

Novel Ebola entry inhibitors were designed and synthesized based on decahydroisoquinolines by streamlining non-essential functional groups that do not compromise activity. All novel derivatives were evaluated for their anti-Ebola activities and cytotoxicitiies in a defective Ebola virus model. A novel tetrahydroisoquinoline Ebola virus entry inhibitor, Hu7, was readily available with antiviral activity comparable to previous findings, while demonstrating a marked reduction in toxicity. Such new compounds with simple and easy-to-synthesize structures could be potential leads for further optimizing the development of anti-Ebola drugs.

引用次数: 0

Optimization of a DNA encoded library derived autotaxin inhibitor hit to a potent in vivo LPA lowering quinazolinone compound with a non‑zinc binding mode

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-05 DOI: 10.1016/j.bmcl.2025.130221

Rainer E. Martin , Alexander L. Satz , Christoph Kuratli, Daniel Hunziker , Patrizio Mattei , Jérôme Hert , Christoph Ullmer , Markus G. Rudolph , André M. Alker, Remo Hochstrasser, Andreas Marx, Martin Binder, Stephan Müller

In recent years, lysophospholipase autotaxin (ATX) has emerged as an attractive target for treating a variety of human diseases, including inflammation, neurodegeneration, angiogenesis, cancer, ocular and fibrotic diseases, among others. Starting with the quinazolinone hit structure 1, which emerged from a DNA-encoded library screen, the potent, non-Zn²⁺ binding ATX inhibitor 31 with good overall physicochemical properties has been developed. This compound demonstrated a sustained reduction of lysophosphatidic acid (LPA) in an in vivo rat experiment, qualifying it as a proof-of-concept compound for further mechanistic studies.

引用次数: 0

Design and synthesis of β-carboline-benzofuran based hybrids as antibacterial agents against Staphylococcus aureus

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-04 DOI: 10.1016/j.bmcl.2025.130220

Mursalim Ali Khan , Kishan Kumar Parida , Dastari Sowmya , Naveen Chand Rallabandi , Nitin Pal Kalia , Nagula Shankaraiah

The significant threat posed by Staphylococcus aureus (MRSA) is attributed to various antibiotic resistance and its role in severe infections. As an approach to combat this, a series of novel β-carboline-benzofuran based molecular hybrids were designed, synthesized, and evaluated for their antibacterial activity against Staphylococcus aureus ATCC 29213. Among the series, the minimum inhibitory concentration (MIC) of key compounds 13e, 13 h, and 13q was determined to be 4 μg/mL, compared to ciprofloxacin 0.125 μg/mL. The docking results also supported the potent compounds' ability to inhibit DNA gyrase. These compounds demonstrated bacteriostatic effects at higher concentrations, with significant inhibition of biofilm formation (MBIC₅₀ ranging from 12.78 to 30.68 μg/mL). Additionally, the compounds displayed minimal cytotoxicity against HepG2 cells and inhibited DNA gyrase, which is proven by DNA supercoiling assays and molecular docking studies. In addition, ADMET predictions indicated favorable drug-like properties, adhering to Lipinski's rule of five. These findings suggest that the synthesized β-carboline-benzofuran hybrids possess significant potential as leads for developing new antibacterial agents against MRSA.

{"title":"Design and synthesis of β-carboline-benzofuran based hybrids as antibacterial agents against Staphylococcus aureus","authors":"Mursalim Ali Khan , Kishan Kumar Parida , Dastari Sowmya , Naveen Chand Rallabandi , Nitin Pal Kalia , Nagula Shankaraiah","doi":"10.1016/j.bmcl.2025.130220","DOIUrl":"10.1016/j.bmcl.2025.130220","url":null,"abstract":"<div><div>The significant threat posed by <em>Staphylococcus aureus</em> (MRSA) is attributed to various antibiotic resistance and its role in severe infections. As an approach to combat this, a series of novel β-carboline-benzofuran based molecular hybrids were designed, synthesized, and evaluated for their antibacterial activity against <em>Staphylococcus aureus</em> ATCC 29213. Among the series, the minimum inhibitory concentration (MIC) of key compounds <strong>13e</strong>, <strong>13</strong> <strong>h</strong>, and <strong>13q</strong> was determined to be 4 μg/mL, compared to ciprofloxacin 0.125 μg/mL. The docking results also supported the potent compounds' ability to inhibit DNA gyrase. These compounds demonstrated bacteriostatic effects at higher concentrations, with significant inhibition of biofilm formation (MBIC<sub>50</sub> ranging from 12.78 to 30.68 μg/mL). Additionally, the compounds displayed minimal cytotoxicity against HepG2 cells and inhibited DNA gyrase, which is proven by DNA supercoiling assays and molecular docking studies. In addition, ADMET predictions indicated favorable drug-like properties, adhering to Lipinski's rule of five. These findings suggest that the synthesized β-carboline-benzofuran hybrids possess significant potential as leads for developing new antibacterial agents against MRSA.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130220"},"PeriodicalIF":2.5,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794401","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

DNA binding studies of abietane diterpenes natural products using isothermal titration calorimetry, circular dichroism, fluorescence and gel assays

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-03 DOI: 10.1016/j.bmcl.2025.130216

Ruel E. McKnight , Gavin S. Gullickson , Benjamin Kasper , Kevin Siegenthaler , Duanne A.C. Biggs , Roy B. Porter

A group of four structurally related abietane diterpenes (including royleanone and 7-acetoxy-horminone) were investigated for their DNA binding capabilities using isothermal titration calorimetry (ITC), circular dichroism (CD) and fluorescence displacement spectroscopy, and a topoisomerase DNA-unwinding assay. Both ITC and CD spectroscopy data indicate that the abietane diterpenes of this study exhibit strong binding to DNA, likely preferring a DNA-groove binding mode. Binding constants (K) were found to be in the order of 10^6–8 M⁻¹ and were strongly enthalpically driven. The binding of all compounds to DNA was accompanied by large negative enthalpy changes (more than −20 kcal/mol) and negative entropy changes. The substituent at the 7th position of the abietane ring system was important in determining both the magnitude of binding and the propensity to stack within their DNA binding sites, with derivatives 7-one/ene > 7-OAc/H. This is significant given the reports that the identity of the substituent at position-7 is a strong determinant for bioactivity. Although the specific CD data observed was compound-dependent, most showed strong signal perturbations around one or both of the DNA signature wavelengths (245 and 280 nm). However, we do not attribute these perturbations to DNA intercalation. Compounds that were capable of self-stacking (i.e., 7-ene and 7-one) were also able to elicit very strong positively induced CD signal (ICD) around 330 nm, as well as perturbations at higher wavelengths. Additionally, topoisomerase DNA-unwinding and ethidium fluorescence displacement assays were used to corroborate the DNA binding mode, which was found to be consistent with the abietane diterpene compounds adopting a non-intercalative DNA binding mode.

研究人员利用等温滴定量热法（ITC）、圆二色光谱法（CD）和荧光位移光谱法以及拓扑异构酶 DNA 解旋试验，对一组结构相关的四种阿比坦二萜（包括罗利酮和 7-乙酰氧基荷茗酮）的 DNA 结合能力进行了研究。ITC 和 CD 光谱数据都表明，本研究中的阿比坦二萜与 DNA 的结合力很强，可能更倾向于 DNA 沟槽结合模式。研究发现，结合常数（K）在 106-8 M-1 的数量级，具有很强的焓驱动性。所有化合物与 DNA 的结合都伴随着巨大的负焓变（超过 -20 kcal/mol）和负熵变。阿比坦环系统第 7 位上的取代基对决定其 DNA 结合位点的结合程度和堆叠倾向都很重要，其中衍生物 7-one/ene > 7-OAc/H。鉴于有报告称 7 号位取代基的特性是生物活性的重要决定因素，这一点意义重大。虽然观察到的特定 CD 数据取决于化合物，但大多数都在一个或两个 DNA 标志波长（245 和 280 nm）附近显示出强烈的信号扰动。不过，我们并没有将这些扰动归因于 DNA 插层。能够自叠层的化合物（即 7-ene 和 7-one）也能在 330 nm 附近引起非常强的正向诱导 CD 信号 (ICD)，并在更高波长处产生扰动。此外，研究人员还使用拓扑异构酶 DNA 解旋和乙酞荧光位移试验来证实 DNA 结合模式，结果表明阿比特烷二萜化合物采用了非交联 DNA 结合模式。

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引用次数: 0

Discovery of novel inhibitors for malate synthase of Mycobacterium Tuberculosis from natural products

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-03 DOI: 10.1016/j.bmcl.2025.130217

Zhili Wu , Yuchen Wu , Yanhong Niu , Qianfang Hu , Qihua Jiang , Lingbing Liao , Guorong Qi , Haoyang Lan , Xiaolan Yang

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains a global public health threat, particularly due to dormant Mtb, which necessitates prolonged drug treatment. Mycobacterium tuberculosis malate synthase (MtbMS) is a key rate-limiting enzyme in the glyoxylate shunt, essential for the survival of dormant Mtb but absent in the host. Using target-based virtual screening and biochemical approaches, we identified novel natural inhibitors of MtbMS. Molecular docking by Schrödinger and subsequent manual selection identified 11 compounds as potential inhibitors. Molecular dynamics (MD) simulations and binding-free energy analysis (MM/GBSA) demonstrated high stability and binding affinity of MtbMS with Nordihydroguaiaretic Acids (NDGA) and Meso-NDGA. NDGA and Meso-NDGA by inhibition experiment exhibited half-maximal inhibitory concentrations (IC₅₀) against MtbMS at 1.10 ± 0.01 μM and 14.29 ± 0.95 μM and by Isothermal Titration Calorimetry (ITC) showed binding constants (K_d) of 5.66 μM and 34.90 μM, respectively. Their minimum inhibitory concentrations (MIC) against Mtb H37Rv were 60.47 μg/mL and 30.24 μg/mL, respectively. In conclusion, natural products NDGA and Meso-NDGA are potent inhibitors of MtbMS and represent promising new scaffolds for combating dormant Mtb.

由结核分枝杆菌（Mtb）引起的结核病（TB）仍然是一个全球性的公共卫生威胁，尤其是休眠的Mtb，需要长期的药物治疗。结核分枝杆菌苹果酸合成酶（MtbMS）是乙醛酸分流过程中的一个关键限速酶，对休眠 Mtb 的生存至关重要，但在宿主体内却不存在。利用基于靶点的虚拟筛选和生化方法，我们发现了新型的MtbMS天然抑制剂。通过薛定谔分子对接和随后的人工筛选，确定了 11 种化合物为潜在的抑制剂。分子动力学（MD）模拟和无结合能分析（MM/GBSA）证明了MtbMS与Nordihydroguaiaretic Acids（NDGA）和Meso-NDGA的高稳定性和结合亲和力。通过抑制实验，NDGA 和 Meso-NDGA 对 MtbMS 的半最大抑制浓度（IC50）分别为 1.10 ± 0.01 μM 和 14.29 ± 0.95 μM，通过等温滴定量热法（ITC）显示的结合常数（Kd）分别为 5.66 μM 和 34.90 μM。它们对 Mtb H37Rv 的最低抑制浓度（MIC）分别为 60.47 μg/mL 和 30.24 μg/mL。总之，天然产物NDGA和Meso-NDGA是MtbMS的强效抑制剂，是抗击休眠Mtb的有前途的新支架。

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引用次数: 0

Aptamer-modified GSH-degradable honokiol polyprodrug nanoparticles for ovarian cancer-specific targeting therapy

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-04-01 DOI: 10.1016/j.bmcl.2025.130215

Chunhua Guo, Xiaowei Cheng, Yuxing Yang, Lijuan Wang, Wenfang Wang, Liping Shao

Honokiol (HK) is a polyphenol isolated from the Magnolia genus, a component of traditional Chinese herbal medicine, which can effectively suppress the growth of various tumors, including ovarian cancer. However, its low water solubility and lack of tumor-targeting ability have greatly hindered the clinical application of HK. Herein, a glutathione (GSH)-sensitive HK polyprodrug was prepared using HK as the backbone. An EpCAM-specific aptamer and poly(ethylene glycol) (PEG) were then conjugated to the HK polyprodrug, and the resulting polyprodrug was assembled into nanoparticles (NPs) in water. The HK polyprodrug-formed NPs achieved high drug loading and GSH-responsive drug release. Moreover, after optimization, HK polyprodrug NPs (A/P-PHK NP40), formed by aptamer-modified and PEG-modified prodrug at a feed molar ratio of 2: 3, exhibited the highest ability to target EpCAM-overexpressing ovarian cancer cells. A/P-PHK NP40 also demonstrated a greater cell growth inhibition effect in ovarian cancer cells compared to free HK and control HK NPs. All in all, this work reported a novel strategy for HK delivery based on microenvironment responsiveness polyprodrug, which provided a potential method for ovarian cancer targeting therapy.

{"title":"Aptamer-modified GSH-degradable honokiol polyprodrug nanoparticles for ovarian cancer-specific targeting therapy","authors":"Chunhua Guo, Xiaowei Cheng, Yuxing Yang, Lijuan Wang, Wenfang Wang, Liping Shao","doi":"10.1016/j.bmcl.2025.130215","DOIUrl":"10.1016/j.bmcl.2025.130215","url":null,"abstract":"<div><div>Honokiol (HK) is a polyphenol isolated from the Magnolia genus, a component of traditional Chinese herbal medicine, which can effectively suppress the growth of various tumors, including ovarian cancer. However, its low water solubility and lack of tumor-targeting ability have greatly hindered the clinical application of HK. Herein, a glutathione (GSH)-sensitive HK polyprodrug was prepared using HK as the backbone. An EpCAM-specific aptamer and poly(ethylene glycol) (PEG) were then conjugated to the HK polyprodrug, and the resulting polyprodrug was assembled into nanoparticles (NPs) in water. The HK polyprodrug-formed NPs achieved high drug loading and GSH-responsive drug release. Moreover, after optimization, HK polyprodrug NPs (A/P-PHK NP40), formed by aptamer-modified and PEG-modified prodrug at a feed molar ratio of 2: 3, exhibited the highest ability to target EpCAM-overexpressing ovarian cancer cells. A/P-PHK NP40 also demonstrated a greater cell growth inhibition effect in ovarian cancer cells compared to free HK and control HK NPs. All in all, this work reported a novel strategy for HK delivery based on microenvironment responsiveness polyprodrug, which provided a potential method for ovarian cancer targeting therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130215"},"PeriodicalIF":2.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778529","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 novel pyridine skeleton derivatives as potent CLK2/3 inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-29 DOI: 10.1016/j.bmcl.2025.130212

Jie Wei , Guochuang Zheng , Tingting Yu , Qi Liu , Wenying Yu , Cheng Jiang , Xu Quan

The CLK family plays a crucial role in regulating the transcript splicing, catalyzing the molecular mechanism of spliceosomes. It also regulates the activity or expression of non-spliced proteins by phosphorylating SR proteins. Hence, CLKs are promising therapeutic targets for a variety of diseases, especially in tumors. Several small molecule CLK2/3 inhibitors were under the clinical studies, while most of these molecule possessed N-containing bicyclic heteroaryl as the skeleton. The goal of this work was to introduce a novel skeleton as well as provide structure diversity to the development of CLK2/3 inhibitors. Herein, a series of pyridine derivatives (5a-5h, 6a-6e, and 7a-7g) were designed, synthesized and evaluated. Among them, compound 7c was identified to have good inhibitory activities against both CLK2/3 and proliferation of SW480 tumor cell. Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of 7c. The good in vitro activity and promising pharmacokinetic properties indicated that the 7c was a reliable lead compound for further development.

{"title":"Discovery of novel pyridine skeleton derivatives as potent CLK2/3 inhibitors","authors":"Jie Wei , Guochuang Zheng , Tingting Yu , Qi Liu , Wenying Yu , Cheng Jiang , Xu Quan","doi":"10.1016/j.bmcl.2025.130212","DOIUrl":"10.1016/j.bmcl.2025.130212","url":null,"abstract":"<div><div>The CLK family plays a crucial role in regulating the transcript splicing, catalyzing the molecular mechanism of spliceosomes. It also regulates the activity or expression of non-spliced proteins by phosphorylating SR proteins. Hence, CLKs are promising therapeutic targets for a variety of diseases, especially in tumors. Several small molecule CLK2/3 inhibitors were under the clinical studies, while most of these molecule possessed N-containing bicyclic heteroaryl as the skeleton. The goal of this work was to introduce a novel skeleton as well as provide structure diversity to the development of CLK2/3 inhibitors. Herein, a series of pyridine derivatives (<strong>5a-5h</strong>, <strong>6a-6e</strong>, and <strong>7a-7g</strong>) were designed, synthesized and evaluated. Among them, compound <strong>7c</strong> was identified to have good inhibitory activities against both CLK2/3 and proliferation of SW480 tumor cell. Additionally, pharmacokinetic study in mice as well as the stability assay were performed to investigate the druggability of <strong>7c</strong>. The good in vitro activity and promising pharmacokinetic properties indicated that the <strong>7c</strong> was a reliable lead compound for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"123 ","pages":"Article 130212"},"PeriodicalIF":2.5,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750571","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 novel 4-Arylaminoquinolines derivatives as EGFR/HDAC inhibitors

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-29 DOI: 10.1016/j.bmcl.2025.130214

Keke Yao , Yaxin Li , Wei Wei , Sisi Liu , Xiaoli Wang , Jiamin Xu , Ranran Zhang , Zhigang Wu , Chunyan Guo , Leifu Yang , Liming Hu

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the role of epigenetic modifications, such as histone deacetylation, in cancer progression underscore the need for novel therapeutic strategies. This study reports the design, synthesis, and biological evaluation of novel 4-arylaminoquinoline derivatives as dual inhibitors targeting EGFR and histone deacetylase (HDAC). Leveraging structure-activity relationship insights, a series of compounds were synthesized by integrating pharmacophoric elements of EGFR-TKIs and HDAC inhibitors and their kinase and cellular activities were evaluated. Compound 22c2 exhibited the highest inhibitory activities against EGFR (IC₅₀ = 4.81 nM) and HDAC (IC₅₀ = 119.4 nM and 354.8 nM for HDAC1 and HDAC3, respectively). Moreover, 22c2 demonstrated excellent anti-proliferative effects on four human cancer cell lines. These findings provide a foundation for developing dual EGFR/HDAC inhibitors as potential anticancer therapeutics.

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引用次数: 0

A small-molecule pretargeting approach for PSMA-targeted conjugates

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters

Pub Date : 2025-03-28 DOI: 10.1016/j.bmcl.2025.130213

Nooshin Mesbahi, Hosog Yoon, Melody D. Fulton, Clifford E. Berkman

We developed pretargeting approach for the targeted delivery of molecular payloads to prostate cancer cells expressing the hallmark enzyme-biomarker, prostate-specific membrane antigen (PSMA). We employed a phosphoramidate-based PSMA ligand (CTT1298) with a click-ready DBCO group for strain-promoted azide-alkyne cycloaddition (SPAAC) and used 6-FAM-Azide as a model payload. PSMA+ cells were treated with a fluorescent PSMA-targeted probe (FAM-C6–1298), confirming delivery and accumulation. Further, live-cell experiments with DBCO-C6–1298 and 5-FAM-azide demonstrated selective pretargeted delivery. These results validate the feasibility of this pretargeting strategy in PSMA+ cells, suggesting its potential for preclinical applications with therapeutic and diagnostic payloads, enhancing the specificity and safety of prostate cancer treatments.

引用次数: 0

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