Pub Date : 2026-01-20DOI: 10.1016/j.bmcl.2026.130557
Monika Tvrdoňová , Yuliia Zuzak , Martina Bago Pilátová , Dávid Jáger , Roman Mezencev , Miroslava Martinková
A novel 4-C-branched sugar mimetic based on a 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) scaffold was designed and synthesised. Its construction features an early-stage introduction of the side chain via an OCM reaction followed by an alkylative cyclisation, providing the desired heterocyclic system. The subsequent interconversion of functional groups accompanied by the selective deprotection protocol allowed the tetrahydrofuran ring to be cleaved. Cell viability experiments revealed a cytotoxic effect of the target compound comparable to that of cisplatin on the A2058 and MCF-7 cancer cell lines. Moreover, 4-C-tridecyl-DIL proved to be moderately active against Jurkat and HeLa cells (IC50 = 20.58 μM and 22.7 μM, respectively). In addition, docking studies identified the binding modes of this novel pyrrolidine-based iminosugar to human β-glucocerebrosidase.
{"title":"Synthesis and biological profile of a novel 4-C-branched pyrrolidine-containing iminosugar","authors":"Monika Tvrdoňová , Yuliia Zuzak , Martina Bago Pilátová , Dávid Jáger , Roman Mezencev , Miroslava Martinková","doi":"10.1016/j.bmcl.2026.130557","DOIUrl":"10.1016/j.bmcl.2026.130557","url":null,"abstract":"<div><div>A novel 4-<em>C</em>-branched sugar mimetic based on a 1,4-dideoxy-1,4-imino-<span>d</span>-lyxitol (DIL) scaffold was designed and synthesised. Its construction features an early-stage introduction of the side chain <em>via</em> an OCM reaction followed by an alkylative cyclisation, providing the desired heterocyclic system. The subsequent interconversion of functional groups accompanied by the selective deprotection protocol allowed the tetrahydrofuran ring to be cleaved. Cell viability experiments revealed a cytotoxic effect of the target compound comparable to that of cisplatin on the A2058 and MCF-7 cancer cell lines. Moreover, 4-<em>C</em>-tridecyl-DIL proved to be moderately active against Jurkat and HeLa cells (IC<sub>50</sub> = 20.58 μM and 22.7 μM, respectively). In addition, docking studies identified the binding modes of this novel pyrrolidine-based iminosugar to human β-glucocerebrosidase.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130557"},"PeriodicalIF":2.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-19DOI: 10.1016/j.bmcl.2026.130549
Hwan Jung Lim , Uk-Il Kim , Kwang Rok Kim , Jun Mi Lee , Kyeong-Yong Park , Hyung Tae Bang , Jihye Yoon , Eunsol Jo , Kyungjin Kim , Jung-Nyoung Heo
We report the design, synthesis, and characterization of a novel series of triazolopyrimidinone and imidazotriazinone derivatives as potent and selective TNKS1/2 inhibitors. These compounds bind to the nicotinamide pocket of TNKS and exhibit strong enzymatic inhibition and cellular Wnt/β-catenin pathway suppression, with minimal off-target activity against other PARP family members. Among them, 11b (STP1002, Basroparib) demonstrated the most favorable profile, with sub-nanomolar IC50 values for TNKS1/2, high selectivity, and excellent physicochemical and ADME properties. These findings support the further development of STP1002 as a promising therapeutic candidate for Wnt-driven cancers, with potential applications as both a monotherapy and in combination with other targeted agents.
{"title":"Synthesis of triazolopyrimidinone- and imidazotriazinone-based tankyrase inhibitors: Identification of Basroparib (STP1002) as a clinical candidate","authors":"Hwan Jung Lim , Uk-Il Kim , Kwang Rok Kim , Jun Mi Lee , Kyeong-Yong Park , Hyung Tae Bang , Jihye Yoon , Eunsol Jo , Kyungjin Kim , Jung-Nyoung Heo","doi":"10.1016/j.bmcl.2026.130549","DOIUrl":"10.1016/j.bmcl.2026.130549","url":null,"abstract":"<div><div>We report the design, synthesis, and characterization of a novel series of triazolopyrimidinone and imidazotriazinone derivatives as potent and selective TNKS1/2 inhibitors. These compounds bind to the nicotinamide pocket of TNKS and exhibit strong enzymatic inhibition and cellular Wnt/β-catenin pathway suppression, with minimal off-target activity against other PARP family members. Among them, <strong>11b</strong> (STP1002, Basroparib) demonstrated the most favorable profile, with sub-nanomolar IC<sub>50</sub> values for TNKS1/2, high selectivity, and excellent physicochemical and ADME properties. These findings support the further development of STP1002 as a promising therapeutic candidate for Wnt-driven cancers, with potential applications as both a monotherapy and in combination with other targeted agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130549"},"PeriodicalIF":2.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.bmcl.2026.130554
Xia Chen , Ruilin Zhang , Zhaolong He , Xin Qian , Chuxin Yao , Xiaoyu Xiong , Fangke Weng , Shiqiang Xu , Ya Wu , Zihui Li
In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (5a–5n). Cytotoxicity assessment in RAW 264.7 cells indicated minimal toxicity for most compounds under experimental conditions. Notably, compound 5j exhibited superior anti-inflammatory activity, significantly attenuating intracellular reactive oxygen species (ROS) while maintaining exceptional cytocompatibility (>100% cell viability at 1.25–20 μM) and demonstrating the most potent suppression of lipid accumulation. Mechanistic studies revealed that compound 5j synergistically modulates two key pathways: downregulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and restoration of cholesterol homeostasis via upregulation of ABCG1, leading to enhanced cholesterol efflux and 69.9% inhibition of foam cell formation at 3.25 μM (p < 0.001). SwissADME predictions indicated that compound 5j possesses favorable membrane permeability, high gastrointestinal absorption, and potential oral bioavailability. These findings establish compound 5j as a potential lead for developing atherosclerosis therapies through coordinated modulation of inflammation and lipid metabolism.
{"title":"Synthesis of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives and its potential applications in atherosclerosis","authors":"Xia Chen , Ruilin Zhang , Zhaolong He , Xin Qian , Chuxin Yao , Xiaoyu Xiong , Fangke Weng , Shiqiang Xu , Ya Wu , Zihui Li","doi":"10.1016/j.bmcl.2026.130554","DOIUrl":"10.1016/j.bmcl.2026.130554","url":null,"abstract":"<div><div>In the search for novel anti-atherosclerotic agents, we herein report the design, synthesis, and evaluation of a series of benzo[e][1,2,4]thiadiazine 1,1-dioxide derivatives (<strong>5a</strong>–<strong>5n</strong>). Cytotoxicity assessment in RAW 264.7 cells indicated minimal toxicity for most compounds under experimental conditions. Notably, compound <strong>5j</strong> exhibited superior anti-inflammatory activity, significantly attenuating intracellular reactive oxygen species (ROS) while maintaining exceptional cytocompatibility (>100% cell viability at 1.25–20 μM) and demonstrating the most potent suppression of lipid accumulation. Mechanistic studies revealed that compound <strong>5j</strong> synergistically modulates two key pathways: downregulation of pro-inflammatory cytokines (TNF-<em>α</em>, IL-1<em>β</em>, IL-6) and restoration of cholesterol homeostasis via upregulation of ABCG1, leading to enhanced cholesterol efflux and 69.9% inhibition of foam cell formation at 3.25 μM (<em>p</em> < 0.001). SwissADME predictions indicated that compound <strong>5j</strong> possesses favorable membrane permeability, high gastrointestinal absorption, and potential oral bioavailability. These findings establish compound <strong>5j</strong> as a potential lead for developing atherosclerosis therapies through coordinated modulation of inflammation and lipid metabolism.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130554"},"PeriodicalIF":2.2,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.bmcl.2026.130541
Otília Höeller Guarnieri , Mariza Gabriela Faleiro de Moura Lodi Cruz , Daniela de Melo Resende , Carime L.M. Pontes , Igor Vivan Roberto , Luiza Schmidt D'Agostini , Bertha Chithambo , Niklas Ehlenz , Xavier Siwe-Noundou , Rui W.M. Krause , Maique W. Biavatti , Jaya R. Lakkakula , Nilesh Shirish Wagh , Mario Steindel , Till Opatz , Silvane M. Fonseca Murta , Louis P. Sandjo
Trypanosoma cruzi and Leishmania spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared N1,N4-bisbenzylbutane-1,4-diamines against recombinant T. cruzi and L. infantum as well as their inhibitory effects against the T. cruzi recombinant trypanothione reductase (TcTR). N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC50 of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC50 of 14.6). It moderately inhibited TcTR with an IC50 of 55.6 ± 18.6 μM. N1,N4-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited L. infantum with an IC50 of 19.3 ± 1.2 μM (SI of 3.4). N1,N4-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against T. cruzi (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC50 of 3.9 ± 1.9 μM. Alongside the two diamines, nine other synthesized derivatives displayed antitrypanosomal activity with IC50 ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during in silico studies of the active compounds using TcTR (PDB ID 4NEW), N1,N4-bis((E)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.
{"title":"Inhibitory effects against Trypanosoma cruzi, Leishmania infantum and trypanothione reductase of N1,N4-bisbenzylbutane-1,4-diamines","authors":"Otília Höeller Guarnieri , Mariza Gabriela Faleiro de Moura Lodi Cruz , Daniela de Melo Resende , Carime L.M. Pontes , Igor Vivan Roberto , Luiza Schmidt D'Agostini , Bertha Chithambo , Niklas Ehlenz , Xavier Siwe-Noundou , Rui W.M. Krause , Maique W. Biavatti , Jaya R. Lakkakula , Nilesh Shirish Wagh , Mario Steindel , Till Opatz , Silvane M. Fonseca Murta , Louis P. Sandjo","doi":"10.1016/j.bmcl.2026.130541","DOIUrl":"10.1016/j.bmcl.2026.130541","url":null,"abstract":"<div><div><em>Trypanosoma cruzi</em> and <em>Leishmania</em> spp. are the protozoan parasites responsible for Chagas disease and leishmaniasis. The treatment of these neglected diseases relies on repurposed drugs and faces several challenges including high toxicity, and the emergence of resistant strain. Therefore, there is a constant demand for promising antiparasitic agents. The present work aimed to investigate seventeen prepared <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bisbenzylbutane-1,4-diamines against recombinant <em>T. cruzi</em> and <em>L. infantum</em> as well as their inhibitory effects against the <em>T. cruzi</em> recombinant trypanothione reductase (TcTR). <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis(4-chlorobenzyl)butane-1,4-diamine showed significant trypanocidal activity with an IC<sub>50</sub> of 6.0 ± 0.9 μM with a selectivity index of 4.3. This compound was more active than the positive control, benznidazole (IC<sub>50</sub> of 14.6). It moderately inhibited TcTR with an IC<sub>50</sub> of 55.6 ± 18.6 μM. <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis(4-chlorobenzyl)butane-1,4-diamine also inhibited <em>L. infantum</em> with an IC<sub>50</sub> of 19.3 ± 1.2 μM (SI of 3.4). <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis((<em>E</em>)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine exhibited potent inhibitory effect against <em>T. cruzi</em> (2.4 ± 0.3 μM); However, it also turned out to be highly cytotoxic to the L929 fibroblast cell line. Its inhibitory effect against TcTR was also significant, with an IC<sub>50</sub> of 3.9 ± 1.9 μM. Alongside the two diamines, nine other synthesized derivatives displayed antitrypanosomal activity with IC<sub>50</sub> ranging from 8 to 150 μM. Concerning the leishmanicidal effects, all tested compounds were moderately active. Moreover, during <em>in silico</em> studies of the active compounds using TcTR (PDB ID <span><span>4NEW</span><svg><path></path></svg></span>), <em>N</em><sup>1</sup>,<em>N</em><sup>4</sup>-bis((<em>E</em>)-3-(2-methoxyphenyl)allyl)butane-1,4-diamine emerged as the most promising candidate, displaying both strong binding affinity and significant biological activity.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130541"},"PeriodicalIF":2.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145963073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.bmcl.2026.130540
Anggit Fitria, Yehezkiel Steven Kurniawan, Eti Nurwening Sholikhah, Harno Dwi Pranowo, Jumina
The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (4a-4f) as cytotoxic agents. These derivatives were obtained via the O-allylation of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 4-hydroxybenzaldehyde with resorcinol, pyrogallol, or 2-methylresorcinol. All compounds were examined for their in vitro anticancer activity against human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, analogue 4a exhibited moderate cytotoxicity in breast cancer cell lines, i.e., MCF-7 cells (IC50 = 8.27 μM), showing notable cytotoxicity in the low micromolar range, comparable to that of cisplatin and within the same order of magnitude as doxorubicin. Accompanied by apoptosis profiling, compound 4a at 1 × and 2 × IC50 showed a concentration-dependent increase in apoptosis cell death compared to untreated controls. Meanwhile, computational studies were conducted to explore potential interactions with EGFR as a putative target, suggesting that compound 4a may possibly interact with EGFR through hydrogen bonding and hydrophobic contacts.
{"title":"Allyl-functionalized calix[4]resorcinarenes against breast cancer cells: Synthesis, cytotoxicity, apoptosis induction, and computational insights.","authors":"Anggit Fitria, Yehezkiel Steven Kurniawan, Eti Nurwening Sholikhah, Harno Dwi Pranowo, Jumina","doi":"10.1016/j.bmcl.2026.130540","DOIUrl":"10.1016/j.bmcl.2026.130540","url":null,"abstract":"<p><p>The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (4a-4f) as cytotoxic agents. These derivatives were obtained via the O-allylation of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 4-hydroxybenzaldehyde with resorcinol, pyrogallol, or 2-methylresorcinol. All compounds were examined for their in vitro anticancer activity against human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, analogue 4a exhibited moderate cytotoxicity in breast cancer cell lines, i.e., MCF-7 cells (IC<sub>50</sub> = 8.27 μM), showing notable cytotoxicity in the low micromolar range, comparable to that of cisplatin and within the same order of magnitude as doxorubicin. Accompanied by apoptosis profiling, compound 4a at 1 × and 2 × IC<sub>50</sub> showed a concentration-dependent increase in apoptosis cell death compared to untreated controls. Meanwhile, computational studies were conducted to explore potential interactions with EGFR as a putative target, suggesting that compound 4a may possibly interact with EGFR through hydrogen bonding and hydrophobic contacts.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130540"},"PeriodicalIF":2.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-09DOI: 10.1016/j.bmcl.2026.130539
Eun-Young Lee, Mücahit Varlı, Hiyoung Kim, Soyeong Kim, Seongeun Kang, Jungwook Chin, Hongchan An, Hangun Kim, Sang-Jip Nam
Wounds pose significant healthcare challenges, prompting the need for novel therapeutics with pro-regenerative potential. Natural products from marine-derived actinomycetes are a promising source of small bioactive molecules. The first total syntheses of monaprenylindole A (1) and its analog (2) were accomplished. Here, we report the isolation, structural characterization, synthesis, and pharmacological evaluation of monaprenylindole A (1) and its analog, 6-isoprenylindole-3-carboxylic acid (2), for their wound healing potential. Compounds 1 and 2 were isolated from a marine-derived Streptomyces sp. and structurally characterized using mass spectrometry (MS), ultraviolet (UV), and nuclear magnetic resonance (NMR) analyses. Firstly, we analyzed the predicted favorable pharmacokinetics and safety of the compounds for their underlying translational potential. Furthermore, pharmacological network analysis identified multiple wound healing-related gene targets that were modulated by these molecules, suggesting a multi-target mechanism. In vitro assays showed that all compounds enhanced keratinocyte invasion, with compound 1 demonstrating the strongest effects by upregulating genes involved in cell motility. Furthermore, compound 1 promoted the upregulation of key motility-related genes, suggesting that this compound promotes wound healing through activating transcriptional programs involved in adhesion, cytoskeletal remodeling, growth factors, and spheroid formation, indicating a shift toward regenerative epithelial behavior. Finally, topical treatment with 1 significantly accelerated wound closure in a murine model. These results highlight the potential of monaprenylindole A as promising multi-target therapeutics for skin repair.
{"title":"Monaprenylindole A, a prenylated indole derivative from marine-derived Streptomyces sp., accelerates wound healing through the enhancement of keratinocyte motility via the modulation of cytoskeletal remodeling and growth factor pathways.","authors":"Eun-Young Lee, Mücahit Varlı, Hiyoung Kim, Soyeong Kim, Seongeun Kang, Jungwook Chin, Hongchan An, Hangun Kim, Sang-Jip Nam","doi":"10.1016/j.bmcl.2026.130539","DOIUrl":"10.1016/j.bmcl.2026.130539","url":null,"abstract":"<p><p>Wounds pose significant healthcare challenges, prompting the need for novel therapeutics with pro-regenerative potential. Natural products from marine-derived actinomycetes are a promising source of small bioactive molecules. The first total syntheses of monaprenylindole A (1) and its analog (2) were accomplished. Here, we report the isolation, structural characterization, synthesis, and pharmacological evaluation of monaprenylindole A (1) and its analog, 6-isoprenylindole-3-carboxylic acid (2), for their wound healing potential. Compounds 1 and 2 were isolated from a marine-derived Streptomyces sp. and structurally characterized using mass spectrometry (MS), ultraviolet (UV), and nuclear magnetic resonance (NMR) analyses. Firstly, we analyzed the predicted favorable pharmacokinetics and safety of the compounds for their underlying translational potential. Furthermore, pharmacological network analysis identified multiple wound healing-related gene targets that were modulated by these molecules, suggesting a multi-target mechanism. In vitro assays showed that all compounds enhanced keratinocyte invasion, with compound 1 demonstrating the strongest effects by upregulating genes involved in cell motility. Furthermore, compound 1 promoted the upregulation of key motility-related genes, suggesting that this compound promotes wound healing through activating transcriptional programs involved in adhesion, cytoskeletal remodeling, growth factors, and spheroid formation, indicating a shift toward regenerative epithelial behavior. Finally, topical treatment with 1 significantly accelerated wound closure in a murine model. These results highlight the potential of monaprenylindole A as promising multi-target therapeutics for skin repair.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130539"},"PeriodicalIF":2.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.bmcl.2026.130537
Xin-Yu Huang , Xiao-He Liu , Na Xu , Ting Peng , Xi-Yuan Hu , Min Su , Zhi-Yong Luo , Su-You Liu , Da-You Ma
Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against various cancer cell lines. While ASS1 has emerged as a promising target for anticancer therapy, the development of ASS1 activators remains a largely unexplored research area. Previous work by our group identified Spinosyn A as the first-in-class ASS1 activator. In this study, to further elucidate the structure–activity relationship (SAR) of Spinosyn A as both an ASS1 activator and a tumor inhibitor, we introduced structural modifications at the nitrogen atom, yielding 25 novel derivatives. Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.
{"title":"Spinosyn A derivatives as ASS1 activators and tumor inhibitors","authors":"Xin-Yu Huang , Xiao-He Liu , Na Xu , Ting Peng , Xi-Yuan Hu , Min Su , Zhi-Yong Luo , Su-You Liu , Da-You Ma","doi":"10.1016/j.bmcl.2026.130537","DOIUrl":"10.1016/j.bmcl.2026.130537","url":null,"abstract":"<div><div>Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against various cancer cell lines. While ASS1 has emerged as a promising target for anticancer therapy, the development of ASS1 activators remains a largely unexplored research area. Previous work by our group identified Spinosyn A as the first-in-class ASS1 activator. In this study, to further elucidate the structure–activity relationship (SAR) of Spinosyn A as both an ASS1 activator and a tumor inhibitor, we introduced structural modifications at the nitrogen atom, yielding 25 novel derivatives. Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130537"},"PeriodicalIF":2.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.bmcl.2026.130538
Yangyang Chen , Ruiqiong Li , Yuanping Chen , Chi Li , Mengting Pan , Peipei Chen , Yanling Jiang , Jiani Chen , Zehao Huang , Yaqian Feng , Yali Wang , Hua Li , Shaohua Xu
This study investigated the ethnomedicine Celastrus rosthornianus Lose. for its chemical constituents and anti-nonalcoholic fatty liver disease (NAFLD) potential. Phytochemical analysis led to the isolation of six diterpenoids (1–6), including two new structures (1 and 2). In a HepG2 cell model, compounds 2 and 6 significantly inhibited intracellular lipid accumulation. Mechanistic studies revealed that these active diterpenoids exert their anti-NAFLD effects by interfering with the maturation of the lipogenic transcription factor SREBP1, thereby suppressing the de novo lipogenesis (DNL) pathway. These findings not only expand the chemical profile of C. rosthornianus Lose., but also highlight specific diterpenoids as promising candidates for further development as NAFLD therapeutics.
本研究对民族药赤藤进行了研究。其化学成分和抗非酒精性脂肪性肝病（NAFLD）的潜力。植物化学分析分离出6个二萜类化合物（1 - 6），包括两个新结构（1和2）。在HepG2细胞模型中，化合物2和6显著抑制细胞内脂质积累。机制研究表明，这些活性二萜通过干扰脂肪生成转录因子SREBP1的成熟，从而抑制de novo lipogenesis （DNL）途径，发挥其抗nafld作用。这些发现不仅扩大了红棘虫的化学特征。，但也强调了特定的二萜类化合物作为NAFLD治疗药物进一步发展的有希望的候选者。
{"title":"Inhibitory effects of diterpenoids from Celastrus rosthornianus Lose. on lipid accumulation","authors":"Yangyang Chen , Ruiqiong Li , Yuanping Chen , Chi Li , Mengting Pan , Peipei Chen , Yanling Jiang , Jiani Chen , Zehao Huang , Yaqian Feng , Yali Wang , Hua Li , Shaohua Xu","doi":"10.1016/j.bmcl.2026.130538","DOIUrl":"10.1016/j.bmcl.2026.130538","url":null,"abstract":"<div><div>This study investigated the ethnomedicine <em>Celastrus rosthornianus</em> Lose. for its chemical constituents and anti-nonalcoholic fatty liver disease (NAFLD) potential. Phytochemical analysis led to the isolation of six diterpenoids (<strong>1</strong>–<strong>6</strong>), including two new structures (<strong>1</strong> and <strong>2</strong>). In a HepG2 cell model, compounds <strong>2</strong> and <strong>6</strong> significantly inhibited intracellular lipid accumulation. Mechanistic studies revealed that these active diterpenoids exert their anti-NAFLD effects by interfering with the maturation of the lipogenic transcription factor SREBP1, thereby suppressing the de novo lipogenesis (DNL) pathway. These findings not only expand the chemical profile of <em>C. rosthornianus</em> Lose., but also highlight specific diterpenoids as promising candidates for further development as NAFLD therapeutics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130538"},"PeriodicalIF":2.2,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1016/j.bmcl.2026.130536
Jeetal Vyas , Anuj S. Jamenis , Krishna Kaku , Yesha Shah , Kristin M. Miner , Tarun N. Bhatia , Roxanne E. Kim , Ruoli Bai , Ernest Hamel , Rehana K. Leak , Aleem Gangjee
There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds 1 and 2) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS in vivo. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.
{"title":"Discovery of multitargeting single agents as a novel route to the potential treatment of neurodegenerative diseases","authors":"Jeetal Vyas , Anuj S. Jamenis , Krishna Kaku , Yesha Shah , Kristin M. Miner , Tarun N. Bhatia , Roxanne E. Kim , Ruoli Bai , Ernest Hamel , Rehana K. Leak , Aleem Gangjee","doi":"10.1016/j.bmcl.2026.130536","DOIUrl":"10.1016/j.bmcl.2026.130536","url":null,"abstract":"<div><div>There are no cures for neurodegenerative diseases. The biggest hurdle to treating these disorders is that their clinical manifestation is rooted in multiple physiological processes. Therefore, efficacious pharmaceutical options will likely require two or more agents with different mechanisms of action. However, drug combinations have significant drawbacks, including overlapping toxicities and unique pharmacokinetic properties, particularly the rate and extent of central nervous system (CNS) penetration. A single agent with multiple mechanisms of action could overcome these drawbacks. We have recently discovered first-in-class novel single agents (compounds <strong>1</strong> and <strong>2</strong>) that mildly inhibit clinically important kinases and subtly favor microtubule stability at concentrations that show no evidence of neuronal toxicity in primary neurons, while maintaining their ability to penetrate the CNS <em>in vivo</em>. It is important to note that the effects of these analogs are mild and are predicated on avoiding neurotoxicity. These multitargeting single agents provide a new structural modality with the potential to influence treatments for Parkinson's and Alzheimer's disease and serve as lead compounds for further optimization.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130536"},"PeriodicalIF":2.2,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145922060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1016/j.bmcl.2026.130535
Yaxi Xu , Yupei Sun , Zongwei Yu , Xiangyang Zhang , Zhiming Liu , Jianzeng Xin , Sheng Liu , Feng Zhao
The tetrahydro-β-carboline (THβC) scaffold is a promising chemotype in anticancer drug discovery whose development is hindered by poor aqueous solubility and underexplored functionalization at the N-2 position. To overcome these limitations, we designed a series of novel THβC derivatives via molecular hybridization at the N-2 site using natural unsaturated carboxylic acids, aiming to improve solubility and biological activity. Among the synthesized compounds, derivative 9 exhibited potent and selective anti-proliferative activity against MCF-7 breast cancer cells. Based on this promising activity, we first investigated its effect on key oncogenic pathways. Western blot analysis revealed that compound 9 significantly downregulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) without affecting the NF-κB p65 subunit, suggesting a selective mechanism of action. Subsequent molecular docking studies provided a structural rationale for this selectivity, showing favorable binding modes of 9 within the ERK1/2 kinase domains. Collectively, this work establishes N-2 functionalization as a viable strategy for developing THβC-based anticancer agents with optimized pharmacological profiles.
{"title":"Design, synthesis of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivatives as potential anticancer agents","authors":"Yaxi Xu , Yupei Sun , Zongwei Yu , Xiangyang Zhang , Zhiming Liu , Jianzeng Xin , Sheng Liu , Feng Zhao","doi":"10.1016/j.bmcl.2026.130535","DOIUrl":"10.1016/j.bmcl.2026.130535","url":null,"abstract":"<div><div>The tetrahydro-β-carboline (THβC) scaffold is a promising chemotype in anticancer drug discovery whose development is hindered by poor aqueous solubility and underexplored functionalization at the N-2 position. To overcome these limitations, we designed a series of novel THβC derivatives via molecular hybridization at the N-2 site using natural unsaturated carboxylic acids, aiming to improve solubility and biological activity. Among the synthesized compounds, derivative <strong>9</strong> exhibited potent and selective anti-proliferative activity against MCF-7 breast cancer cells. Based on this promising activity, we first investigated its effect on key oncogenic pathways. Western blot analysis revealed that compound <strong>9</strong> significantly downregulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) without affecting the NF-κB p65 subunit, suggesting a selective mechanism of action. Subsequent molecular docking studies provided a structural rationale for this selectivity, showing favorable binding modes of <strong>9</strong> within the ERK1/2 kinase domains. Collectively, this work establishes N-2 functionalization as a viable strategy for developing THβC-based anticancer agents with optimized pharmacological profiles.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"133 ","pages":"Article 130535"},"PeriodicalIF":2.2,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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