Pub Date : 2024-08-21DOI: 10.1016/j.bioorg.2024.107716
Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1β production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.
{"title":"Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis","authors":"","doi":"10.1016/j.bioorg.2024.107716","DOIUrl":"10.1016/j.bioorg.2024.107716","url":null,"abstract":"<div><p><em>Lycodine</em> alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of <em>Lycodine</em> alkaloid via selective <em>O</em>-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1β production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, <strong>3</strong><strong>k</strong> and <strong>3q</strong> possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural <em>Lycodine</em> alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142040088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.bioorg.2024.107729
This study describes the synthesis and characterization of a novel near-infrared (NIR) fluorescent probe RBNE based on a hybrid rhodamine dye, which shows excellent optical capability for detecting and imaging ONOO− in necrotizing enterocolitis (NEC) mouse model. The probe RBNE undergoes hydrazine redox-process, and subsequently the spirocyclic structure’s opening, resulting in a turn-on fluorescence emission with the presence of ONOO−, which exhibits several excellent features, including a significant Stokes shift of 108 nm, near-infrared emission at 668 nm, a lower detection limit of 56 nM, low cytotoxicity, and excellent imaging ability for ONOO− both in vitro and in vivo. The presented study introduces a novel optical tool that has the potential to significantly advance our understanding of peroxynitrite (ONOO−) behaviors in necrotizing enterocolitis (NEC).
{"title":"Development of a hybrid rhodamine-hydrazine NIR fluorescent probe for sensitive detection and imaging of peroxynitrite in necrotizing enterocolitis model","authors":"","doi":"10.1016/j.bioorg.2024.107729","DOIUrl":"10.1016/j.bioorg.2024.107729","url":null,"abstract":"<div><p>This study describes the synthesis and characterization of a novel near-infrared (NIR) fluorescent probe RBNE based on a hybrid rhodamine dye, which shows excellent optical capability for detecting and imaging ONOO<sup>−</sup> in necrotizing enterocolitis (NEC) mouse model. The probe RBNE undergoes hydrazine redox-process, and subsequently the spirocyclic structure’s opening, resulting in a turn-on fluorescence emission with the presence of ONOO<sup>−</sup>, which exhibits several excellent features, including a significant Stokes shift of 108 nm, near-infrared emission at 668 nm, a lower detection limit of 56 nM, low cytotoxicity, and excellent imaging ability for ONOO<sup>−</sup> both in vitro and in vivo. The presented study introduces a novel optical tool that has the potential to significantly advance our understanding of peroxynitrite (ONOO<sup>−</sup>) behaviors in necrotizing enterocolitis (NEC).</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142040160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1016/j.bioorg.2024.107731
Background
Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer.
Methods
Cell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models in vitro. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety in vivo. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets.
Results
PM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation.
Conclusion
PM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest.
{"title":"Reynoutria multiflora (Thunb.) Moldenke and its ingredient suppress lethal prostate cancer growth by inducing CDC25B-CDK1 mediated cell cycle arrest","authors":"","doi":"10.1016/j.bioorg.2024.107731","DOIUrl":"10.1016/j.bioorg.2024.107731","url":null,"abstract":"<div><h3>Background</h3><p><em>Reynoutria multiflora</em> (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer.</p></div><div><h3>Methods</h3><p>Cell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models <em>in vitro</em>. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety <em>in vivo</em>. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets.</p></div><div><h3>Results</h3><p>PM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation.</p></div><div><h3>Conclusion</h3><p>PM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142049771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-18DOI: 10.1016/j.bioorg.2024.107726
Fusicoccane (FC)-type diterpenoids are a class of diterpenoids characterized by a unique 5–8–5 ring system and exhibit diverse biological activities. Recently, we identified a novel FC-type diterpene synthase MgMS, which produces a myrothec-15(17)-en-7-ol (1) hydrocarbon skeleton, however, its tailoring congeners have not been elucidated. Here, we discovered two additional gene clusters Bn and Np, each encoding a highly homologous terpene synthase to MgMS but distinct tailoring enzymes. Heterologous expression of the terpene synthases BnMS and NpMS yielded the same product as MgMS. Subsequent introduction of three P450 enzymes MgP450, BnP450 and NpP450 from individual gene clusters resulted in four new FC-type diterpenoids 2–5. Notably, MgP450 serves as the first enzyme responsible for hydroxylation of the C19 methyl group, whereas NpP450 functions as a multifunctional P450 enzyme involved in the oxidations at C5, C6, and C19 positions of the 5–8–5 tricyclic skeleton. C5 oxidation of the hydrocarbon skeleton 1 led to broadening of the NMR signals and incomplete spectra, which was resolved by high-temperature NMR spectral analysis.
{"title":"Identification of three novel P450 enzymes involved in the oxidative modification of a newly discovered fusicoccane diterpene","authors":"","doi":"10.1016/j.bioorg.2024.107726","DOIUrl":"10.1016/j.bioorg.2024.107726","url":null,"abstract":"<div><p>Fusicoccane (FC)-type diterpenoids are a class of diterpenoids characterized by a unique 5–8–5 ring system and exhibit diverse biological activities. Recently, we identified a novel FC-type diterpene synthase MgMS, which produces a myrothec-15(17)-en-7-ol (<strong>1</strong>) hydrocarbon skeleton, however, its tailoring congeners have not been elucidated. Here, we discovered two additional gene clusters <em>Bn</em> and <em>Np</em>, each encoding a highly homologous terpene synthase to MgMS but distinct tailoring enzymes. Heterologous expression of the terpene synthases BnMS and NpMS yielded the same product as MgMS. Subsequent introduction of three P450 enzymes MgP450, BnP450 and NpP450 from individual gene clusters resulted in four new FC-type diterpenoids <strong>2</strong>–<strong>5</strong>. Notably, MgP450 serves as the first enzyme responsible for hydroxylation of the C19 methyl group, whereas NpP450 functions as a multifunctional P450 enzyme involved in the oxidations at C5, C6, and C19 positions of the 5–8–5 tricyclic skeleton. C5 oxidation of the hydrocarbon skeleton <strong>1</strong> led to broadening of the NMR signals and incomplete spectra, which was resolved by high-temperature NMR spectral analysis.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142049802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-17DOI: 10.1016/j.bioorg.2024.107728
In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-β kinases showing IC50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.
{"title":"Novel benzenesulfonamides as dual VEGFR2/FGFR1 inhibitors targeting breast cancer: Design, synthesis, anticancer activity and in silico studies","authors":"","doi":"10.1016/j.bioorg.2024.107728","DOIUrl":"10.1016/j.bioorg.2024.107728","url":null,"abstract":"<div><p>In the current study, a new series of benzenesulfonamides <strong>6a-r</strong> was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide <strong>6l</strong> exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC<sub>50</sub> values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound <strong>6l</strong> was further tested on EGFR and PDGFR-β kinases showing IC<sub>50</sub> values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound <strong>6l</strong> displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds <strong>6a</strong>, <strong>6b</strong>, <strong>6e</strong>, <strong>6f</strong>, <strong>6h-l</strong>, and <strong>6n-r</strong> revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC<sub>50</sub> determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds <strong>6e</strong>, <strong>6h-j</strong>, <strong>6l</strong> and <strong>6o</strong> revealed IC<sub>50</sub> values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds <strong>6i</strong>, and <strong>6l</strong> in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds <strong>6i</strong>, and <strong>6l</strong> to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds <strong>6i</strong> and <strong>6l</strong> have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds <strong>6a-r</strong> on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-17DOI: 10.1016/j.bioorg.2024.107734
Because of the high similarity in structure and sequence, it is challenging to distinguish the S1 pocket among serine proteases, primarily due to the only variability at residue 190 (A190 and S190). Peptide or protein-based inhibitors typically target the negatively charged S1 pocket using lysine or arginine as the P1 residue, yet neither discriminates between the two S1 pocket variants. This study introduces two arginine analogues, L-4-guanidinophenylalanine (12) and L-3-(N-amidino-4-piperidyl)alanine (16), as novel P1 residues in peptide inhibitors. 16 notably enhances affinities across all tested proteases, whereas 12 specifically improved affinities towards proteases possessing S190 in the S1 pocket. By crystallography and molecular dynamics simulations, we discovered a novel mechanism involving a water exchange channel at the bottom of the S1 pocket, modulated by the variation of residue 190. Additionally, the specificity of 12 towards the S190-presenting S1 pocket is dependent on this water channel. This study not only introduces novel P1 residues to engineer inhibitory potency and specificity of peptide inhibitors targeting serine proteases, but also unveils a water-mediated molecular mechanism of targeting serine proteases.
{"title":"Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue","authors":"","doi":"10.1016/j.bioorg.2024.107734","DOIUrl":"10.1016/j.bioorg.2024.107734","url":null,"abstract":"<div><p>Because of the high similarity in structure and sequence, it is challenging to distinguish the S1 pocket among serine proteases, primarily due to the only variability at residue 190 (A190 and S190). Peptide or protein-based inhibitors typically target the negatively charged S1 pocket using lysine or arginine as the P1 residue, yet neither discriminates between the two S1 pocket variants. This study introduces two arginine analogues, L-4-guanidinophenylalanine (<strong>12</strong>) and L-3-(<em>N</em>-amidino-4-piperidyl)alanine (<strong>16</strong>), as novel P1 residues in peptide inhibitors. <strong>16</strong> notably enhances affinities across all tested proteases, whereas <strong>12</strong> specifically improved affinities towards proteases possessing S190 in the S1 pocket. By crystallography and molecular dynamics simulations, we discovered a novel mechanism involving a water exchange channel at the bottom of the S1 pocket, modulated by the variation of residue 190. Additionally, the specificity of <strong>12</strong> towards the S190-presenting S1 pocket is dependent on this water channel. This study not only introduces novel P1 residues to engineer inhibitory potency and specificity of peptide inhibitors targeting serine proteases, but also unveils a water-mediated molecular mechanism of targeting serine proteases.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142011842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1016/j.bioorg.2024.107732
Phytochemical analysis of the peeled stems of Syringa pinnatifolia Hemsl. led to the discovery of 13 undescribed lignans, namely helanols A and B (1 and 2) and alashanenols W–G1 (3–13), as well as four known analogues, of which helanols A and B were lignans with novel skeleton of α-β′ linkage. The structures were unambiguously established by extensive spectroscopic analyses, NMR calculations, ECD calculations, and single crystal X-ray crystallography. Five lignans (1, 2, 5, 11 and 13) exhibited a moderate protective effect against H2O2-induced oxidative injuries in H9c2 cells with the protective rates of 11.3–20.6 % at the concentration of 0.3–20 μM, while the positive control quercetin showed protective rates of 58.7 % at 10 μM. Further mechanism investigation suggested that 1 and 2 exerted the protective effect by regulating the expression of Nrf2/HO-1.
通过对羽叶忍冬(Syringa pinnatifolia Hemsl.)的去皮茎进行植物化学分析,发现了 13 种未曾描述过的木质素,即 helanols A 和 B(1 和 2)和 alashanenols W-G1(3-13),以及 4 种已知的类似物,其中 helanols A 和 B 是具有新型 α-β′ 连接骨架的木质素。通过大量的光谱分析、核磁共振计算、ECD 计算和单晶 X 射线晶体学研究,它们的结构被明确地确定下来。五种木脂素(1、2、5、11 和 13)对 H2O2 诱导的 H9c2 细胞氧化损伤具有中度保护作用,在 0.3-20 μM 浓度下保护率为 11.3-20.6%,而阳性对照槲皮素在 10 μM 浓度下的保护率为 58.7%。进一步的机理研究表明,1和2是通过调节Nrf2/HO-1的表达来发挥保护作用的。
{"title":"Novel lignans from Syringa pinnatifolia and protective effect against H2O2-induced oxidative injury through regulating the expression of Nrf2/HO-1 in H9c2 cells","authors":"","doi":"10.1016/j.bioorg.2024.107732","DOIUrl":"10.1016/j.bioorg.2024.107732","url":null,"abstract":"<div><p>Phytochemical analysis of the peeled stems of <em>Syringa pinnatifolia</em> Hemsl. led to the discovery of 13 undescribed lignans, namely helanols A and B (<strong>1</strong> and <strong>2</strong>) and alashanenols W–G<sub>1</sub> (<strong>3</strong>–<strong>13</strong>), as well as four known analogues, of which helanols A and B were lignans with novel skeleton of <em>α-β′</em> linkage. The structures were unambiguously established by extensive spectroscopic analyses, NMR calculations, ECD calculations, and single crystal X-ray crystallography. Five lignans (<strong>1</strong>, <strong>2</strong>, <strong>5</strong>, <strong>11</strong> and <strong>13</strong>) exhibited a moderate protective effect against H<sub>2</sub>O<sub>2</sub>-induced oxidative injuries in H9c2 cells with the protective rates of 11.3–20.6 % at the concentration of 0.3–20 μM, while the positive control quercetin showed protective rates of 58.7 % at 10 μM. Further mechanism investigation suggested that <strong>1</strong> and <strong>2</strong> exerted the protective effect by regulating the expression of Nrf2/HO-1.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1016/j.bioorg.2024.107733
A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (–SeCN and –SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.
{"title":"Design, synthesis and biological evaluation of artesunate-Se derivatives as anticancer agents by inducing GPX4-mediated ferroptosis","authors":"","doi":"10.1016/j.bioorg.2024.107733","DOIUrl":"10.1016/j.bioorg.2024.107733","url":null,"abstract":"<div><p>A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (–SeCN and –SeCF<sub>3</sub>) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF<sub>3</sub> derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds <strong>2c</strong>, <strong>2f</strong> and <strong>3e</strong> have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound <strong>2c</strong> exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound <strong>2c</strong> induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that <strong>2c</strong> resulted in mitochondrial dysfunction and ferroptosis. Moreover, <strong>2c</strong> could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound <strong>2c</strong> may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142049769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1016/j.bioorg.2024.107730
Breast cancer is the most prevalent cancer among women globally, with triple-negative breast cancer (TNBC) associated with poor prognosis and low five-year survival rates. Schiff base compounds, known for their extensive pharmacological activities, have garnered significant attention in cancer drug research. This study aimed to evaluate the anticancer potential of a novel β-diiminato compound and elucidate its mechanism of action. The compound’s effect on cell viability was assessed using MTT assays in breast cancer cell lines including MCF-7 and MDA-MB-231. Cytotoxic effects were further analyzed using trypan blue exclusion and lactate dehydrogenase (LDH) release assays. In order to assess the mechanism of inhibitory activity and mode of cell death induced by this compound, flow cytometry of cell cycle distribution and apoptosis analysis were carried out. Apoptosis incidence was initially assessed through cell and nuclear morphological changes (Hoechst 33342/Propidium iodide (PI) staining) and further confirmed by Annexin V/PI staining and flow cytometry analysis. In addition, the effect of this compound on the disruption of mitochondrial membrane potential (MMP) and generation of the reactive oxygen species (ROS) was determined using the JC-1 indicator and DCFDA dye, respectively. The results demonstrated that the 24 h treatment with β-diiminato compound significantly suppressed the viability of MDA-MB-231 and MCF-7 cancer cells in a dose-dependent manner with the IC50 value of 2.41 ± 0.29 and 3.51 ± 0.14, respectively. The cytotoxic effect of the compound was further confirmed with a dose-dependent increase in the number of dead cells and enhanced LDH level in the culture medium. This compound exerted its anti-proliferative effect by G2/M phase cell growth arrest in MDA-MB-231 breast cancer cells and induced apoptosis-mediated cell death, which involved characteristic changes in cell and nuclear morphology, phosphatidylserine externalization, mitochondrial membrane depolarization, and increased ROS level. Neither hepatotoxicity nor nephrotoxicity was detected in the biochemical and histopathological analysis confirming the safety characterization of this compound usage. Therefore, the results significantly confirmed the potential anticancer activity of a novel β-diiminato compound, as evidenced by the induction of cell cycle arrest and apoptosis, which might be driven by the ROS‑mediated mitochondrial death pathway. This compound can be a promising candidate for future anticancer drug design and TNBC treatment, and further preclinical and clinical studies are warranted.
{"title":"Novel indole Schiff base β-diiminato compound as an anti-cancer agent against triple-negative breast cancer: In vitro anticancer activity evaluation and in vivo acute toxicity study","authors":"","doi":"10.1016/j.bioorg.2024.107730","DOIUrl":"10.1016/j.bioorg.2024.107730","url":null,"abstract":"<div><p>Breast cancer is the most prevalent cancer among women globally, with triple-negative breast cancer (TNBC) associated with poor prognosis and low five-year survival rates. Schiff base compounds, known for their extensive pharmacological activities, have garnered significant attention in cancer drug research. This study aimed to evaluate the anticancer potential of a novel β-diiminato compound and elucidate its mechanism of action. The compound’s effect on cell viability was assessed using MTT assays in breast cancer cell lines including MCF-7 and MDA-MB-231. Cytotoxic effects were further analyzed using trypan blue exclusion and lactate dehydrogenase (LDH) release assays. In order to assess the mechanism of inhibitory activity and mode of cell death induced by this compound, flow cytometry of cell cycle distribution and apoptosis analysis were carried out. Apoptosis incidence was initially assessed through cell and nuclear morphological changes (Hoechst 33342/Propidium iodide (PI) staining) and further confirmed by Annexin V/PI staining and flow cytometry analysis. In addition, the effect of this compound on the disruption of mitochondrial membrane potential (MMP) and generation of the reactive oxygen species (ROS) was determined using the JC-1 indicator and DCFDA dye, respectively. The results demonstrated that the 24 h treatment with β-diiminato compound significantly suppressed the viability of MDA-MB-231 and MCF-7 cancer cells in a dose-dependent manner with the IC<sub>50</sub> value of 2.41 ± 0.29 and 3.51 ± 0.14, respectively. The cytotoxic effect of the compound was further confirmed with a dose-dependent increase in the number of dead cells and enhanced LDH level in the culture medium. This compound exerted its anti-proliferative effect by G2/M phase cell growth arrest in MDA-MB-231 breast cancer cells and induced apoptosis-mediated cell death, which involved characteristic changes in cell and nuclear morphology, phosphatidylserine externalization, mitochondrial membrane depolarization, and increased ROS level. Neither hepatotoxicity nor nephrotoxicity was detected in the biochemical and histopathological analysis confirming the safety characterization of this compound usage. Therefore, the results significantly confirmed the potential anticancer activity of a novel β-diiminato compound, as evidenced by the induction of cell cycle arrest and apoptosis, which might be driven by the ROS‑mediated mitochondrial death pathway. This compound can be a promising candidate for future anticancer drug design and TNBC treatment, and further preclinical and clinical studies are warranted.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0045206824006357/pdfft?md5=35ba369af80bcba527586e0cccb42a4f&pid=1-s2.0-S0045206824006357-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142095835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}