Bioorganic & Medicinal Chemistry最新文献

{"title":"Discovery of potent free fatty acid receptor 1 full agonists with a novel scaffold bearing conjugated double bond linker","authors":"Ziwei Yang ,&nbsp;Jun Sun ,&nbsp;Tifei Xu ,&nbsp;Yu Wang ,&nbsp;Jiahui Fang ,&nbsp;Kai Wang ,&nbsp;Shimeng Guo ,&nbsp;Xin Xie ,&nbsp;Jianhua Shen","doi":"10.1016/j.bmc.2025.118158","DOIUrl":"10.1016/j.bmc.2025.118158","url":null,"abstract":"<div><div>GPR40 full agonists can not only lower blood glucose via glucose-stimulated insulin secretion (GSIS) with a low risk of hypoglycemia, but also promote incretin release such as glucagon-like peptide-1 (GLP-1). Compared with partial agonists, full agonists are superior in the treatment of diabetes and obesity. Based on patent research, we combined the highly compatible linker with CPL207280, a GPR40 partial agonist that metabolized mainly through oxidation, to design a potent GPR40 full agonist with a novel scaffold. We explored the linker, tail and acid head and finally found compound H1-2 with excellent glucose-lowering ability.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118158"},"PeriodicalIF":3.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143695947","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}

{"title":"Photocaging of N-pyridinyl amide scaffold-based PIM inhibitors for spatiotemporal controlled anticancer bioactivity","authors":"Mingzhu Lu ,&nbsp;Haifeng Liu ,&nbsp;Ruiqing Xiang ,&nbsp;Jianing Li ,&nbsp;Tianze Wu ,&nbsp;Mingli Deng ,&nbsp;Yu Jia ,&nbsp;Xiaofeng Liu ,&nbsp;Yongtai Yang ,&nbsp;Yu Ge ,&nbsp;Tong Cai ,&nbsp;Jianming Wu ,&nbsp;Yun Ling ,&nbsp;Yaming Zhou","doi":"10.1016/j.bmc.2025.118159","DOIUrl":"10.1016/j.bmc.2025.118159","url":null,"abstract":"<div><div>Photocaging is an ideal way to enable spatiotemporal control over the release of bioactive compounds for cancer treatments. In this work, a series of photocaged <em>N</em>-pyridinyl amide scaffold-based PIM inhibitors were developed by rendering the amino group unable to bind to the Asp128/Glu171 sites of PIM kinase with a photoremovable protecting group (PPG). Upon light irradiation, our studies revealed the structure-dependent photouncaging efficiency and screened out the photocaged PIM inhibitor FD1024-PPG. Its spatiotemporally controlled bioactivity was confirmed by cell-based <em>in-vitro</em> assays and revealed that it exerts the antiproliferation and induction of cell apoptosis through inhibition of PIM kinase upon light irradiation. Furthermore, the spatiotemporal control over the <em>in-vivo</em> anticancer activity was demonstrated using zebrafish xenograft model.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"124 ","pages":"Article 118159"},"PeriodicalIF":3.3,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143769138","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}

{"title":"Synthesis and biological activity of 1H-pyrrolo[3,2-g]isoquinolines as Haspin kinase inhibitors","authors":"Killian Malosse ,&nbsp;Marie Ben Doula ,&nbsp;Béatrice Josselin ,&nbsp;Thomas Robert ,&nbsp;Fabrice Anizon ,&nbsp;Sandrine Ruchaud ,&nbsp;Francis Giraud ,&nbsp;Pascale Moreau","doi":"10.1016/j.bmc.2025.118157","DOIUrl":"10.1016/j.bmc.2025.118157","url":null,"abstract":"<div><div>Based on previous results, new 1<em>H</em>-pyrrolo[3,2-<em>g</em>]isoquinolines were synthesized and evaluated for their ability to inhibit Haspin. Considering that analogues methylated at the indole nitrogen could retain their Haspin inhibitory potency, conjugates that could be suitable for a use in a PROTAC approach were prepared by <em>N</em>-alkylation. In addition, based on the Haspin inhibitory potency of 1<em>H</em>-pyrrolo[3,2-<em>g</em>]isoquinoline-3-carbaldehyde analogue, an additional PROTAC candidate was synthesized by carbonylation at the 3-position. Unfortunately, none of these conjugates exhibited Haspin inhibitory potency. Nevertheless, <em>N</em>-methylated derivative <strong>10</strong> bearing a pyridin-4-yl substituent at the 3-position is the best selective Haspin inhibitor identified to date in these series, with an IC₅₀ value of 23.6 nM and a selectivity index superior to 14 compared to other protein kinases tested. Additionally, this compound showed both interesting effects on cell viability of various human cell lines and significant inhibitory properties on cellular Haspin kinase.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118157"},"PeriodicalIF":3.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143697926","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}

{"title":"Discovery and rational optimization of 2, 2′-((1H-indole-2,3-diyl) bis (thio))diacetamide as novel SARS-CoV-2 RdRp inhibitors","authors":"Yu Shi ,&nbsp;Jianyuan Zhao ,&nbsp;Min Li ,&nbsp;Liya Wei ,&nbsp;Qi Shan ,&nbsp;Minghua Wang ,&nbsp;Mei Zhu ,&nbsp;Shan Cen ,&nbsp;Guoning Zhang ,&nbsp;Juxian Wang ,&nbsp;Yucheng Wang","doi":"10.1016/j.bmc.2025.118153","DOIUrl":"10.1016/j.bmc.2025.118153","url":null,"abstract":"<div><div>The COVID-19 pandemic has significantly strained global health infrastructures while profoundly affecting the socio-economic landscape. RNA-dependent RNA polymerase (RdRp) plays a pivotal role in the replication and transcription of RNA viruses, making it a critical target for antiviral drug development. In this work, we describe the discovery, rational optimization, and synthesis of a novel series of non-nucleoside SARS-CoV-2 RdRp inhibitors featuring a 2,2′-((1H-indole-2,3-diyl)bis (thio))diacetamide core. The inhibitory activity of these compounds was evaluated, with most demonstrating a higher inhibitory effect than Remdesivir. Notably, the most potent candidates suppressed RNA synthesis dose-dependently and exhibited greater resistance to nsp14/nsp10 exonuclease-mediated proofreading compared to Remdesivir. Furthermore, <strong>10b6</strong> and <strong>10b12</strong> showed 1.6- to 2-fold lower EC₅₀ values against coronavirus HCoV-OC43 than Remdesivir, highlighting their potential for further development as broad-spectrum antiviral agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118153"},"PeriodicalIF":3.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143684972","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}

{"title":"Rational design, synthesis and anti-inflammatory activity of 6-substituted dihydrobenzophenanthridine derivatives","authors":"Lei Huang ,&nbsp;Wei Liu ,&nbsp;Xinye Lv ,&nbsp;Xiaomei Ge ,&nbsp;Zhehao He ,&nbsp;Yingxue Yang ,&nbsp;Yuhui Tang ,&nbsp;Lin Wang ,&nbsp;Jianguo Zeng ,&nbsp;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}

{"title":"Design, synthesis and antibacterial evaluation of oxazolidinone derivatives containing N-methylglycyl or quaternary ammonium salts","authors":"Maxwell Ampomah-Wireko ,&nbsp;Ye Qu ,&nbsp;Daran Li ,&nbsp;Yuequan Wu ,&nbsp;Ruirui Li ,&nbsp;Yuanbo Li ,&nbsp;Hongtao Kong ,&nbsp;Zhi-Hao Li ,&nbsp;Ya-Na Wang ,&nbsp;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}

{"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 ,&nbsp;Hwa Kyung Kim ,&nbsp;Nguyen Duc Thien ,&nbsp;Do Thi Mai Dung ,&nbsp;Ji Su Kim ,&nbsp;Jiyeon Kim ,&nbsp;Jong Soon Kang ,&nbsp;Dao Thi Kim Oanh ,&nbsp;Truong Thanh Tung ,&nbsp;Nguyen Quoc Thang ,&nbsp;Duong Tien Anh ,&nbsp;Sang-Bae Han ,&nbsp;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 IC₅₀ 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 (IC₅₀ 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}

{"title":"Discovery of novel benzoxazole analogues as potential anticancer agent selectively targeting aromatase","authors":"Sandip Gadakh ,&nbsp;Balasaheb Aghav ,&nbsp;Nishith Teraiya ,&nbsp;Dhaval Prajapati ,&nbsp;Jignesh H. Kamdar ,&nbsp;Bhumika Patel ,&nbsp;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 (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 <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}

{"title":"A comprehensive review of fused imidazonaphthyridine derivatives: Synthetic approaches and biological applications","authors":"Siew Fang Wong,&nbsp;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}

{"title":"Fatty acid binding protein 5 inhibitors as novel anticancer agents against metastatic castration-resistant prostate cancer","authors":"Hehe Wang ,&nbsp;Chuanzhou Zhu ,&nbsp;Manojit M. Swamynathan ,&nbsp;Shubhra Rajput ,&nbsp;Kalani Jayanetti ,&nbsp;Dominick Rendina ,&nbsp;Kathryn Takemura ,&nbsp;Diane Bogdan ,&nbsp;Liqun Wang ,&nbsp;Robert C. Rizzo ,&nbsp;Martin Kaczocha ,&nbsp;Lloyd C. Trotman ,&nbsp;Agnieszka B. Bialkowska ,&nbsp;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}