Bioorganic & Medicinal Chemistry最新文献

英文中文

Structure-activity relationship studies and pharmacological evaluation of 4-phenylthiazoles as dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-17 DOI: 10.1016/j.bmc.2025.118112

Cassandra Yuan , Amanda Tsang , Manuel Berumen , Adriana Rodriguez , Faye Yun , Anesa Mesic , Annie Olivares , Lissette Dubon , Allen Nguyen , Lucy Pavana , Madison Mercado , Gabrielle Gorostiza , Christophe Morisseau , Bruce D. Hammock , Ram Kandasamy , Stevan Pecic

Forty-two 4-phenylthiazole analogs, organized in two libraries 4a-u and 6a-u, were prepared and biologically evaluated in human fatty acid amide hydrolase (FAAH), and human, rat and mouse soluble epoxide hydrolase (sEH) inhibition assays. This structure–activity relationship (SAR) study explores the impact of electronic and steric changes on the molecule’s potency and binding affinity to better understand the structural features important for dual sEH/FAAH inhibition which will guide the development of novel treatments for pain and inflammation. Our SAR revealed that electron-donating groups on the aromatic ring of the 4-phenylthiazole moiety are particularly well tolerated by both enzymes when placed at the ortho, meta and para positions; however, the overall 3D shape of the molecule is very important for the potent FAAH inhibition, suggesting more restricted size of the FAAH binding pocket compared to sEH binding pocket. Two selected dual inhibitors, 4p and 4s, were tested in the rat liver microsomes stability assays and evaluated in vivo in the formalin test. Systemic administration of 4p and 4s via intraperitoneal injection decreased nociceptive behavior (i.e., licking of the injected paw) in male rats, and this effect was dose-dependent for both compounds. Two doses, 1 and 3 mg/kg of 4p, decreased nociceptive behavior to a similar extent to that of 30 mg/kg ketoprofen, a traditional nonsteroidal anti-inflammatory drug. However, only 3 mg/kg of 4s decreased nociceptive behavior compared to vehicle-treated animals, and this effect was comparable to ketoprofen-treated animals. Taken together, these findings reveal the antinociceptive potential of 4-phenylthiazole-based dual FAAH and sEH inhibitors and suggest pharmacodynamic differences within this class of inhibitors despite similar potencies in vitro.

{"title":"Structure-activity relationship studies and pharmacological evaluation of 4-phenylthiazoles as dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors","authors":"Cassandra Yuan , Amanda Tsang , Manuel Berumen , Adriana Rodriguez , Faye Yun , Anesa Mesic , Annie Olivares , Lissette Dubon , Allen Nguyen , Lucy Pavana , Madison Mercado , Gabrielle Gorostiza , Christophe Morisseau , Bruce D. Hammock , Ram Kandasamy , Stevan Pecic","doi":"10.1016/j.bmc.2025.118112","DOIUrl":"10.1016/j.bmc.2025.118112","url":null,"abstract":"<div><div>Forty-two 4-phenylthiazole analogs, organized in two libraries <strong>4a-u</strong> and <strong>6a-u</strong>, were prepared and biologically evaluated in human fatty acid amide hydrolase (FAAH), and human, rat and mouse soluble epoxide hydrolase (sEH) inhibition assays. This structure–activity relationship (SAR) study explores the impact of electronic and steric changes on the molecule’s potency and binding affinity to better understand the structural features important for dual sEH/FAAH inhibition which will guide the development of novel treatments for pain and inflammation. Our SAR revealed that electron-donating groups on the aromatic ring of the 4-phenylthiazole moiety are particularly well tolerated by both enzymes when placed at the ortho, meta and para positions; however, the overall 3D shape of the molecule is very important for the potent FAAH inhibition, suggesting more restricted size of the FAAH binding pocket compared to sEH binding pocket. Two selected dual inhibitors, <strong>4p</strong> and <strong>4s</strong>, were tested in the rat liver microsomes stability assays and evaluated <em>in vivo</em> in the formalin test. Systemic administration of <strong>4p</strong> and <strong>4s</strong> via intraperitoneal injection decreased nociceptive behavior (i.e., licking of the injected paw) in male rats, and this effect was dose-dependent for both compounds. Two doses, 1 and 3 mg/kg of <strong>4p</strong>, decreased nociceptive behavior to a similar extent to that of 30 mg/kg ketoprofen, a traditional nonsteroidal anti-inflammatory drug. However, only 3 mg/kg of <strong>4s</strong> decreased nociceptive behavior compared to vehicle-treated animals, and this effect was comparable to ketoprofen-treated animals. Taken together, these findings reveal the antinociceptive potential of 4-phenylthiazole-based dual FAAH and sEH inhibitors and suggest pharmacodynamic differences within this class of inhibitors despite similar potencies <em>in vitro</em>.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118112"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of niclosamide as a p300/transcription factor protein–protein interaction inhibitor

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-15 DOI: 10.1016/j.bmc.2025.118114

Dhina Fitriastuti , Kazuki Miura , Satoshi Okada , Hiroyuki Hirano , Hiroyuki Osada , Hiroyuki Nakamura

Protein-protein interactions (PPIs) are crucial in various biological processes and are attractive targets for drug discovery. In this study, we identified niclosamide (9) as a novel inhibitor of the hypoxia-inducible factor 1α (HIF-1α)/p300 PPI from the RIKEN NPDepo compound library using a fluorescence anisotropy-based screening method. We synthesized niclosamide azide (10) as a photoaffinity labelling probe to identify the p300 binding site of compound 9 and elucidated the binding mode using photoaffinity labelling experiments and molecular docking simulations. Furthermore, we demonstrated that compound 9 inhibited not only HIF-1α/p300 PPI but also p300-transcription factor PPIs, including interaction with p53 and STAT3, thereby suppressing the expression of BAX and c-MYC, respectively.

引用次数: 0

Chemical modification for improving drug-like molecular properties of climacostol, a natural resorcinolic lipid

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-12 DOI: 10.1016/j.bmc.2025.118113

Gabriele Lupidi , Elisabetta Catalani , Federico Buonanno , Dario Gentili , Simone Giorgi , Vishnuprasad Ponnarassery Aravindakshan , Serena Gabrielli , Kashi Brunetti , Anna Maria Fausto , Simona Picchietti , Claudio Ortenzi , Enrico Marcantoni , Davide Cervia

Small organic molecules are compounds that are manufactured through chemical synthesis. One of the key advantages of small molecules is that they have a low molecular weight and simple chemical structures. This allows more predictability to their pharmacokinetics and pharmacodynamics, which means that dosing is simpler. To use small molecules as a useful tool to address human health issues, the collaboration between disciplines, especially chemistry and biology, is essential. In recent years in our laboratories, we have demonstrated that climacostol, a 5-alkenyl resorcinolic produced by eukaryotic microorganisms as secondary metabolite and obtained by our synthetic strategy too, it shows important biological and pharmacological activities. These ones are highly dependent on the 5-alkenyl chain, and chemical modifications to the resorcinolic moiety can be exploited to achieve higher toxicity against pathogen microbes and protists than climacostol. In this study, we have designed and made a synthetic strategy for a new analogue of climacostol (AN3), and evaluated how the new hydroxyl group at position four in the aromatic ring influences its biological effects on prokaryotic and free-living protists and on non-target cells/organisms, especially with regard to cytotoxic properties.

{"title":"Chemical modification for improving drug-like molecular properties of climacostol, a natural resorcinolic lipid","authors":"Gabriele Lupidi , Elisabetta Catalani , Federico Buonanno , Dario Gentili , Simone Giorgi , Vishnuprasad Ponnarassery Aravindakshan , Serena Gabrielli , Kashi Brunetti , Anna Maria Fausto , Simona Picchietti , Claudio Ortenzi , Enrico Marcantoni , Davide Cervia","doi":"10.1016/j.bmc.2025.118113","DOIUrl":"10.1016/j.bmc.2025.118113","url":null,"abstract":"<div><div>Small organic molecules are compounds that are manufactured through chemical synthesis. One of the key advantages of small molecules is that they have a low molecular weight and simple chemical structures. This allows more predictability to their pharmacokinetics and pharmacodynamics, which means that dosing is simpler. To use small molecules as a useful tool to address human health issues, the collaboration between disciplines, especially chemistry and biology, is essential. In recent years in our laboratories, we have demonstrated that climacostol, a 5-alkenyl resorcinolic produced by eukaryotic microorganisms as secondary metabolite and obtained by our synthetic strategy too, it shows important biological and pharmacological activities. These ones are highly dependent on the 5-alkenyl chain, and chemical modifications to the resorcinolic moiety can be exploited to achieve higher toxicity against pathogen microbes and protists than climacostol. In this study, we have designed and made a synthetic strategy for a new analogue of climacostol (<strong>AN3</strong>), and evaluated how the new hydroxyl group at position four in the aromatic ring influences its biological effects on prokaryotic and free-living protists and on non-target cells/organisms, especially with regard to cytotoxic properties.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118113"},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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, biological evaluation, and mechanism of action of new pyrazines as anticancer agents in vitro and in vivo

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-11 DOI: 10.1016/j.bmc.2025.118108

Jin-Xia Lan , Le-Jun Huang , Si-Shuang Kang , Hao-Huang , Sheng-Lan Liu , Wei Dai , Xin-Liang Xu , Jin-Yang Wang , Guang-Zhao Shu , Wen Hou

Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. N-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity in vitro and in vivo. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds B-11 and C-27 demonstrated significant anticancer activity in vivo in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.

{"title":"Design, synthesis, biological evaluation, and mechanism of action of new pyrazines as anticancer agents in vitro and in vivo","authors":"Jin-Xia Lan , Le-Jun Huang , Si-Shuang Kang , Hao-Huang , Sheng-Lan Liu , Wei Dai , Xin-Liang Xu , Jin-Yang Wang , Guang-Zhao Shu , Wen Hou","doi":"10.1016/j.bmc.2025.118108","DOIUrl":"10.1016/j.bmc.2025.118108","url":null,"abstract":"<div><div>Cancer is the second leading cause of mortality worldwide. The development of innovative antitumor pharmaceuticals is urgently needed to alter this circumstance. <em>N</em>-heterocycles, pyrazines for example are prevalent pharmacophores in the architecture of anticancer medicines. This research involved the design and synthesis of seventy-seven new pyrazine derivatives, followed by an evaluation of their anticancer activity <em>in vitro</em> and <em>in vivo</em>. Several new pyrazines exhibiting remarkable antiproliferative activity and selectivity were identified. The links between structure and function were analyzed, and the mechanisms of action were examined. Our mechanistic investigations indicated that these chemicals triggered mitochondria-associated apoptosis in cancer cells. Moreover, they suppressed the phosphorylation of STAT3, concomitant with the down-regulation of BcL-2, BcL-XL, c-Myc, XIAP, GLI1, TAZ, MCL1, JAK1, JAK2 and up-regulation of Bax, p21. Furthermore, the lead compounds <strong>B-11</strong> and <strong>C-27</strong> demonstrated significant anticancer activity <em>in vivo</em> in the SKOV3 xenograft nude mouse model. Our research establishes a basis for the identification of pyrazines as JAK/STAT3 inhibition based anticancer lead compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118108"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Ligustrazine as a multitarget scaffold in drug design and discovery

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-11 DOI: 10.1016/j.bmc.2025.118110

Xueyang Jiang , Siyi Li , Ning Wang , Jiaming Li

Ligustrazine has gained significant attention for its unique structural role in natural medicinal chemistry and its potential in drug discovery and development. The ligustrazine structure has been recognized as a clinical drug for treating cardiovascular and cerebrovascular diseases, especially in the design of neuroprotective agents. Recently, ligustrazine-based anti-tumor agents have also been reported. This knowledge can undoubtedly be applied to design multi-target-directed ligands, a highly relevant strategy for the complex pathological conditions of multifactorial diseases. In this review, we first discuss the biological properties and clinical applications of ligustrazine, then focus on the rational design of ligustrazine-based multifunctional ligands.

女贞嗪因其在天然药物化学中的独特结构作用及其在药物发现和开发中的潜力而备受关注。女贞嗪结构已被公认为治疗心脑血管疾病的临床药物，特别是在设计神经保护剂方面。最近，基于女贞嗪的抗肿瘤药物也有报道。这些知识无疑可用于设计多靶点配体，这是一种与多因素疾病的复杂病理条件高度相关的策略。在这篇综述中，我们首先讨论了女贞嗪的生物学特性和临床应用，然后重点讨论了基于女贞嗪的多功能配体的合理设计。

引用次数: 0

Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-11 DOI: 10.1016/j.bmc.2025.118109

Yun-He Liu , Zi-Yue Wang , Yi-Fei Du , Xuan-Han Liu , Jin-Bo Niu , Jian Song , Cheng-Yun Jin , Sai-Yang Zhang

Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure–activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.

{"title":"Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities","authors":"Yun-He Liu , Zi-Yue Wang , Yi-Fei Du , Xuan-Han Liu , Jin-Bo Niu , Jian Song , Cheng-Yun Jin , Sai-Yang Zhang","doi":"10.1016/j.bmc.2025.118109","DOIUrl":"10.1016/j.bmc.2025.118109","url":null,"abstract":"<div><div>Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure–activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118109"},"PeriodicalIF":3.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 biological activity of human glutaminyl cyclase inhibitors against Alzheimer’s disease

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-08 DOI: 10.1016/j.bmc.2025.118105

Jingjing Li , Keli Zong , Chaochun Wei , Qidi Zhong , Hong Yan , Juan Wang , Xingzhou Li

Human glutaminyl cyclase (hQC) has emerged as a critical target in Alzheimer’s disease (AD) due to its role in generating pyroglutamate-modified amyloid β (pE-Aβ). In this study, 13 compounds were designed as target compounds by fragment-based drug design (FBDD) and molecular docking, and subsequently assessed for drug-like properties and predicted inhibitory activities through ADMET analysis and Uni-QSAR modeling. Target compounds were synthesized via systematic multi-step approaches, with acceptable yields. The in vitro hQC enzyme inhibition assay revealed that all target compounds exhibited superior inhibitory activity compared to the reference compound PBD150 (140.50

\pm

0.93 nM), with compounds A3 (3.36

\pm

0.90 nM), A4 (3.20

\pm

1.15 nM), B1 (3.99

\pm

0.99 nM), and B2 (3.64

\pm

0.98 nM) standing out for further investigation. Further, molecular dynamics (MD) simulations were conducted on compounds A3, A4, B1, and B2, revealing the stability and binding interactions of the compounds within the hQC active site over a 200 ns simulation period. Then, the results of binding free energy calculations validated the superior binding affinities of compounds A3, A4, B1, and B2 than PBD150. These findings highlight A3, A4, B1, and B2 as promising hQC inhibitors, offering insights for AD drug development.

{"title":"Design, synthesis, and biological activity of human glutaminyl cyclase inhibitors against Alzheimer’s disease","authors":"Jingjing Li , Keli Zong , Chaochun Wei , Qidi Zhong , Hong Yan , Juan Wang , Xingzhou Li","doi":"10.1016/j.bmc.2025.118105","DOIUrl":"10.1016/j.bmc.2025.118105","url":null,"abstract":"<div><div>Human glutaminyl cyclase (hQC) has emerged as a critical target in Alzheimer’s disease (AD) due to its role in generating pyroglutamate-modified amyloid β (pE-Aβ). In this study, 13 compounds were designed as target compounds by fragment-based drug design (FBDD) and molecular docking, and subsequently assessed for drug-like properties and predicted inhibitory activities through ADMET analysis and Uni-QSAR modeling. Target compounds were synthesized via systematic multi-step approaches, with acceptable yields. The <em>in vitro</em> hQC enzyme inhibition assay revealed that all target compounds exhibited superior inhibitory activity compared to the reference compound <strong>PBD150</strong> (140.50 <span><math><mo>±</mo></math></span> 0.93 nM), with compounds <strong>A3</strong> (3.36 <span><math><mo>±</mo></math></span> 0.90 nM), <strong>A4</strong> (3.20 <span><math><mo>±</mo></math></span> 1.15 nM), <strong>B1</strong> (3.99 <span><math><mo>±</mo></math></span> 0.99 nM), and <strong>B2</strong> (3.64 <span><math><mo>±</mo></math></span> 0.98 nM) standing out for further investigation. Further, molecular dynamics (MD) simulations were conducted on compounds <strong>A3</strong>, <strong>A4</strong>, <strong>B1</strong>, and <strong>B2</strong>, revealing the stability and binding interactions of the compounds within the hQC active site over a 200 ns simulation period. Then, the results of binding free energy calculations validated the superior binding affinities of compounds <strong>A3</strong>, <strong>A4</strong>, <strong>B1</strong>, and <strong>B2</strong> than <strong>PBD150</strong>. These findings highlight <strong>A3</strong>, <strong>A4</strong>, <strong>B1</strong>, and <strong>B2</strong> as promising hQC inhibitors, offering insights for AD drug development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118105"},"PeriodicalIF":3.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Fatty acid conjugated BimBH3 analogues with d‑amino acid substitution as PTPN1 inhibitors with enhanced activity, biostability and orally available potency for the treatment of diabetes

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-07 DOI: 10.1016/j.bmc.2025.118107

Liyan Gong , Guozhen Dong , Qianqian Zhang , Yiying Shi , Zongwen Gu , Xianmin Yang , Xiang Gao , Yaning Zheng , Chuanliang Zhang

Protein tyrosine phosphatase non-receptor type 1 (PTPN1) is a crucial regulator of insulin and leptin signaling pathways, positioning it as a promising therapeutic target for the development of insulin sensitizers in the treatment of type 2 diabetes mellitus (T2DM). Our previous studies demonstrated that lipidated/acylated BimBH3 core peptide analogues function as potent PTPN1 inhibitors with potential for once-weekly hypoglycemic efficacy. Additionally, alanine scanning identified specific residues that could be modified without compromising inhibitory activity. In this study, we designed and synthesized 14 lipidated BimBH3 analogues incorporating d-amino acids through site-specific modifications to enhance peptide stability and activity. Among these, analogues D-1, D-9, D-10, D-11, D-12, and D-14 exhibited potent PTPN1 inhibitory activity, demonstrated significant resistance to proteolytic degradation, and showed good stability in mouse plasma. Notably, in glucose tolerance tests, subcutaneous administration of D-14 led to a significant 26.2 % reduction in blood glucose (AUC_0–120 min), while oral administration achieved a 15.4 % reduction (AUC_0–180 min), indicating promising oral bioavailability. Further analysis using molecular docking and kinetic studies confirmed the strong binding affinity of d-amino acid-containing BimBH3 analogues for PTPN1, supporting their potential for sustained hypoglycemic effects. Overall, our findings demonstrate that the dual modifications of d-amino acid substitution and lipid conjugation significantly enhance the inhibitory activity, bio-stability, and oral availability of BimBH3 analogues, highlighting their potential as novel, long-acting therapeutics for T2DM management.

{"title":"Fatty acid conjugated BimBH3 analogues with d‑amino acid substitution as PTPN1 inhibitors with enhanced activity, biostability and orally available potency for the treatment of diabetes","authors":"Liyan Gong , Guozhen Dong , Qianqian Zhang , Yiying Shi , Zongwen Gu , Xianmin Yang , Xiang Gao , Yaning Zheng , Chuanliang Zhang","doi":"10.1016/j.bmc.2025.118107","DOIUrl":"10.1016/j.bmc.2025.118107","url":null,"abstract":"<div><div>Protein tyrosine phosphatase non-receptor type 1 (PTPN1) is a crucial regulator of insulin and leptin signaling pathways, positioning it as a promising therapeutic target for the development of insulin sensitizers in the treatment of type 2 diabetes mellitus (T2DM). Our previous studies demonstrated that lipidated/acylated BimBH3 core peptide analogues function as potent PTPN1 inhibitors with potential for once-weekly hypoglycemic efficacy. Additionally, alanine scanning identified specific residues that could be modified without compromising inhibitory activity. In this study, we designed and synthesized 14 lipidated BimBH3 analogues incorporating <span>d</span>-amino acids through site-specific modifications to enhance peptide stability and activity. Among these, analogues D-1, D-9, D-10, D-11, D-12, and D-14 exhibited potent PTPN1 inhibitory activity, demonstrated significant resistance to proteolytic degradation, and showed good stability in mouse plasma. Notably, in glucose tolerance tests, subcutaneous administration of D-14 led to a significant 26.2 % reduction in blood glucose (AUC<sub>0–120</sub> min), while oral administration achieved a 15.4 % reduction (AUC<sub>0–180</sub> min), indicating promising oral bioavailability. Further analysis using molecular docking and kinetic studies confirmed the strong binding affinity of <span>d</span>-amino acid-containing BimBH3 analogues for PTPN1, supporting their potential for sustained hypoglycemic effects. Overall, our findings demonstrate that the dual modifications of <span>d</span>-amino acid substitution and lipid conjugation significantly enhance the inhibitory activity, bio-stability, and oral availability of BimBH3 analogues, highlighting their potential as novel, long-acting therapeutics for T2DM management.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118107"},"PeriodicalIF":3.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Research progress of flavonoids targeting estrogen receptor in the treatment of breast cancer

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-07 DOI: 10.1016/j.bmc.2025.118106

Jianling Long , Pengju Ye , Weixi Yuan , Qixian Yang , Zhe Wang , Hongxiang Xiao , Zhizhong Xie , Xiaoyong Lei , Xiaoyan Yang , Xiangping Deng , Guotao Tang

Breast cancer (BC) stands as the most prevalent malignancy among women. Targeting the estrogen receptor (ER) or ER pathway is one of the important approaches for ER⁺ BC treatment. As a class of phytoestrogens, flavonoids possess notable anti-tumor properties and hold immense potential in regulating ER signaling. In this review, we reported the recent advances in both in vitro and in vivo studies of flavonoids and their synthetic derivatives targeting the ER signaling pathway, including the target and mechanism of action of these molecules, as well as their structure–activity relationship. Based on the available literature, the beneficial effects of flavonoids as ER targeting agents are promising but they require further in vitro and in vivo studies to enable its translation from bench to bedside. This review will provide valuable guidance and insights for the future development of drugs targeting the ER pathway.

{"title":"Research progress of flavonoids targeting estrogen receptor in the treatment of breast cancer","authors":"Jianling Long , Pengju Ye , Weixi Yuan , Qixian Yang , Zhe Wang , Hongxiang Xiao , Zhizhong Xie , Xiaoyong Lei , Xiaoyan Yang , Xiangping Deng , Guotao Tang","doi":"10.1016/j.bmc.2025.118106","DOIUrl":"10.1016/j.bmc.2025.118106","url":null,"abstract":"<div><div>Breast cancer (BC) stands as the most prevalent malignancy among women. Targeting the estrogen receptor (ER) or ER pathway is one of the important approaches for ER<sup>+</sup> BC treatment. As a class of phytoestrogens, flavonoids possess notable anti-tumor properties and hold immense potential in regulating ER signaling. In this review, we reported the recent advances in both <em>in vitro</em> and <em>in vivo</em> studies of flavonoids and their synthetic derivatives targeting the ER signaling pathway, including the target and mechanism of action of these molecules, as well as their structure–activity relationship. Based on the available literature, the beneficial effects of flavonoids as ER targeting agents are promising but they require further <em>in vitro</em> and <em>in vivo</em> studies to enable its translation from bench to bedside. This review will provide valuable guidance and insights for the future development of drugs targeting the ER pathway.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118106"},"PeriodicalIF":3.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143378045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Rational design and synthesis of pyrazole derivatives as potential SARS-CoV-2 Mpro inhibitors: An integrated approach merging combinatorial chemistry, molecular docking, and deep learning

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry

Pub Date : 2025-02-03 DOI: 10.1016/j.bmc.2025.118095

Arthur Antunes Ferrarezi , João Vítor Perez de Souza , Bernard Maigret , Érika Seki Kioshima , Sidnei Moura , Arildo José Braz de Oliveira , Fernanda Andreia Rosa , Regina Aparecida Correia Gonçalves

The global impact of SARS-CoV-2 has highlighted the urgent need for novel antiviral therapies. This study integrates combinatorial chemistry, molecular docking, and deep learning to design, evaluate and synthesize new pyrazole derivatives as potential inhibitors of the SARS-CoV-2 main protease (M^pro). A library of over 60,000 pyrazole-based structures was generated through scaffold decoration to enhance chemical diversity. Virtual screening employed molecular docking (ChemPLP scoring) and deep learning (DeepPurpose), with consensus ranking to identify top candidates. Binding free energy calculations refined the selection, revealing critical structural features such as tryptamine and N-phenyl fragments for M^pro binding. High-temperature solvent-free amidation allowed the synthesis of a selected derivative. Final compounds demonstrated favorable drug-likeness properties based on Lipinski’s and Veber’s rules. This work highlights the integration of computational and synthetic strategies to accelerate the discovery of M^pro inhibitors and provides a framework for future antiviral development.

{"title":"Rational design and synthesis of pyrazole derivatives as potential SARS-CoV-2 Mpro inhibitors: An integrated approach merging combinatorial chemistry, molecular docking, and deep learning","authors":"Arthur Antunes Ferrarezi , João Vítor Perez de Souza , Bernard Maigret , Érika Seki Kioshima , Sidnei Moura , Arildo José Braz de Oliveira , Fernanda Andreia Rosa , Regina Aparecida Correia Gonçalves","doi":"10.1016/j.bmc.2025.118095","DOIUrl":"10.1016/j.bmc.2025.118095","url":null,"abstract":"<div><div>The global impact of SARS-CoV-2 has highlighted the urgent need for novel antiviral therapies. This study integrates combinatorial chemistry, molecular docking, and deep learning to design, evaluate and synthesize new pyrazole derivatives as potential inhibitors of the SARS-CoV-2 main protease (M<sup>pro</sup>). A library of over 60,000 pyrazole-based structures was generated through scaffold decoration to enhance chemical diversity. Virtual screening employed molecular docking (ChemPLP scoring) and deep learning (DeepPurpose), with consensus ranking to identify top candidates. Binding free energy calculations refined the selection, revealing critical structural features such as tryptamine and <em>N</em>-phenyl fragments for M<sup>pro</sup> binding. High-temperature solvent-free amidation allowed the synthesis of a selected derivative. Final compounds demonstrated favorable drug-likeness properties based on Lipinski’s and Veber’s rules. This work highlights the integration of computational and synthetic strategies to accelerate the discovery of M<sup>pro</sup> inhibitors and provides a framework for future antiviral development.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"120 ","pages":"Article 118095"},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Bioorganic & Medicinal Chemistry

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀