In this study, we have identified two novel peptides, 19Ac (comprising residues 91–105) and 20Ac (encompassing residues 96–110), from a systematically designed peptide library based on the Hepatitis B virus (HBV) core protein, that inhibit the assembly of HBV capsid. Peptide 20Ac exhibited about twofold the inhibitory potency of 19Ac and proved effective against both standard and morphothiadin (GLS4)-resistant HBV strains. Molecular dynamics simulations revealed that despite their overlapping sequence, 19Ac and 20Ac bonded to different regions of the core protein, thereby inhibiting capsid assembly through distinct mechanisms. These peptides could serve as valuable seed compounds for the further development of HBV capsid inhibitors, including GLS4-resistant strains.
{"title":"Identification of peptide-based hepatitis B virus capsid inhibitors based on the viral core protein","authors":"Junko Fujimoto , Kazutoshi Kawahara , Kazuma Takeda , Sayuri Takeo , Kohei Sato , Kenji Nakashima , Nobuyuki Mase , Masaru Yokoyama , Tetsuro Suzuki , Tetsuo Narumi","doi":"10.1016/j.bmcl.2024.130054","DOIUrl":"10.1016/j.bmcl.2024.130054","url":null,"abstract":"<div><div>In this study, we have identified two novel peptides, <strong>19Ac</strong> (comprising residues 91–105) and <strong>20Ac</strong> (encompassing residues 96–110), from a systematically designed peptide library based on the Hepatitis B virus (HBV) core protein, that inhibit the assembly of HBV capsid. Peptide <strong>20Ac</strong> exhibited about twofold the inhibitory potency of <strong>19Ac</strong> and proved effective against both standard and morphothiadin (GLS4)-resistant HBV strains. Molecular dynamics simulations revealed that despite their overlapping sequence, <strong>19Ac</strong> and <strong>20Ac</strong> bonded to different regions of the core protein, thereby inhibiting capsid assembly through distinct mechanisms. These peptides could serve as valuable seed compounds for the further development of HBV capsid inhibitors, including GLS4-resistant strains.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"117 ","pages":"Article 130054"},"PeriodicalIF":2.5,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790521","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 : 2024-12-03DOI: 10.1016/j.bmcl.2024.130060
Bhakti P. Rout , Sarupa Roy , Seergazhi G. Srivatsan
DNA sequences that are composed of multiple G- and C-tracts can potentially form non-canonical structures called G-quadruplex (GQ) or i-motif (iM), respectively. Such sequences are found at the ends of chromosomes (telomeric repeats) and in the promoter region of several genes that cause cancer. Despite extensive studies, distinguishing different GQ and iM topologies is not easy. In this work, we have used one of the conservatively modified nucleoside analogs, namely 5-fluoro-2′-deoxyuridine (FdU) to study different GQ and iM structures of the human telomeric (H-Telo) DNA repeat sequence using 19F NMR technique. The probe is minimally perturbing and distinguishes different GQ topologies by providing unique 19F signatures. Our findings suggest that the telomeric repeat assumes hybrid-type GQ structures in intracellular ionic conditions as opposed to a parallel form predicted by using synthetic cellular crowding mimics. Further, with the incorporation of the probe into a C-rich H-Telo DNA ON, we were able to study the transition from iM structure to a random coil structure. Taken together, FdU is a promising probe, which could be used to determine the structure of non-canonical nucleic acid motifs in vitro and potentially in the native cellular environment.
由多个G-束和c -束组成的DNA序列可能分别形成称为G-四重体（GQ）或i-基序（iM）的非规范结构。这些序列存在于染色体末端（端粒重复序列）和几种致癌基因的启动子区域。尽管有广泛的研究，区分不同的GQ和iM拓扑并不容易。在这项工作中，我们使用一种保守修饰的核苷类似物，即5-氟-2'-脱氧尿苷（FdU），利用19F NMR技术研究了人类端粒（H-Telo） DNA重复序列的不同GQ和iM结构。探针的干扰最小，并通过提供唯一的19F签名来区分不同的GQ拓扑。我们的研究结果表明，在细胞内离子条件下，端粒重复呈现混合型GQ结构，而不是使用合成细胞拥挤模拟物预测的平行形式。此外，通过将探针结合到富含c的H-Telo DNA ON中，我们能够研究从iM结构到随机线圈结构的转变。综上所述，FdU是一种很有前途的探针，可用于确定体外和天然细胞环境中非典型核酸基序的结构。
{"title":"5-Fluoro-2′-deoxyuridine as an efficient 19F NMR reporter for G-quadruplex and i-motif structures","authors":"Bhakti P. Rout , Sarupa Roy , Seergazhi G. Srivatsan","doi":"10.1016/j.bmcl.2024.130060","DOIUrl":"10.1016/j.bmcl.2024.130060","url":null,"abstract":"<div><div>DNA sequences that are composed of multiple G- and C-tracts can potentially form non-canonical structures called G-quadruplex (GQ) or i-motif (iM), respectively. Such sequences are found at the ends of chromosomes (telomeric repeats) and in the promoter region of several genes that cause cancer. Despite extensive studies, distinguishing different GQ and iM topologies is not easy. In this work, we have used one of the conservatively modified nucleoside analogs, namely 5-fluoro-2′-deoxyuridine (FdU) to study different GQ and iM structures of the human telomeric (H-Telo) DNA repeat sequence using <sup>19</sup>F NMR technique. The probe is minimally perturbing and distinguishes different GQ topologies by providing unique <sup>19</sup>F signatures. Our findings suggest that the telomeric repeat assumes hybrid-type GQ structures in intracellular ionic conditions as opposed to a parallel form predicted by using synthetic cellular crowding mimics. Further, with the incorporation of the probe into a C-rich H-Telo DNA ON, we were able to study the transition from iM structure to a random coil structure. Taken together, FdU is a promising probe, which could be used to determine the structure of non-canonical nucleic acid motifs <em>in vitro</em> and potentially in the native cellular environment.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"117 ","pages":"Article 130060"},"PeriodicalIF":2.5,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783440","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 : 2024-12-02DOI: 10.1016/j.bmcl.2024.130045
Matheus Barbosa Belchior , Riley T. Kane , Jason D. Huber , Werner J. Geldenhuys
Monoamine oxidase (MAO) B is a promising target for treating stroke reperfusion injury, Parkinson’s disease as well as other neurodegenerative diseases. Pharmacological inhibitors of this enzyme have demonstrated the ability to modulate critical neurotransmitter levels, decrease damaging reactive oxygen species and neuroinflammation, and improve mitochondrial dysfunction. We identified TT01001 from a pilot screen which showed good potency for inhibiting MAO-B, with a half-maximal inhibitory concentration below 10 μM. In this study, we explored quantitative-structure activity relationships (QSAR) of 60 derivatives of TT01001 evaluated for MAO-B. Approximately half of these 60 compounds showed IC50 values superior to that of TT01001 (10). Two of the compounds, 37 and 57, displayed improved MAO-B potency and selectivity from MAO-A, with IC50 values of 270 and 460 nM respectively. The mode of inhibition of was determined to be both competitive and reversible, and both compounds exhibited moderate ability to passively diffuse across biological membranes. These compounds can be offered as-is for subsequent drug development processes, or they can be derivatized further using the structure–activity relationship information found herein.
{"title":"Synthesis and evaluation of enzyme inhibition by novel TT01001 derivatives as monoamine oxidase B inhibitors","authors":"Matheus Barbosa Belchior , Riley T. Kane , Jason D. Huber , Werner J. Geldenhuys","doi":"10.1016/j.bmcl.2024.130045","DOIUrl":"10.1016/j.bmcl.2024.130045","url":null,"abstract":"<div><div>Monoamine oxidase (MAO) B is a promising target for treating stroke reperfusion injury, Parkinson’s disease as well as other neurodegenerative diseases. Pharmacological inhibitors of this enzyme have demonstrated the ability to modulate critical neurotransmitter levels, decrease damaging reactive oxygen species and neuroinflammation, and improve mitochondrial dysfunction. We identified TT01001 from a pilot screen which showed good potency for inhibiting MAO-B, with a half-maximal inhibitory concentration below 10 μM. In this study, we explored quantitative-structure activity relationships (QSAR) of 60 derivatives of TT01001 evaluated for MAO-B. Approximately half of these 60 compounds showed IC<sub>50</sub> values superior to that of TT01001 (10). Two of the compounds, 37 and 57, displayed improved MAO-B potency and selectivity from MAO-A, with IC<sub>50</sub> values of 270 and 460 nM respectively. The mode of inhibition of was determined to be both competitive and reversible, and both compounds exhibited moderate ability to passively diffuse across biological membranes. These compounds can be offered as-is for subsequent drug development processes, or they can be derivatized further using the structure–activity relationship information found herein.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"117 ","pages":"Article 130045"},"PeriodicalIF":2.5,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779089","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 : 2024-11-30DOI: 10.1016/j.bmcl.2024.130055
Hyuk Yoon , Seunghyun Ahn , Dongsoo Koh , Yoongho Lim , Euitaek Jung , Jung Kul Lee , Soon Young Shin
Early growth response 1 (EGR-1) is a key transcription factor that boosts the inflammatory response. Therefore, targeting EGR-1 with small-molecule drugs may be a novel strategy for treating inflammatory diseases, such as atopic dermatitis. (E)-2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-6-nitro-4H-chromen-4-one (AB1711) was previously found to be an active compound that disrupts EGR-1–DNA binding. Structural modifications were performed to identify compounds with better activity. Seventy compounds with pyrazolo-1-carbothioamide moieties were derived. Fifty-one compounds showed greater disruption of EGR-1 DNA binding than that induced by AB1711. To determine why the compounds tested in this study showed good activity, pharmacophores were derived based on comparative molecular field and comparative molecular similarity index analyses. Of the 70 compounds tested, compound 36, N-(2,4-dimethoxyphenyl)-3-(1-hydroxynaphthalen-2-yl)-5-(2,4,6-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide showed the best activity. The binding mode between EGR-1 and compound 36 was elucidated using in silico docking. Pharmacophores derived from quantitative structure–activity relationships matched well with the results obtained from in silico docking. To determine the role of compound 36 in cells, further experiments, including electrophoretic mobility shift and reverse-transcription polymerase chain reaction assays, were carried out. These findings demonstrated that compound 36 is a good disruptor of EGR-1–DNA binding.
{"title":"Pyrazolo-1-carbothioamides as EGR-1–DNA binding disruptors","authors":"Hyuk Yoon , Seunghyun Ahn , Dongsoo Koh , Yoongho Lim , Euitaek Jung , Jung Kul Lee , Soon Young Shin","doi":"10.1016/j.bmcl.2024.130055","DOIUrl":"10.1016/j.bmcl.2024.130055","url":null,"abstract":"<div><div>Early growth response 1 (EGR-1) is a key transcription factor that boosts the inflammatory response. Therefore, targeting EGR-1 with small-molecule drugs may be a novel strategy for treating inflammatory diseases, such as atopic dermatitis. (<em>E</em>)-2-(2,4-dimethoxy-6-(4-methoxystyryl)phenyl)-3-hydroxy-6-nitro-4<em>H</em>-chromen-4-one (AB1711) was previously found to be an active compound that disrupts EGR-1–DNA binding. Structural modifications were performed to identify compounds with better activity. Seventy compounds with pyrazolo-1-carbothioamide moieties were derived. Fifty-one compounds showed greater disruption of EGR-1 DNA binding than that induced by AB1711. To determine why the compounds tested in this study showed good activity, pharmacophores were derived based on comparative<!--> <!-->molecular field and comparative molecular<!--> <!-->similarity index analyses. Of the 70 compounds tested, compound <strong>36</strong>, <em>N</em>-(2,4-dimethoxyphenyl)-3-(1-hydroxynaphthalen-2-yl)-5-(2,4,6-trimethoxyphenyl)-4,5-dihydro-1<em>H</em>-pyrazole-1-carbothioamide showed the best activity. The binding mode between EGR-1 and compound <strong>36</strong> was elucidated using <em>in silico</em> docking. Pharmacophores derived from quantitative structure–activity relationships matched well with the results obtained from <em>in silico</em> docking. To determine the role of compound <strong>36</strong> in cells, further experiments, including electrophoretic mobility shift and reverse-transcription polymerase chain reaction assays, were carried out. These findings demonstrated that compound <strong>36</strong> is a good disruptor of EGR-1–DNA binding.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"117 ","pages":"Article 130055"},"PeriodicalIF":2.5,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764659","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 : 2024-11-26DOI: 10.1016/j.bmcl.2024.130044
Shuhua Ren , Fengling Liu , Man Chi , Jinfeng Liu , Yi Huang , Weiwei Huang , Wenjing Gu , Yaxia Yuan , Shurong Hou , Xiabin Chen , Lei Ma
We synthesized and evaluated a series of derivatives based on the pyrimidine-2,4-diamine scaffold as potential JNK1 inhibitors, incorporating bridging rings and spirocyclic modifications to enhance their inhibitory activity. These compounds were biologically assessed through JNK enzyme inhibition assays and Western Blot analysis. Compounds 13, 14 and 19 demonstrated significant inhibitory activity at both the enzyme and cellular level compared to the lead compound 1 and clinical candidate CC-90001. Notably, 14 exhibited strong inhibitory potency against JNK1 with sub-nanomolar efficacy and suppresses TGF-β-induced epithelial-mesenchymal transition, indicating its potential as a promising candidate for further development as an anti-pulmonary fibrosis agent targeting JNK1.
{"title":"Discovery of a selective and potent inhibitor of c-Jun N-terminal kinase 1 with anti-pulmonary fibrosis effect","authors":"Shuhua Ren , Fengling Liu , Man Chi , Jinfeng Liu , Yi Huang , Weiwei Huang , Wenjing Gu , Yaxia Yuan , Shurong Hou , Xiabin Chen , Lei Ma","doi":"10.1016/j.bmcl.2024.130044","DOIUrl":"10.1016/j.bmcl.2024.130044","url":null,"abstract":"<div><div>We synthesized and evaluated a series of derivatives based on the pyrimidine-2,4-diamine scaffold as potential JNK1 inhibitors, incorporating bridging rings and spirocyclic modifications to enhance their inhibitory activity. These compounds were biologically assessed through JNK enzyme inhibition assays and Western Blot analysis. Compounds <strong>13</strong>, <strong>14</strong> and <strong>19</strong> demonstrated significant inhibitory activity at both the enzyme and cellular level compared to the lead compound <strong>1</strong> and clinical candidate <strong>CC-90001</strong>. Notably, <strong>14</strong> exhibited strong inhibitory potency against JNK1 with sub-nanomolar efficacy and suppresses TGF-β-induced epithelial-mesenchymal transition, indicating its potential as a promising candidate for further development as an anti-pulmonary fibrosis agent targeting JNK1.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130044"},"PeriodicalIF":2.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142745138","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 : 2024-11-26DOI: 10.1016/j.bmcl.2024.130042
Tayssa S.A. Barreto , Tamiris A.C. Santos , Audrey R.S.T. Silva , Emmanoel V. Costa , Liciane A. Pinheiro , Roberta P.M. Fernandes , Ricardo Scher , Péricles B. Alves
Leishmaniasis is a group of diseases caused by protozoa of the genus Leishmania. They are considered neglected diseases and are endemic to tropical and subtropical regions, affecting thousands of people annually. Leishmaniasis has a wide global distribution, present on four continents. Various drugs have been used to control leishmaniasis; however, obstacles such as high toxicity to patients and the occurrence of resistance have led to the search for alternatives. Chalcones are α, β-unsaturated ketones that can occur in the secondary metabolism of plants or can be obtained through organic synthesis. In this study, 21 chalcones brominated were synthesized via the Claisen-Schmidt condensation synthesis and characterized by UHRMS and NMR. The biological activity was evaluated for antiprotozoal potential against Leishmania amazonensis and cytotoxicity against L929 fibroblasts. Eighteen chalcones showed viability inhibition rates above 80 % at a concentration of 50 µM. Six chalcones demonstrated IC50 values ranging from 6.33 ± 0.70 µM to 23.95 ± 2.94 µM and maintained 70 % viability in L929 fibroblasts at 50 µM. The (E)-1-(4-bromophenyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one, with a trimethoxylation at positions 2, 4, and 5 of ring B and a bromine substituent at position 4 of ring A, exhibited the lowest IC50 value (6.33 µM). These results indicate that these brominated chalcones have potential for studies aiming at the development of new drugs for leishmaniasis control.
{"title":"Brominated chalcones as promising antileishmanial agents","authors":"Tayssa S.A. Barreto , Tamiris A.C. Santos , Audrey R.S.T. Silva , Emmanoel V. Costa , Liciane A. Pinheiro , Roberta P.M. Fernandes , Ricardo Scher , Péricles B. Alves","doi":"10.1016/j.bmcl.2024.130042","DOIUrl":"10.1016/j.bmcl.2024.130042","url":null,"abstract":"<div><div>Leishmaniasis is a group of diseases caused by protozoa of the genus <em>Leishmania</em>. They are considered neglected diseases and are endemic to tropical and subtropical regions, affecting thousands of people annually. Leishmaniasis has a wide global distribution, present on four continents. Various drugs have been used to control leishmaniasis; however, obstacles such as high toxicity to patients and the occurrence of resistance have led to the search for alternatives. Chalcones are α, β-unsaturated ketones that can occur in the secondary metabolism of plants or can be obtained through organic synthesis. In this study, 21 chalcones brominated were synthesized via the Claisen-Schmidt condensation synthesis and characterized by UHRMS and NMR. The biological activity was evaluated for antiprotozoal potential against <em>Leishmania amazonensis</em> and cytotoxicity against L929 fibroblasts. Eighteen chalcones showed viability inhibition rates above 80 % at a concentration of 50 µM. Six chalcones demonstrated IC50 values ranging from 6.33 ± 0.70 µM to 23.95 ± 2.94 µM and maintained 70 % viability in L929 fibroblasts at 50 µM. The (<em>E</em>)-1-(4-bromophenyl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one, with a trimethoxylation at positions 2, 4, and 5 of ring B and a bromine substituent at position 4 of ring A, exhibited the lowest IC50 value (6.33 µM). These results indicate that these brominated chalcones have potential for studies aiming at the development of new drugs for leishmaniasis control.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130042"},"PeriodicalIF":2.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749723","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}
The accumulation of reactive oxygen species (ROS) disrupts reduction–oxidation homeostasis, which can result in damage to cancer cells. To identify the compounds generating ROS, compounds containing Michael acceptors were designed because they are suggested to be critical for ROS elevation via glutathione depletion. Twelve (E)-3-(3-([1,1′-biphenyl]-4-yl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-ones were synthesized and identified using nuclear magnetic resonance spectroscopy and mass spectrometry. Intracellular ROS levels induced by treatment with the compounds were determined using fluorescence microscopy with the oxidant-sensing fluorescent probe 2′,7′-dichlorodihydrofluorescein diacetate. We selected compound 9, which showed the highest activity, and performed further biological experiments, including glutathione depletion and apoptosis assays, using MIA PaCa-2 pancreatic cancer cells. Additionally, the reason why the intracellular ROS level by compound 9 was lower than that of menadione used as a control was explained through in silico docking experiments. Our findings suggest that compound 9 has the potential to act as an anticancer agent by inducing ROS generation through the depletion of intracellular glutathione.
{"title":"(E)-3-(3-([1,1′-Biphenyl]-4-yl)-1-phenyl-1H-pyrazol-4-yl)-1-phenylprop-2-en-1-ones inducing reactive oxygen species generation through glutathione depletion","authors":"Youngshim Lee , Seunghyun Ahn , Euitaek Jung , Yoongho Lim , Dongsoo Koh , Dong-Ho Bae , Soon Young Shin","doi":"10.1016/j.bmcl.2024.130043","DOIUrl":"10.1016/j.bmcl.2024.130043","url":null,"abstract":"<div><div>The accumulation of reactive oxygen species (ROS) disrupts reduction–oxidation homeostasis, which can result in damage to cancer cells. To identify the compounds generating ROS, compounds containing Michael acceptors were designed because they are suggested to be critical for ROS elevation via glutathione depletion. Twelve (<em>E</em>)-3-(3-([1,1′-biphenyl]-4-yl)-1-phenyl-1<em>H</em>-pyrazol-4-yl)-1-phenylprop-2-en-1-ones were synthesized and identified using nuclear magnetic resonance spectroscopy and mass spectrometry. Intracellular ROS levels induced by treatment with the compounds were determined using fluorescence microscopy with the oxidant-sensing fluorescent probe 2′,7′-dichlorodihydrofluorescein diacetate. We selected compound <strong>9</strong>, which showed the highest activity, and performed further biological experiments, including glutathione depletion and apoptosis assays, using MIA PaCa-2 pancreatic cancer cells. Additionally, the reason why the intracellular ROS level by compound <strong>9</strong> was lower than that of menadione used as a control was explained through <em>in silico</em> docking experiments. Our findings suggest that compound <strong>9</strong> has the potential to act as an anticancer agent by inducing ROS generation through the depletion of intracellular glutathione.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"117 ","pages":"Article 130043"},"PeriodicalIF":2.5,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749718","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}
Two types of drimanyl indole fragments of drimentine alkaloids were synthesized and evaluated their in vitro antibacterial activities using minimum inhibitory concentration. Analysis of structure–activity relationship against Ralstonia solanacearum revealed that fragment I exhibited superior inhibitory activity compared to fragment II. Notably, free NH of the indole motif was essential for antibacterial activity, while C12OH of the drimane skeleton was beneficial for enhancing the inhibitory effect. Compound 2, possessing these structural features, showed the highest activity to R. solanacearum among all the tested compounds with a MIC value of 8 µg/mL, indicating its potential as a promising lead for the development of novel antibiotics.
研究人员合成了两种地米星生物碱的地米酰吲哚片段，并利用最小抑菌浓度评估了它们的体外抗菌活性。对茄属拉氏菌（Ralstonia solanacearum）的结构-活性关系分析表明，与片段 II 相比，片段 I 表现出更强的抑制活性。值得注意的是，吲哚基团的游离 NH 是抗菌活性的关键，而二氢大麻烷骨架的 C12OH 则有利于增强抑菌效果。具有这些结构特征的化合物 2 在所有测试化合物中对 R. solanacearum 的活性最高，其 MIC 值为 8 µg/mL，这表明它有望成为开发新型抗生素的先导化合物。
{"title":"Synthesis of drimanyl indole fragments of drimentine alkaloids and their antibacterial activities","authors":"Jili Feng , Nini Qu , Summia Kalsoom , Zunjun Zhou , Shiyi Zhang , Zhe Cui , Chongmin Zhong , Miaofeng Ma","doi":"10.1016/j.bmcl.2024.130040","DOIUrl":"10.1016/j.bmcl.2024.130040","url":null,"abstract":"<div><div>Two types of drimanyl indole fragments of drimentine alkaloids were synthesized and evaluated their <em>in vitro</em> antibacterial activities using minimum inhibitory concentration. Analysis of structure–activity relationship against <em>Ralstonia solanacearum</em> revealed that fragment I exhibited superior inhibitory activity compared to fragment II. Notably, free N<img>H of the indole motif was essential for antibacterial activity, while C<sup>12</sup><img>OH of the drimane skeleton was beneficial for enhancing the inhibitory effect. Compound <strong>2</strong>, possessing these structural features, showed the highest activity to <em>R</em>. <em>solanacearum</em> among all the tested compounds with a MIC value of 8 µg/mL, indicating its potential as a promising lead for the development of novel antibiotics.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130040"},"PeriodicalIF":2.5,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715039","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 : 2024-11-23DOI: 10.1016/j.bmcl.2024.130039
Wenkang Guo , Manchun Chen , Changjie Zou , Weizhi Liu , Weidong Wang , Heyong Gao
To discover new potential drug for acute kidney injury (AKI), a series of novel alginate oligosaccharide derivatives were synthesized and characterized by the spectroscopic analysis. By using the controlled experimental method, the target compounds were evaluated preliminarily for therapeutic activity in AKI. The results demonstrated that compounds 2a, 2b, 2c and 3b exhibited notable inhibitory activity against the expression of related proteins at 250 μg/ml in vitro. Furthermore, the in vivo activity of 2a and 2b was found to be comparable to that of the trisaccharide (AOSC).
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Pub Date : 2024-11-22DOI: 10.1016/j.bmcl.2024.130037
Yong-Chang Zhao , Liang-Qing Yan , Yuan Xu
Cancer treatment always a huge challenge amidst the resistance and relapse caused by the various treatments. Inhibitors targeting mitosis have been considered as promising therapeutic drugs in clinic, of which tubulins play an important role. Selenium (Se) as an essential microelement in humans and animals, playing a crucial role in the formation of anti-oxidase (glutathione peroxidase) and selenoprotein, also attracted broad attention in cancer therapy. Because the introduction of Se atom could change the length and angle of chemical bond and alter their functional properties, regulating selenized chemotherapeutics has become one of the hot spots. However, little attention has been paid to studying the combination of Se and tubulin inhibitors. Herein, we review the latest research results of selenized tubulin inhibitors in cancer therapy, including its mechanisms, categories and biological activities, providing a theoretical basis for different selenized microtubules inhibitors therapies.
癌症治疗始终是一个巨大的挑战，因为各种治疗方法都会引起抗药性和复发。针对有丝分裂的抑制剂被认为是临床上很有前景的治疗药物，其中管蛋白发挥着重要作用。硒（Se）作为人类和动物必需的微量元素，在抗氧化物酶（谷胱甘肽过氧化物酶）和硒蛋白的形成中发挥着重要作用，在癌症治疗中也引起了广泛关注。由于 Se 原子的引入可改变化学键的长度和角度，从而改变其功能特性，因此硒化化疗药物的调控已成为研究热点之一。然而，人们很少关注 Se 与小管蛋白抑制剂的结合研究。在此，我们综述了硒化微管蛋白抑制剂在癌症治疗中的最新研究成果，包括其机制、类别和生物活性，为不同的硒化微管蛋白抑制剂疗法提供理论依据。
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