Osteosarcoma is one of the most prevalent malignant bone tumors, and despite advances in treatment, significant improvements in survival rates for osteosarcoma patients remain elusive. There is an urgent need for developing novel molecules for the targeted treatment of osteosarcoma. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly overexpressed in osteosarcoma. Here, we evaluated a series of in-house NQO1-targeting compounds, including NQO1 substrates and β-lap prodrugs, through phenotypic screening using NQO1-positive methylnitronitrosoguanidine-induced human osteosarcoma cells (MNNG) and NQO1-negative normal human umbilical vein endothelial cells (HUVEC), aiming to identify novel candidate compounds for osteosarcoma therapy. As a result, compound 21, an NQO1 substrate, was identified as a potent anti-osteosarcoma agent that promotes apoptosis and induces cell cycle arrest in osteosarcoma cells in vitro, while significantly inhibiting tumor growth in vivo. These findings suggest that compound 21 holds promise as a candidate for osteosarcoma treatment. Moreover, NQO1-targeting substrates present a promising pathway for the discovery of novel anti-osteosarcoma agents.
{"title":"Identification of effective anti-osteosarcoma agents via screening of an in-house NQO1-targeted compound library.","authors":"Xiang Li, Qijie Gong, Jianglin Yu, Jiaqi Liang, Rui Yao, Jian Zhou, Yaxin Chen, Zhijie Lei, Zhan Yu, Xiaojin Zhang, Xusheng Qiu","doi":"10.1016/j.bmc.2025.118162","DOIUrl":"https://doi.org/10.1016/j.bmc.2025.118162","url":null,"abstract":"<p><p>Osteosarcoma is one of the most prevalent malignant bone tumors, and despite advances in treatment, significant improvements in survival rates for osteosarcoma patients remain elusive. There is an urgent need for developing novel molecules for the targeted treatment of osteosarcoma. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly overexpressed in osteosarcoma. Here, we evaluated a series of in-house NQO1-targeting compounds, including NQO1 substrates and β-lap prodrugs, through phenotypic screening using NQO1-positive methylnitronitrosoguanidine-induced human osteosarcoma cells (MNNG) and NQO1-negative normal human umbilical vein endothelial cells (HUVEC), aiming to identify novel candidate compounds for osteosarcoma therapy. As a result, compound 21, an NQO1 substrate, was identified as a potent anti-osteosarcoma agent that promotes apoptosis and induces cell cycle arrest in osteosarcoma cells in vitro, while significantly inhibiting tumor growth in vivo. These findings suggest that compound 21 holds promise as a candidate for osteosarcoma treatment. Moreover, NQO1-targeting substrates present a promising pathway for the discovery of novel anti-osteosarcoma agents.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"118162"},"PeriodicalIF":3.3,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673032","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}
Pub Date : 2025-03-03DOI: 10.1016/j.bmc.2025.118145
Lei Huang , Wei Liu , Xinye Lv , Xiaomei Ge , Zhehao He , Yingxue Yang , Yuhui Tang , Lin Wang , Jianguo Zeng , Pi Cheng
a series of 6-substituted dihydrobenzophenanthridine alkaloids were synthesized by introduction of different functional groups to C-6 of dihydrobenzophenanthridine backbone. The preliminary anti-inflammatory activities of all compounds were screened by investigating the inhibitory ability on NO production in LPS-stimulated RAW 264.7 cells. Among synthesized compounds, 6-(N-phenyl)-aminocarbonyl methyl dihydrochelerythrine (compound 12b) showed increased anti-inflammatory ability and decreased cytotoxicity and could inhibit the expression of pro-inflammatory factors TNF-α and IL-6 in RAW 264.7 macrophages. The anti-inflammatory ability of compound 12b was further evaluated using DSS-induced mice colitis models based on colonic tissue damage assessment, histopathological assessment and immunohistochemical analysis. In vivoexperiment revealed that compound 12b had good alleviating effect on acute colitis in mice. In conclusion, compound 12b may be a promising anti-inflammatory lead compound.
{"title":"Rational design, synthesis and anti-inflammatory activity of 6-substituted dihydrobenzophenanthridine derivatives","authors":"Lei Huang , Wei Liu , Xinye Lv , Xiaomei Ge , Zhehao He , Yingxue Yang , Yuhui Tang , Lin Wang , Jianguo Zeng , Pi Cheng","doi":"10.1016/j.bmc.2025.118145","DOIUrl":"10.1016/j.bmc.2025.118145","url":null,"abstract":"<div><div>a series of 6-substituted dihydrobenzophenanthridine alkaloids were synthesized by introduction of different functional groups to C-6 of dihydrobenzophenanthridine backbone. The preliminary anti-inflammatory activities of all compounds were screened by investigating the inhibitory ability on NO production in LPS-stimulated RAW 264.7 cells. Among synthesized compounds, 6-(<em>N</em>-phenyl)-aminocarbonyl methyl dihydrochelerythrine (compound <strong>12b</strong>) showed increased anti-inflammatory ability and decreased cytotoxicity and could inhibit the expression of pro-inflammatory factors TNF-α and IL-6 in RAW 264.7 macrophages. The anti-inflammatory ability of compound <strong>12b</strong> was further evaluated using DSS-induced mice colitis models based on colonic tissue damage assessment, histopathological assessment and immunohistochemical analysis. <em>In vivo</em> <u>experiment</u> revealed that compound <strong>12b</strong> had good alleviating effect on acute colitis in mice. In conclusion, compound <strong>12b</strong> may be a promising anti-inflammatory lead compound.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118145"},"PeriodicalIF":3.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563368","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}
Pub Date : 2025-03-02DOI: 10.1016/j.bmc.2025.118144
Maxwell Ampomah-Wireko , Ye Qu , Daran Li , Yuequan Wu , Ruirui Li , Yuanbo Li , Hongtao Kong , Zhi-Hao Li , Ya-Na Wang , En Zhang
The continuous evolution of multidrug-resistant (MDR) bacteria to existing antibiotic treatment regimens poses a serious threat to human health, so the discovery of new and potent antimicrobial drugs that are less likely to develop resistance is of great clinical significance. As a result, oxazolidinone antibiotics have emerged as a significant class of bacterial protein synthesis inhibitors, with particular success in the treatment of MDR Gram-positive infections. Herein, a series of novel C-ring modified oxazolidinone derivatives with the introduction of N-methylglycyl groups or quaternary ammonium salts were synthesized and evaluated for their antibacterial efficacy, among which most of the N-methylglycyl derivatives showed significant activity against E. faecalis. Notably, compounds 11g–11i showed good activity against E. faecalis and S. aureus with MICs of 2–8 μg/mL. The selected compound 11g exhibited rapid bactericidal properties, good biofilm disruption capacity, low tendency to induce bacterial resistance, and low cytotoxicity against mammalian cells (HeLa). Furthermore, compound 11g showed relatively good stability in mammalian body fluids and exhibited a longer post-antibiotic effect (PAE). Mechanistic studies showed that compound 11g exerted its antibacterial effect by inhibiting glutathione (GSH) activity and inducing reactive oxygen species (ROS) accumulation, leading to bacterial death. These findings suggest that 11g is a promising candidate for the exploitation of N-methylglycyl oxazolidinones as novel antibacterial agents.
{"title":"Design, synthesis and antibacterial evaluation of oxazolidinone derivatives containing N-methylglycyl or quaternary ammonium salts","authors":"Maxwell Ampomah-Wireko , Ye Qu , Daran Li , Yuequan Wu , Ruirui Li , Yuanbo Li , Hongtao Kong , Zhi-Hao Li , Ya-Na Wang , En Zhang","doi":"10.1016/j.bmc.2025.118144","DOIUrl":"10.1016/j.bmc.2025.118144","url":null,"abstract":"<div><div>The continuous evolution of multidrug-resistant (MDR) bacteria to existing antibiotic treatment regimens poses a serious threat to human health, so the discovery of new and potent antimicrobial drugs that are less likely to develop resistance is of great clinical significance. As a result, oxazolidinone antibiotics have emerged as a significant class of bacterial protein synthesis inhibitors, with particular success in the treatment of MDR Gram-positive infections. Herein, a series of novel C-ring modified oxazolidinone derivatives with the introduction of <em>N</em>-methylglycyl groups or quaternary ammonium salts were synthesized and evaluated for their antibacterial efficacy, among which most of the <em>N</em>-methylglycyl derivatives showed significant activity against <em>E. faecalis</em>. Notably, compounds <strong>11g–11i</strong> showed good activity against <em>E. faecalis</em> and <em>S. aureus</em> with MICs of 2–8 μg/mL. The selected compound <strong>11g</strong> exhibited rapid bactericidal properties, good biofilm disruption capacity, low tendency to induce bacterial resistance, and low cytotoxicity against mammalian cells (HeLa). Furthermore, compound <strong>11g</strong> showed relatively good stability in mammalian body fluids and exhibited a longer post-antibiotic effect (PAE). Mechanistic studies showed that compound <strong>11g</strong> exerted its antibacterial effect by inhibiting glutathione (GSH) activity and inducing reactive oxygen species (ROS) accumulation, leading to bacterial death. These findings suggest that <strong>11g</strong> is a promising candidate for the exploitation of <em>N</em>-methylglycyl oxazolidinones as novel antibacterial agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118144"},"PeriodicalIF":3.3,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563367","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}
Pub Date : 2025-03-01DOI: 10.1016/j.bmc.2025.118143
Tran Thi Lan Huong , Hwa Kyung Kim , Nguyen Duc Thien , Do Thi Mai Dung , Ji Su Kim , Jiyeon Kim , Jong Soon Kang , Dao Thi Kim Oanh , Truong Thanh Tung , Nguyen Quoc Thang , Duong Tien Anh , Sang-Bae Han , Nguyen-Hai Nam
Histone deacetylases (HDACs) have emerged as compelling targets in developing anticancer therapeutics. This study outlines the development, synthesis, and biological evaluation of novel hydroxamic acid derivatives featuring a 2-oxoindoline scaffold, which exhibit high HDAC inhibitory activity and potential anticancer effects. Three series of N-hydroxycinnamamides, N-hydroxyheptanamides, and N-hydroxybenzamides were synthesized and assessed for their biological activity. The results of the biological activity evaluation indicated that the synthesized derivatives exhibited notable inhibitory effects against SW620 (colon cancer) and HCT116 (human colorectal carcinoma). Compound N-hydroxy-7-(2-oxoindolin-1-yl)heptanamide (6a) exhibited remarkable HDAC inhibitory activity, achieving sub-nanomolar potency with an IC50 value of less than 0.001 µM. While this potent HDAC inhibition suggests strong enzymatic activity, the anticancer activity of 6a against SW620 and HCT116 was comparable to that of SAHA (IC50 of 0.101 µM). Analysis of selected compound 6a also revealed that this compound effectively triggered both early and late stages of apoptosis and caused cell cycle arrest at the G2/M phase in SW620 cells. Finally, docking studies and molecular dynamics study conducted on the HDAC isoforms for series 6a-e identified key structural features that play a significant role in the inhibitory activity of the synthesized compounds.
{"title":"Design, synthesis and biological evaluation of novel hydroxamic acid-derived histone deacetylase inhibitors bearing a 2-oxoindoline scaffold as potential antitumor agents","authors":"Tran Thi Lan Huong , Hwa Kyung Kim , Nguyen Duc Thien , Do Thi Mai Dung , Ji Su Kim , Jiyeon Kim , Jong Soon Kang , Dao Thi Kim Oanh , Truong Thanh Tung , Nguyen Quoc Thang , Duong Tien Anh , Sang-Bae Han , Nguyen-Hai Nam","doi":"10.1016/j.bmc.2025.118143","DOIUrl":"10.1016/j.bmc.2025.118143","url":null,"abstract":"<div><div>Histone deacetylases (HDACs) have emerged as compelling targets in developing anticancer therapeutics. This study outlines the development, synthesis, and biological evaluation of novel hydroxamic acid derivatives featuring a 2-oxoindoline scaffold, which exhibit high HDAC inhibitory activity and potential anticancer effects. Three series of <em>N</em>-hydroxycinnamamides, <em>N</em>-hydroxyheptanamides, and <em>N</em>-hydroxybenzamides were synthesized and assessed for their biological activity. The results of the biological activity evaluation indicated that the synthesized derivatives exhibited notable inhibitory effects against SW620 (colon cancer) and HCT116 (human colorectal carcinoma). Compound <em>N</em>-hydroxy-7-(2-oxoindolin-1-yl)heptanamide (<strong>6a</strong>) exhibited remarkable HDAC inhibitory activity, achieving sub-nanomolar potency with an IC<sub>50</sub> value of less than 0.001 µM. While this potent HDAC inhibition suggests strong enzymatic activity, the anticancer activity of <strong>6a</strong> against SW620 and HCT116 was comparable to that of SAHA (IC<sub>50</sub> of 0.101 µM). Analysis of selected compound <strong>6a</strong> also revealed that this compound effectively triggered both early and late stages of apoptosis and caused cell cycle arrest at the G2/M phase in SW620 cells. Finally, docking studies and molecular dynamics study conducted on the HDAC isoforms for series <strong>6a-e</strong> identified key structural features that play a significant role in the inhibitory activity of the synthesized compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118143"},"PeriodicalIF":3.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550872","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}
Pub Date : 2025-02-28DOI: 10.1016/j.bmc.2025.118141
Siew Fang Wong, Joo Kheng Goh
Fused heterocyclic imidazonaphthyridine compounds stand at the forefront of global research, captivating remarkable interest in medicinal and synthetic organic chemistry. These compounds possess a range of potent biological and pharmacological properties, rendering them invaluable for medical and therapeutic research, particularly in drug design and discovery. Despite their significance, no dedicated review has focused on fused heterocyclic imidazonaphthyridine derivatives. This comprehensive review aims to consolidate and explore the cutting-edge synthesis approaches tailored specifically for these unique imidazonaphthyridine derivatives. It highlights their current applications in various biological realms and provides insights into potential future trajectories. By steering forthcoming research endeavours towards innovative design and synthesis of novel imidazonaphthyridines, this review seeks to diversify these compounds, paving the way for biological applications that have yet to be fully realized. Overall, as a burgeoning area of research, this review underscores the potential of imidazonaphthyridines as promising candidates for biomedical applications, offering a snapshot of current research and suggesting future avenues for investigation.
{"title":"A comprehensive review of fused imidazonaphthyridine derivatives: Synthetic approaches and biological applications","authors":"Siew Fang Wong, Joo Kheng Goh","doi":"10.1016/j.bmc.2025.118141","DOIUrl":"10.1016/j.bmc.2025.118141","url":null,"abstract":"<div><div>Fused heterocyclic imidazonaphthyridine compounds stand at the forefront of global research, captivating remarkable interest in medicinal and synthetic organic chemistry. These compounds possess a range of potent biological and pharmacological properties, rendering them invaluable for medical and therapeutic research, particularly in drug design and discovery. Despite their significance, no dedicated review has focused on fused heterocyclic imidazonaphthyridine derivatives. This comprehensive review aims to consolidate and explore the cutting-edge synthesis approaches tailored specifically for these unique imidazonaphthyridine derivatives. It highlights their current applications in various biological realms and provides insights into potential future trajectories. By steering forthcoming research endeavours towards innovative design and synthesis of novel imidazonaphthyridines, this review seeks to diversify these compounds, paving the way for biological applications that have yet to be fully realized. Overall, as a burgeoning area of research, this review underscores the potential of imidazonaphthyridines as promising candidates for biomedical applications, offering a snapshot of current research and suggesting future avenues for investigation.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118141"},"PeriodicalIF":3.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579834","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}
Estrogen play an important role in the development of breast cancer in menopausal women. Aromatase, an enzyme that catalyses the last step in the production of estrogen, has been identified as a promising target for clinical development. In the present investigation, novel 2-substituted benzoxazoles were synthesized and evaluated for inhibition against aromatase. Among the studied compound, 6a exhibited 4.04-fold greater cytotoxicity (IC50 = 0.22 µM) than doxorubicin (IC50 = 0.89 µM). It also showed higher selectivity (26.30–304.95) against cancer cells compared to normal (Vero), with a substantial MID of 0.98 µM against the breast cancer subpanel. Furthermore, it displayed a significantly higher affinity for aromatase (IC50 = 64.9 nM) compared to the standard (IC50 = 1850 nM), indicating the mechanism of anticancer action. In the in-vitro enzymatic assay, it demonstrated 8.46–63.14-fold higher selectivity against aromatase compared to other enzymes. Additionally, docking interaction demonstrated a higher dock score of −10.2 kcal/mol to standard (−8.1 kcal/mol). Furthermore, higher stability in the MD simulation established aromatase as an anticancer target and validated the docking methodology. It was also discovered that compound 6a had a binding free energy of −67.72 kcal/mol, which was 1.46 times lower than the standard (−46.17 kcal/mol), supporting the in-silico protocol. Furthermore, MMGBSA discovered that lower binding free energy of Vander Waals force and lipophilicity had a greater impact on aromatase binding affinity and docking scores. These findings imply that compound 6a deserve to be investigated further in the development of potential anticancer agent as aromatase inhibitors.
{"title":"Discovery of novel benzoxazole analogues as potential anticancer agent selectively targeting aromatase","authors":"Sandip Gadakh , Balasaheb Aghav , Nishith Teraiya , Dhaval Prajapati , Jignesh H. Kamdar , Bhumika Patel , Ruchi Yadav","doi":"10.1016/j.bmc.2025.118142","DOIUrl":"10.1016/j.bmc.2025.118142","url":null,"abstract":"<div><div>Estrogen play an important role in the development of breast cancer in menopausal women. Aromatase, an enzyme that catalyses the last step in the production of estrogen, has been identified as a promising target for clinical development. In the present investigation, novel 2-substituted benzoxazoles were synthesized and evaluated for inhibition against aromatase. Among the studied compound, <strong>6a</strong> exhibited 4.04-fold greater cytotoxicity (IC<sub>50</sub> = 0.22 µM) than doxorubicin (IC<sub>50</sub> = 0.89 µM). It also showed higher selectivity (26.30–304.95) against cancer cells compared to normal (Vero), with a substantial MID of 0.98 µM against the breast cancer subpanel. Furthermore, it displayed a significantly higher affinity for aromatase (IC<sub>50</sub> = 64.9 nM) compared to the standard (IC<sub>50</sub> = 1850 nM), indicating the mechanism of anticancer action. In the <em>in-vitro</em> enzymatic assay, it demonstrated 8.46–63.14-fold higher selectivity against aromatase compared to other enzymes. Additionally, docking interaction demonstrated a higher dock score of −10.2 kcal/mol to standard (−8.1 kcal/mol). Furthermore, higher stability in the MD simulation established aromatase as an anticancer target and validated the docking methodology. It was also discovered that compound <strong>6a</strong> had a binding free energy of −67.72 kcal/mol, which was 1.46 times lower than the standard (−46.17 kcal/mol), supporting the <em>in-silico</em> protocol. Furthermore, MMGBSA discovered that lower binding free energy of Vander Waals force and lipophilicity had a greater impact on aromatase binding affinity and docking scores. These findings imply that compound <strong>6a</strong> deserve to be investigated further in the development of potential anticancer agent as aromatase inhibitors.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118142"},"PeriodicalIF":3.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143550873","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}
Pub Date : 2025-02-27DOI: 10.1016/j.bmc.2025.118136
Hehe Wang , Chuanzhou Zhu , Manojit M. Swamynathan , Shubhra Rajput , Kalani Jayanetti , Dominick Rendina , Kathryn Takemura , Diane Bogdan , Liqun Wang , Robert C. Rizzo , Martin Kaczocha , Lloyd C. Trotman , Agnieszka B. Bialkowska , Iwao Ojima
Prostate cancer (PCa) is one of the most common malignancies diagnosed among men and is the second leading cause of cancer-related death. Despite recent advancements in early diagnosis of PCa, androgen deprivation therapy (ADT) remains the most common treatment of PCa. Docetaxel (DTX) and Cabazitaxel (CTX) are two of the most extensively used drugs for metastatic castration-resistant prostate cancer (mCRPC). However, there is a clear medical need for newer and more efficacious therapies for CRPC. FABP5 is overexpressed in prostate cancer cells and chaperones fatty acids to PPARs, which leads to the upregulation of proangiogenic factors, resulting in cell survival and metastasis. The critical role and upregulation of FABP5 in PCa make FABP5 an excellent druggable target for CRPC. We reported a promising anti-PCa activity of truxillic acid monoester (TAME)-based FABP5 inhibitors (SB-FIs) and their synergy with DTX and CTX in vitro and in vivo against PC-3 cells and PC-3 tumor xenografts. In the present work, we performed an extensive SAR study on the potencies of 2nd- and 3rd-generation SB-FIs against PC-3 and RCaP cell lines. RCaP is a mouse PCa cell line, resistant to anti-androgen and first-line taxane chemotherapies, and shows a high level of the Fabp5-gene. This SAR study led to the identification of a number of 3rd-generation SB-FIs with strong cytotoxicity against these two PCa cell lines. Cell cycle analysis of selected SB-FIs revealed a clear evolution of apoptotic potency in the 1st-, 2nd- and 3rd-generation SB-FIs. Since taxanes, DTX and CTX, are ineffective against RCaP cell line, we selected a topoisomerase I inhibitor, topotecan (TPT) as a replacement for taxanes. We screened the library of SB-FIs for synergy with TPT and identified 3 SB-FIs (L3, α-11 and α-4), exhibiting strong synergy, which could remarkably expand the therapeutic window of TPT.
{"title":"Fatty acid binding protein 5 inhibitors as novel anticancer agents against metastatic castration-resistant prostate cancer","authors":"Hehe Wang , Chuanzhou Zhu , Manojit M. Swamynathan , Shubhra Rajput , Kalani Jayanetti , Dominick Rendina , Kathryn Takemura , Diane Bogdan , Liqun Wang , Robert C. Rizzo , Martin Kaczocha , Lloyd C. Trotman , Agnieszka B. Bialkowska , Iwao Ojima","doi":"10.1016/j.bmc.2025.118136","DOIUrl":"10.1016/j.bmc.2025.118136","url":null,"abstract":"<div><div>Prostate cancer (PCa) is one of the most common malignancies diagnosed among men and is the second leading cause of cancer-related death. Despite recent advancements in early diagnosis of PCa, androgen deprivation therapy (ADT) remains the most common treatment of PCa. Docetaxel (DTX) and Cabazitaxel (CTX) are two of the most extensively used drugs for metastatic castration-resistant prostate cancer (mCRPC). However, there is a clear medical need for newer and more efficacious therapies for CRPC. FABP5 is overexpressed in prostate cancer cells and chaperones fatty acids to PPARs, which leads to the upregulation of proangiogenic factors, resulting in cell survival and metastasis. The critical role and upregulation of FABP5 in PCa make FABP5 an excellent druggable target for CRPC. We reported a promising anti-PCa activity of truxillic acid monoester (TAME)-based FABP5 inhibitors (SB-FIs) and their synergy with DTX and CTX <em>in vitro</em> and <em>in vivo</em> against PC-3 cells and PC-3 tumor xenografts. In the present work, we performed an extensive SAR study on the potencies of 2nd- and 3rd-generation SB-FIs against PC-3 and RCaP cell lines. RCaP is a mouse PCa cell line, resistant to anti-androgen and first-line taxane chemotherapies, and shows a high level of the <em>Fabp5</em>-gene. This SAR study led to the identification of a number of 3rd-generation SB-FIs with strong cytotoxicity against these two PCa cell lines. Cell cycle analysis of selected SB-FIs revealed a clear evolution of apoptotic potency in the 1st-, 2nd- and 3rd-generation SB-FIs. Since taxanes, DTX and CTX, are ineffective against RCaP cell line, we selected a topoisomerase I inhibitor, topotecan (TPT) as a replacement for taxanes. We screened the library of SB-FIs for synergy with TPT and identified 3 SB-FIs (<strong>L3</strong>, <strong>α-11</strong> and <strong>α-4</strong>), exhibiting strong synergy, which could remarkably expand the therapeutic window of TPT.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118136"},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579836","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}
Pub Date : 2025-02-26DOI: 10.1016/j.bmc.2025.118132
Jean-Philippe Surivet, Elise M. Jacob, Melanie Kessler, Christopher Kohl, Catherine Vaillant, Olivier Bezençon, Patrick Bouis, Louise Busch, Jean-Christophe Gauvin, Manon Kiry, Chara Litou, Florence Masse, Cary-Ann Mathieu, Azely Mirre, Jens-Uwe Peters, Timo Rager, Markus Rey, Raphaël Ruetsch, Michel Alexander Steiner
We describe the optimization of 2-acyl-1-biarylmethylpyrazolidines, a novel class of dual orexin receptor antagonists (DORAs) designed for the treatment of sleep disorders requiring a rapid onset (<30 min) and a short duration of action (2–4 h). Building on the previously identified lead compound DORA 4, our optimization program yielded several potent pyrazolidine DORAs with carefully tailored in vitro physicochemical and DMPK (drug, metabolism and pharmacokinetics) properties. In vivo studies in animals, combined with pharmacokinetic-pharmacodynamic (PK-PD) simulations, demonstrated that DORA 31 and DORA (R)-38 effectively induced sleep in dogs and met the in silico predicted requirements for rapid onset and short duration in humans. Further analysis of their covalent binding potential in human hepatocytes prioritized DORA 31 as the preferred molecule for additional safety and biopharmaceutical evaluation. In this report we summarize and present the results of all studies that supported the selection of DORA 31 (IDOR-1117-1680) as a preclinical development candidate.
{"title":"Discovery of IDOR-1117-1680, a dual orexin receptor antagonist with fast onset and short duration of action for the treatment of insomnia","authors":"Jean-Philippe Surivet, Elise M. Jacob, Melanie Kessler, Christopher Kohl, Catherine Vaillant, Olivier Bezençon, Patrick Bouis, Louise Busch, Jean-Christophe Gauvin, Manon Kiry, Chara Litou, Florence Masse, Cary-Ann Mathieu, Azely Mirre, Jens-Uwe Peters, Timo Rager, Markus Rey, Raphaël Ruetsch, Michel Alexander Steiner","doi":"10.1016/j.bmc.2025.118132","DOIUrl":"10.1016/j.bmc.2025.118132","url":null,"abstract":"<div><div>We describe the optimization of 2-acyl-1-biarylmethylpyrazolidines, a novel class of dual orexin receptor antagonists (DORAs) designed for the treatment of sleep disorders requiring a rapid onset (<30<!--> <!--> min) and a short duration of action (2–4 h). Building on the previously identified lead compound DORA <strong>4</strong>, our optimization program yielded several potent pyrazolidine DORAs with carefully tailored <em>in vitro</em> physicochemical and DMPK (drug, metabolism and pharmacokinetics) properties. <em>In vivo</em> studies in animals, combined with pharmacokinetic-pharmacodynamic (PK-PD) simulations, demonstrated that DORA <strong>31</strong> and DORA (<em>R</em>)-<strong>38</strong> effectively induced sleep in dogs and met the <em>in silico</em> predicted requirements for rapid onset and short duration in humans. Further analysis of their covalent binding potential in human hepatocytes prioritized DORA <strong>31</strong> as the preferred molecule for additional safety and biopharmaceutical evaluation. In this report we summarize and present the results of all studies that supported the selection of DORA <strong>31</strong> (IDOR-1117-1680) as a preclinical development candidate.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118132"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551582","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}
Pub Date : 2025-02-26DOI: 10.1016/j.bmc.2025.118137
Dittu Suresh , Tsz Tin Yu , Rajesh Kuppusamy , Shekh Sabir , Theerthankar Das , David StC Black , Mark D.P. Willcox , Naresh Kumar
Antimicrobial resistance has grown to become a global crisis consistently participating in the death of millions worldwide and accumulating costs on healthcare. Quorum sensing inhibition is a new alternative antimicrobial strategy that has been gaining attention due to its ability to suppress the resistance of Pseudomonas aeruginosa (PA). This approach shows great potential in overcoming bacterial resistance and could provide a much needed substitute to conventional antibiotics in the future. PA has 3 main quorum sensing systems of which the Las system has been identified to be the most viable therapeutic target. In this study, we report the synthesis of a library of novel broad-spectrum quorum sensing inhibitors from the dihydropyrrol-2-one scaffold to form urea and imidazolium analogues. Molecular docking was performed in parallel to synthesis to aid design. It also confirmed that the molecules comfortably occupy the ligand binding domain in addition to potential key interactions commonly present in LasR inhibitors. As predicted, these compounds displayed low bactericidal effects against P. aeruginosa with most compounds exhibiting MIC of >250 μM, while maintaining moderate activity towards Escherichia coli with the most potent compound having an MIC of 32 μM. The greatest bactericidal effects were present on Staphylococcus aureus with the thiourea based molecule 10c showed the highest antibacterial activity with MIC of 16 µM. Furthermore, several molecules displayed highly potent quorum sensing inhibitory activity with compounds 10g and 9e both demonstrating over 70 % inhibition respectively of the LasR system at 16 µM. These compounds also expressed inhibition of pyocyanin within P. aeruginosa and haemolytic assay indicates a low level of cell lysis and hence low toxicity of the compounds, further demonstrating the potential of these novel compounds.
{"title":"Novel cationic dihydropyrrol-2-one compounds as antimicrobial agents and quorum sensing inhibitors","authors":"Dittu Suresh , Tsz Tin Yu , Rajesh Kuppusamy , Shekh Sabir , Theerthankar Das , David StC Black , Mark D.P. Willcox , Naresh Kumar","doi":"10.1016/j.bmc.2025.118137","DOIUrl":"10.1016/j.bmc.2025.118137","url":null,"abstract":"<div><div>Antimicrobial resistance has grown to become a global crisis consistently participating in the death of millions worldwide and accumulating costs on healthcare. Quorum sensing inhibition is a new alternative antimicrobial strategy that has been gaining attention due to its ability to suppress the resistance of <em>Pseudomonas aeruginosa</em> (PA). This approach shows great potential in overcoming bacterial resistance and could provide a much needed substitute to conventional antibiotics in the future. PA has 3 main quorum sensing systems of which the <em>Las</em> system has been identified to be the most viable therapeutic target. In this study, we report the synthesis of a library of novel broad-spectrum quorum sensing inhibitors from the dihydropyrrol-2-one scaffold to form urea and imidazolium analogues. Molecular docking was performed in parallel to synthesis to aid design. It also confirmed that the molecules comfortably occupy the ligand binding domain in addition to potential key interactions commonly present in <em>LasR</em> inhibitors. As predicted, these compounds displayed low bactericidal effects against <em>P. aeruginosa</em> with most compounds exhibiting MIC of >250 μM, while maintaining moderate activity towards <em>Escherichia coli</em> with the most potent compound having an MIC of 32 μM. The greatest bactericidal effects were present on <em>Staphylococcus aureus</em> with the thiourea based molecule <strong>10c</strong> showed the highest antibacterial activity with MIC of 16 µM. Furthermore, several molecules displayed highly potent quorum sensing inhibitory activity with compounds <strong>10g</strong> and <strong>9e</strong> both demonstrating over 70 % inhibition respectively of the <em>LasR</em> system at 16 µM. These compounds also expressed inhibition of pyocyanin within <em>P. aeruginosa</em> and haemolytic assay indicates a low level of cell lysis and hence low toxicity of the compounds, further demonstrating the potential of these novel compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118137"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579837","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}
Pub Date : 2025-02-26DOI: 10.1016/j.bmc.2025.118135
Honglei Bao , Hui Meng , Shilin Gong , Yaguo Gong , Gao Tu , Zhenya Du , Yuwei Wang , Jianlin Wu , Chunhua Ma , Qinhai Ma , Xiaojun Yao
Since 2020, numerous compounds have been investigated for their potential use in treating SARS-CoV-2 infections. By identifying the molecular targets during the virus replication process, rationally designed anti-SARS-CoV-2 agents are developed. Among these targets, the main protease (Mpro) is a crucial enzyme required for virus replication, and its highly conserved characteristic make it an important drug target for the development of anti-SARS-CoV-2 drugs. Herein, we utilized warhead-based design strategy to conduct the structural optimization of M-1 developed through virtual screening, leading to a series of novel Mpro inhibitors with 4-(quinolin-2-yl)aniline scaffold. Among them, M-32 exhibited good SARS-CoV-2 Mpro inhibitory activity (IC50 = 5.2 μM) with a nearly 25-fold increase. Isothermal titration calorimetry (ITC) directly proved that M-32 binds directly to SARS-CoV-2 Mpro in an entropy-driven manner. Mass spectrometry (MS) further confirmed the covalent binding ability of M-32 to Mpro. Meanwhile, M-32 effectively inhibited the replication of SARS-CoV-2 in Vero E6 cells (EC50 = 5.29 μM).
{"title":"Design, synthesis and activity evaluation of 4-(quinoline-2-yl)aniline derivatives as SARS-CoV‑2 main protease inhibitors","authors":"Honglei Bao , Hui Meng , Shilin Gong , Yaguo Gong , Gao Tu , Zhenya Du , Yuwei Wang , Jianlin Wu , Chunhua Ma , Qinhai Ma , Xiaojun Yao","doi":"10.1016/j.bmc.2025.118135","DOIUrl":"10.1016/j.bmc.2025.118135","url":null,"abstract":"<div><div>Since 2020, numerous compounds have been investigated for their potential use in treating SARS-CoV-2 infections. By identifying the molecular targets during the virus replication process, rationally designed anti-SARS-CoV-2 agents are developed. Among these targets, the main protease (M<sup>pro</sup>) is a crucial enzyme required for virus replication, and its highly conserved characteristic make it an important drug target for the development of anti-SARS-CoV-2 drugs. Herein, we utilized warhead-based design strategy to conduct the structural optimization of <strong>M-1</strong> developed through virtual screening, leading to a series of novel M<sup>pro</sup> inhibitors with 4-(quinolin-2-yl)aniline scaffold. Among them, <strong>M-32</strong> exhibited good SARS-CoV-2 M<sup>pro</sup> inhibitory activity (IC<sub>50</sub> = 5.2 μM) with a nearly 25-fold increase. Isothermal titration calorimetry (ITC) directly proved that <strong>M-32</strong> binds directly to SARS-CoV-2 M<sup>pro</sup> in an entropy-driven manner. Mass spectrometry (MS) further confirmed the covalent binding ability of <strong>M-32</strong> to M<sup>pro</sup>. Meanwhile, <strong>M-32</strong> effectively inhibited the replication of SARS-CoV-2 in Vero E6 cells (EC<sub>50</sub> = 5.29 μM).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118135"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520614","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}
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