Pub Date : 2026-06-01Epub 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":"<div><div>The present study is intended as an initial exploration of allyl-functionalized calix[4]resorcinarenes (<strong>4a–4f</strong>) as cytotoxic agents. These derivatives were obtained <em>via</em> the <em>O</em>-allylation of 3-methoxy-4-hydroxybenzaldehyde (vanillin) and 4-hydroxybenzaldehyde with resorcinol, pyrogallol, or 2-methylresorcinol. All compounds were examined for their <em>in vitro</em> anticancer activity against human breast cancer cell lines (MDA-MB-231 and MCF-7). Among them, analogue <strong>4a</strong> exhibited moderate cytotoxicity in breast cancer cell lines, <em>i.e.</em>, 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 <strong>4a</strong> 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 <strong>4a</strong> may possibly interact with EGFR through hydrogen bonding and hydrophobic contacts.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130540"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","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 : 2026-06-01Epub Date: 2026-01-27DOI: 10.1016/j.bmcl.2026.130563
Junfeng Wang , Jiamin Luo , Zhiguo Mang , Shuai Zhang , Chengtao Sun , Guoyin Kai , Huan Xu , Hao Li
1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-b]furan-7,10,11(6H)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therapy and alleviate its gastrointestinal side effect. The combined cytotoxicity on HT29 and HCT116 colorectal cancer cells induced by TA401 and CPT-11 was comprehensively evaluated in vitro. The classical apoptosis pathway, including Bax, BCL-2, caspase 3, the phosphorylation level of ERK and AKT, was also examined to illustrate molecular mechanisms of the synergistic apoptosis both in vitro and in vivo. Synergistic suppression of colorectal cancer cell proliferation by TA401 and CPT-11 was observed at a fixed ratio (TA401:CPT-11 at 1:20). The apoptosis induced by combined treatment was triggered by activation of classical apoptotic pathway and decreased expression of TOP I, which was further confirmed in vivo. In addition, diarrheic side effect of CPT-11 was reduced by TA401 in the combined treatment. TA401 effectively promoted the anti-tumor effects of CPT-11 with alleviated side effects, which may be developed as a potential candidate for the combined therapy with CPT-11 against colorectal cancer.
{"title":"Combined antitumor efficacy of a new tanshinone IIA analog and irinotecan with alleviating gastrointestinal side effect","authors":"Junfeng Wang , Jiamin Luo , Zhiguo Mang , Shuai Zhang , Chengtao Sun , Guoyin Kai , Huan Xu , Hao Li","doi":"10.1016/j.bmcl.2026.130563","DOIUrl":"10.1016/j.bmcl.2026.130563","url":null,"abstract":"<div><div>1,6,6-Trimethyl-2-((4-methylpiperazin-1-yl)methyl)phenanthrol[1,2-<em>b</em>]furan-7,10,11(6<em>H</em>)-trione (TA401), a newly synthesized tanshinone IIA analog, was developed to enhance the anti-tumor effect of CPT-11 in combined therapy and alleviate its gastrointestinal side effect. The combined cytotoxicity on HT29 and HCT116 colorectal cancer cells induced by TA401 and CPT-11 was comprehensively evaluated <em>in vitro</em>. The classical apoptosis pathway, including Bax, BCL-2, caspase 3, the phosphorylation level of ERK and AKT, was also examined to illustrate molecular mechanisms of the synergistic apoptosis both <em>in vitro</em> and <em>in vivo</em>. Synergistic suppression of colorectal cancer cell proliferation by TA401 and CPT-11 was observed at a fixed ratio (TA401:CPT-11 at 1:20). The apoptosis induced by combined treatment was triggered by activation of classical apoptotic pathway and decreased expression of TOP I, which was further confirmed <em>in vivo</em>. In addition, diarrheic side effect of CPT-11 was reduced by TA401 in the combined treatment. TA401 effectively promoted the anti-tumor effects of CPT-11 with alleviated side effects, which may be developed as a potential candidate for the combined therapy with CPT-11 against colorectal cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130563"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083769","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 : 2026-06-01Epub Date: 2026-01-31DOI: 10.1016/j.bmcl.2026.130567
Dongyu Wang , Shengkai Cui , Jingyi Yuan, Yuyang Li, Yujie Zhang, Yuao Zhang, Weizheng Fan, Chunlei Tang
This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.
{"title":"Design, synthesis, and biological evaluation of cytochrome P450 CYP11A1 inhibitors","authors":"Dongyu Wang , Shengkai Cui , Jingyi Yuan, Yuyang Li, Yujie Zhang, Yuao Zhang, Weizheng Fan, Chunlei Tang","doi":"10.1016/j.bmcl.2026.130567","DOIUrl":"10.1016/j.bmcl.2026.130567","url":null,"abstract":"<div><div>This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4<em>H</em>-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound <strong>II-4</strong> exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, <strong>II-4</strong> showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight <strong>II-4</strong> as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130567"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103254","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 : 2026-06-01Epub Date: 2026-02-05DOI: 10.1016/j.bmcl.2026.130572
Karis Texidor , Dilhumar Uyghur , Noah Wiese , Lindsey O. Davis , Mandy Green , Farjana Sharmen , Adil Ijaz , Kamani M. Barnes , Madison Bagett , Jishi Ye , Stacy M. Abbang , Wenying Piao , Jason Ying Kuen Chan , Yuen-Keng Ng , Vivian W.Y. Lui , Marco Orecchioni , Matteo Borgini
Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate “undruggable” proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of N-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both N-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected N-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.
{"title":"Synthesis and characterization of bicyclo[1.1.0]butane amides and 5-methylene-3-azabicyclo[5.1.0]octan-4-ones as covalent modifiers","authors":"Karis Texidor , Dilhumar Uyghur , Noah Wiese , Lindsey O. Davis , Mandy Green , Farjana Sharmen , Adil Ijaz , Kamani M. Barnes , Madison Bagett , Jishi Ye , Stacy M. Abbang , Wenying Piao , Jason Ying Kuen Chan , Yuen-Keng Ng , Vivian W.Y. Lui , Marco Orecchioni , Matteo Borgini","doi":"10.1016/j.bmcl.2026.130572","DOIUrl":"10.1016/j.bmcl.2026.130572","url":null,"abstract":"<div><div>Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate “undruggable” proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of <em>N</em>-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both <em>N</em>-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected <em>N</em>-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130572"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137021","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 : 2026-06-01Epub Date: 2026-02-10DOI: 10.1016/j.bmcl.2026.130583
Luiz Alberto Ferreira , Angelo Matheus Torres Santos , Rodrigo Cabral de Araújo-Filho , Emanuelly Karla Araújo-Padilha , Clara Andrezza Crisóstomo Bezerra Costa , Johnnatan Duarte de Freitas , Joanna Cytarska , Krzysztof Z. Łączkowski , Edeildo Ferreira da Silva-Júnior , Silvia Helena Cardoso
Tyrosinase is a copper-dependent oxidase that catalyzes the rate-limiting steps of melanogenesis, directly linking its overexpression to hyperpigmentation disorders and melanoma progression. Previously our researcher team found that a coumarin–thiosemicarbazone analog exhibited potent anti-tyrosinase activity (IC50 = 42.16 ± 5.16 μM). Herein, as part of our efforts in this field of study, we report the synthesis and biological evaluation of a new series of coumarin derivatives functionalized with thiosemicarbazone and/or oxime moieties as potent tyrosinase inhibitors. The most active compound, B5, exhibited an IC₅₀ value of 21.91 ± 0.26 μM, showing 3.3- and 17.6-fold higher inhibitory potency than kojic and ascorbic acids, respectively. Kinetic studies revealed a mixed inhibition pattern, suggesting multiple enzyme–inhibitor interactions. In silico 100-ns molecular dynamics simulations against Agaricus bisporus tyrosinase (PDB ID: 2Y9X) confirmed the structural stability of the B5–tyrosinase complex, with a mean RMSD of 1.85 Å for the enzyme and 0.3 Å for the ligand. The thiosemicarbazone moiety played a pivotal role in complex stabilization through hydrogen bonding and coordination with catalytic Cu2+ ions, while hydrophobic and π-stacking contacts contributed to binding persistence. Altogether, these findings highlight compound B5 as a promising lead compound for developing next-generation tyrosinase inhibitors with potential dermatological and photoprotective applications.
{"title":"Development of coumarin-3-thiosemicarbazones and coumarin-3-oximes as potent inhibitors of mushroom tyrosinase/tyrosine hydroxylase","authors":"Luiz Alberto Ferreira , Angelo Matheus Torres Santos , Rodrigo Cabral de Araújo-Filho , Emanuelly Karla Araújo-Padilha , Clara Andrezza Crisóstomo Bezerra Costa , Johnnatan Duarte de Freitas , Joanna Cytarska , Krzysztof Z. Łączkowski , Edeildo Ferreira da Silva-Júnior , Silvia Helena Cardoso","doi":"10.1016/j.bmcl.2026.130583","DOIUrl":"10.1016/j.bmcl.2026.130583","url":null,"abstract":"<div><div>Tyrosinase is a copper-dependent oxidase that catalyzes the rate-limiting steps of melanogenesis, directly linking its overexpression to hyperpigmentation disorders and melanoma progression. Previously our researcher team found that a coumarin–thiosemicarbazone analog exhibited potent anti-tyrosinase activity (IC<sub>50</sub> = 42.16 ± 5.16 μM). Herein, as part of our efforts in this field of study, we report the synthesis and biological evaluation of a new series of coumarin derivatives functionalized with thiosemicarbazone and/or oxime moieties as potent tyrosinase inhibitors. The most active compound, <strong>B5</strong>, exhibited an IC₅₀ value of 21.91 ± 0.26 μM, showing 3.3- and 17.6-fold higher inhibitory potency than kojic and ascorbic acids, respectively. Kinetic studies revealed a mixed inhibition pattern, suggesting multiple enzyme–inhibitor interactions. <em>In silico</em> 100-ns molecular dynamics simulations against <em>Agaricus bisporus</em> tyrosinase (PDB ID: <span><span>2Y9X</span><svg><path></path></svg></span>) confirmed the structural stability of the <strong>B5</strong>–tyrosinase complex, with a mean RMSD of 1.85 Å for the enzyme and 0.3 Å for the ligand. The thiosemicarbazone moiety played a pivotal role in complex stabilization through hydrogen bonding and coordination with catalytic Cu<sup>2+</sup> ions, while hydrophobic and π-stacking contacts contributed to binding persistence. Altogether, these findings highlight compound <strong>B5</strong> as a promising lead compound for developing next-generation tyrosinase inhibitors with potential dermatological and photoprotective applications.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130583"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171822","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 : 2026-06-01Epub Date: 2026-01-23DOI: 10.1016/j.bmcl.2026.130555
Ce Shi , Weisen Zhong , Guowei Qiang , Panjunjie Ying , Junyu Guo , Yameng Si , Jie Mou
The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound 11f exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC50 = 0.26 ± 0.17 μM in vitro; IC50 = 0.33 μM in vivo). Furthermore, compound 11f induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.
{"title":"Novel anticancer paeonol derivatives possessing a nitric oxide donor moiety as TrxR inhibitors: design, synthesis, biological evaluation","authors":"Ce Shi , Weisen Zhong , Guowei Qiang , Panjunjie Ying , Junyu Guo , Yameng Si , Jie Mou","doi":"10.1016/j.bmcl.2026.130555","DOIUrl":"10.1016/j.bmcl.2026.130555","url":null,"abstract":"<div><div>The tumor microenvironment (TME) plays a pivotal role in determining tumor progression and treatment response. Within the TME, redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) are critically involved in regulating intercellular and intracellular signaling. In this study, we hypothesized that conjugating an NO-releasing moiety to paeonol derivatives and introducing a chalcone structure to enhance thioredoxin reductase (TrxR) targeting would yield compounds with potent anticancer activity. Accordingly, a series of mono- and di-substituted nitrate derivatives were synthesized. The inhibitory activities of all synthesized compounds were evaluated against BGC823, HCT116, Hep G2, and MCF-7 cell lines using the CCK-8 assay. Among the paeonol chalcone derivatives, compound <strong>11f</strong> exhibited significant antiproliferative activity across the tested cancer cell panel. It was identified as a promising candidate with potent TrxR inhibitory activity (IC<sub>50</sub> = 0.26 ± 0.17 μM in vitro; IC<sub>50</sub> = 0.33 μM in vivo). Furthermore, compound <strong>11f</strong> induced S-phase arrest and promoted apoptosis in MCF-7 cells. These findings underscore the enhanced anticancer potential of paeonol chalcone derivatives, attributable to the synergistic effects of NO and ROS.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130555"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045921","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 : 2026-06-01Epub Date: 2026-02-05DOI: 10.1016/j.bmcl.2026.130573
Michael Burton , Chris Cains , Danielle J.C. Fenwick , Amy Foster , Clair L. Preece , Sidrah Saleem , Stephen P. Stanforth , Hayley J. Turner , Graeme Turnbull , John D. Perry
We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales (“coliforms”) and Escherichia coli, respectively. These were evaluated alongside the established substrates; o-nitrophenyl-β-D-galactopyranoside (ONPG), p-nitrophenyl-β-D-galactopyranoside (PNPG) and p-nitrophenyl-β-D-glucuronide (PNP-GUR). The evaluation was performed using 30 isolates of Enterobacterales including 19 isolates of E. coli. Hydrolysis of 2-fluoro-p-nitrophenyl-β-D-galactopyranoside (2-fluoro-PNPG) yielded a significantly stronger yellow coloration after a six-hour incubation period compared to hydrolysis of ONPG and PNPG, potentially allowing for a more sensitive detection of Enterobacterales. Similarly, hydrolysis of the novel substrate 2-fluoro-p-nitrophenyl-β-D-glucuronide sodium salt (2-fluoro-PNP-GUR Na) by producers of β-glucuronidase also yielded a significantly stronger yellow colouration, potentially allowing for a more sensitive detection of E. coli. The yellow chromophore 2-fluoro-PNP retained high colour intensity at reduced pH when compared to o-nitrophenol and p-nitrophenol. Both substrates potentially offer enhanced sensitivity for the detection of Enterobacterales and E. coli in environmental samples as markers of faecal pollution.
本文报道了六种卤化硝基苯苷的合成和评价，分别用于肠杆菌（“大肠菌群”）和大肠杆菌中β-半乳糖苷酶和β-葡萄糖醛酸酶活性的检测。这些与确定的底物一起进行评估；邻硝基苯-β- d -半乳糖苷（ONPG）、对硝基苯-β- d -半乳糖苷（PNPG）和对硝基苯-β- d -葡萄糖醛酸（PNP-GUR）。对30株肠杆菌进行评价，其中包括19株大肠杆菌。与ONPG和PNPG的水解相比，2-fluoro-p-nitrophenyl-β-D-galactopyranoside （2-fluoro-PNPG）的水解在6小时的孵育期后产生了明显更强的黄色，可能允许更敏感的肠杆菌检测。同样，新型底物2-氟-对硝基苯-β- d -葡萄糖醛酸钠盐（2-氟- pnp - gur Na）由β-葡萄糖醛酸酶的生产者水解也产生了明显更强的黄色，可能允许更灵敏的大肠杆菌检测。与邻硝基酚和对硝基酚相比，黄色发色团2-氟- pnp在降低的pH下保持较高的显色强度。这两种底物都有可能提高环境样品中肠杆菌和大肠杆菌的检测灵敏度，作为粪便污染的标志物。
{"title":"Glycosides of fluorinated p-nitrophenol offer improved sensitivity for detection of β-galactosidase and β-glucuronidase in Escherichia coli and other Enterobacterales","authors":"Michael Burton , Chris Cains , Danielle J.C. Fenwick , Amy Foster , Clair L. Preece , Sidrah Saleem , Stephen P. Stanforth , Hayley J. Turner , Graeme Turnbull , John D. Perry","doi":"10.1016/j.bmcl.2026.130573","DOIUrl":"10.1016/j.bmcl.2026.130573","url":null,"abstract":"<div><div>We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales (“coliforms”) and <em>Escherichia coli</em>, respectively. These were evaluated alongside the established substrates; <em>o</em>-nitrophenyl-β-D-galactopyranoside (ONPG), <em>p</em>-nitrophenyl-β-D-galactopyranoside (PNPG) and <em>p</em>-nitrophenyl-β-D-glucuronide (PNP-GUR). The evaluation was performed using 30 isolates of Enterobacterales including 19 isolates of <em>E. coli</em>. Hydrolysis of 2-fluoro-<em>p</em>-nitrophenyl-β-D-galactopyranoside (2-fluoro-PNPG) yielded a significantly stronger yellow coloration after a six-hour incubation period compared to hydrolysis of ONPG and PNPG, potentially allowing for a more sensitive detection of Enterobacterales. Similarly, hydrolysis of the novel substrate 2-fluoro-<em>p</em>-nitrophenyl-β-D-glucuronide sodium salt (2-fluoro-PNP-GUR Na) by producers of β-glucuronidase also yielded a significantly stronger yellow colouration, potentially allowing for a more sensitive detection of <em>E. coli</em>. The yellow chromophore 2-fluoro-PNP retained high colour intensity at reduced pH when compared to <em>o</em>-nitrophenol and <em>p</em>-nitrophenol. Both substrates potentially offer enhanced sensitivity for the detection of Enterobacterales and <em>E. coli</em> in environmental samples as markers of faecal pollution.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130573"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146136933","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 : 2026-06-01Epub Date: 2026-02-02DOI: 10.1016/j.bmcl.2026.130570
Die Sun , Meiyan Jiang , YongQuan Wei , Lisheng Wang
Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used systemic therapy for advanced HCC, frequently develops acquired resistance upon long-term treatment, in part due to the overexpression of anti-apoptotic Bcl-2 family proteins. Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. Molecular docking suggested a favorable binding mode, in which the resulting scaffold could occupy the hydrophobic binding pockets of both Bcl-2 and Mcl-1 and engage key residues through hydrogen-bond interactions. In vitro antiproliferative screening (MTT assay) against three human HCC cell lines (Huh-7, MHCC-97H, and HepG2) showed that most compounds exhibited moderate to good activity. Notably, compound S6 emerged as the most potent analogue, with IC₅₀ values of 9.13 ± 0.29 μM (Huh-7), 6.76 ± 0.06 μM (MHCC-97H), and 15.9 ± 0.98 μM (HepG2). Mechanistic studies demonstrated that S6 markedly suppressed proliferation and migration of MHCC-97H cells, induced G1-phase arrest, and promoted apoptosis. Western blot analysis revealed that S6 downregulated anti-apoptotic proteins Bcl-2 and Mcl-1, induced mitochondrial membrane potential (ΔΨm) depolarization, and activated the caspase-dependent apoptotic cascade, as evidenced by caspase-3 activation and PARP1 cleavage. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure–activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.
{"title":"Discovery of novel sophocarpine derivatives as potential dual Bcl-2 and Mcl-1 inhibitors: design, synthesis and anti-hepatocellular carcinoma evaluation","authors":"Die Sun , Meiyan Jiang , YongQuan Wei , Lisheng Wang","doi":"10.1016/j.bmcl.2026.130570","DOIUrl":"10.1016/j.bmcl.2026.130570","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used systemic therapy for advanced HCC, frequently develops acquired resistance upon long-term treatment, in part due to the overexpression of anti-apoptotic Bcl-2 family proteins. Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. Molecular docking suggested a favorable binding mode, in which the resulting scaffold could occupy the hydrophobic binding pockets of both Bcl-2 and Mcl-1 and engage key residues through hydrogen-bond interactions. In vitro antiproliferative screening (MTT assay) against three human HCC cell lines (Huh-7, MHCC-97H, and HepG2) showed that most compounds exhibited moderate to good activity. Notably, compound S6 emerged as the most potent analogue, with IC₅₀ values of 9.13 ± 0.29 μM (Huh-7), 6.76 ± 0.06 μM (MHCC-97H), and 15.9 ± 0.98 μM (HepG2). Mechanistic studies demonstrated that S6 markedly suppressed proliferation and migration of MHCC-97H cells, induced G1-phase arrest, and promoted apoptosis. Western blot analysis revealed that S6 downregulated anti-apoptotic proteins Bcl-2 and Mcl-1, induced mitochondrial membrane potential (ΔΨm) depolarization, and activated the caspase-dependent apoptotic cascade, as evidenced by caspase-3 activation and PARP1 cleavage. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure–activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"135 ","pages":"Article 130570"},"PeriodicalIF":2.2,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117097","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 : 2026-05-01Epub Date: 2026-01-27DOI: 10.1016/j.bmcl.2026.130564
Jonah Fine , John B. Perkins , Vincent Gullo , Ryan D. Cohen , Jun Lu , Sheo B. Singh
Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by Kibdelosporangium banguiense CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA GyrB and ParE through a distinct U-shaped multi-contact binding mechanism and do not display cross-resistance with established antibiotics. To investigate structure-activity relationships, various methodologies were employed to identify new congeners, including the implementation of repeat batch fermentation. This study presents the discovery, isolation, structural elucidation, and antibacterial assessment of two mono des-chloro congeners of kibdelomycin A produced via repeat batch fermentation. The newly discovered compounds displayed inhibitory effects on bacterial growth in Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MIC) ranging from 16 to 64 μg/mL. The MIC values for E. coli are comparable to kibdelomycin, whereas for S. aureus the MIC is 64 times less potent than that of kibdelomycin. AI-assisted docking studies involving DNA gyrase B enzymes provide reasonable support for varying activities of the congeners.
{"title":"Discovery and antibacterial activity of kibdelomycin A-1 and A-2 from repeat batch fermentation of Kibdelosporangium banguiesne","authors":"Jonah Fine , John B. Perkins , Vincent Gullo , Ryan D. Cohen , Jun Lu , Sheo B. Singh","doi":"10.1016/j.bmcl.2026.130564","DOIUrl":"10.1016/j.bmcl.2026.130564","url":null,"abstract":"<div><div>Kibdelomycin and kibdelomycin A are antibiotics biosynthesized by <em>Kibdelosporangium banguiense</em> CA-240109. Kibdelomycin demonstrates broad-spectrum activity, exhibiting significant activity against antibiotic-resistant Gram-positive bacteria. These compounds inhibit DNA GyrB and ParE through a distinct U-shaped multi-contact binding mechanism and do not display cross-resistance with established antibiotics. To investigate structure-activity relationships, various methodologies were employed to identify new congeners, including the implementation of repeat batch fermentation. This study presents the discovery, isolation, structural elucidation, and antibacterial assessment of two mono des-chloro congeners of kibdelomycin A produced via repeat batch fermentation. The newly discovered compounds displayed inhibitory effects on bacterial growth in <em>Staphylococcus aureus</em> and <em>Escherichia coli</em>, with minimum inhibitory concentrations (MIC) ranging from 16 to 64 μg/mL. The MIC values for <em>E. coli</em> are comparable to kibdelomycin, whereas for <em>S. aureus</em> the MIC is 64 times less potent than that of kibdelomycin. AI-assisted docking studies involving DNA gyrase B enzymes provide reasonable support for varying activities of the congeners.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"134 ","pages":"Article 130564"},"PeriodicalIF":2.2,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146075044","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 : 2026-05-01Epub 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":"2026-05-01","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}
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