Bioorganic & Medicinal Chemistry Letters最新文献_第3页

Cyclic vinyl sulfones activate NRF2 to protect from oxidative stress-induced programmed necrosis.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-05 DOI: 10.1016/j.bmcl.2024.130058

Pavel Davidovich, Dmitriy Nikolaev, Raniya Khadiullina, Vladislav Gurzhiy, Emil Bulatov

{"title":"Cyclic vinyl sulfones activate NRF2 to protect from oxidative stress-induced programmed necrosis.","authors":"Pavel Davidovich, Dmitriy Nikolaev, Raniya Khadiullina, Vladislav Gurzhiy, Emil Bulatov","doi":"10.1016/j.bmcl.2024.130058","DOIUrl":"10.1016/j.bmcl.2024.130058","url":null,"abstract":"The NRF2 transcriptional factor is a member of cellular stress response machinery and is activated in response to oxidative stress caused either by cellular homeostasis imbalance or by environmental challenges. NRF2 levels are stringently controlled by rapid and continuous proteasomal degradation. KEAP1 is a specific NRF2 binding protein that acts as a bridge between NRF2 and the E3 ligase Cullin-3. In this study, we examine model cyclic vinyl sulfone derivatives as potential NRF2 activating probes. Previously, we and other authors have found anti-inflammatory properties of these compounds in in vivo models; however, the mechanism of action remained unknown. Here, we show that the naphthohydroquinone derivative LCB1353 efficiently stabilizes NRF2 protein levels and upregulates its target genes. At low 5-10 µM concentrations LCB1353 protects non-small cell lung cancer H1299 cells from ferroptotic death induced by cytotoxic concentrations of RSL3, reducing cell death from 90 % to 5 %. Thus, we suggest that cyclic vinyl sulfones are promising scaffolds for the design of protective molecules for conditions associated with toxic and inflammatory levels of oxidative stress.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"130058"},"PeriodicalIF":2.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142790516","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}

引用次数: 0

Development and characterization of pyridyl carboxamides as potent and highly selective Na_v1.8 inhibitors.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-05 DOI: 10.1016/j.bmcl.2024.130059

Michael Poslusney, Glen Ernst, Yifang Huang, Aaron C Gerlach, Mark L Chapman, Sónia Santos, James C Barrow

引用次数: 0

Identification of N-phenyl-N-(quinolin-4-yl) amino carboxylic acids as URAT1 inhibitors with hypouricemic effects.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-04 DOI: 10.1016/j.bmcl.2024.130053

Xianxin Hou, Mengjie Shao, Lei Zhang, Ying Yang, Zhiyan Xiao

引用次数: 0

Identification of peptide-based hepatitis B virus capsid inhibitors based on the viral core protein.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-04 DOI: 10.1016/j.bmcl.2024.130054

Junko Fujimoto, Kazutoshi Kawahara, Kazuma Takeda, Sayuri Takeo, Kohei Sato, Kenji Nakashima, Nobuyuki Mase, Masaru Yokoyama, Tetsuro Suzuki, Tetsuo Narumi

引用次数: 0

5-Fluoro-2'-deoxyuridine as an efficient ¹⁹F NMR reporter for G-quadruplex and i-motif structures.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-03 DOI: 10.1016/j.bmcl.2024.130060

Bhakti P Rout, Sarupa Roy, Seergazhi G Srivatsan

{"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":"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.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"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}

引用次数: 0

Synthesis and evaluation of enzyme inhibition by novel TT01001 derivatives as monoamine oxidase B inhibitors.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-02 DOI: 10.1016/j.bmcl.2024.130045

Matheus Barbosa Belchior, Riley T Kane, Jason D Huber, Werner J Geldenhuys

{"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":"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.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"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}

引用次数: 0

Pyrazolo-1-carbothioamides as EGR-1-DNA binding disruptors.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-11-30 DOI: 10.1016/j.bmcl.2024.130055

Hyuk Yoon, Seunghyun Ahn, Dongsoo Koh, Yoongho Lim, Euitaek Jung, Jung Kul Lee, Soon Young Shin

{"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":"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 comparativemolecular field and comparative molecularsimilarity 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.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"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}

引用次数: 0

Brominated chalcones as promising antileishmanial agents

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-11-26 DOI: 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

{"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 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.</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}

引用次数: 0

Discovery of a selective and potent inhibitor of c-Jun N-terminal kinase 1 with anti-pulmonary fibrosis effect

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-11-26 DOI: 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

引用次数: 0

(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.

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-11-26 DOI: 10.1016/j.bmcl.2024.130043

Youngshim Lee, Seunghyun Ahn, Euitaek Jung, Yoongho Lim, Dongsoo Koh, Dong-Ho Bae, Soon Young Shin

{"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":"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.","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":" ","pages":"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}

引用次数: 0