ACS Bio & Med Chem Au最新文献

New Catalytic Residues and Catalytic Mechanism of the RNase T1 Family RNase T1 家族的新催化残基和催化机理

IF 3.8

ACS Bio & Med Chem Au Pub Date : 2024-09-20 DOI: 10.1021/acsbiomedchemau.4c0004610.1021/acsbiomedchemau.4c00046

Katsuki Takebe, Mamoru Suzuki, Yumiko Hara, Takuya Katsutani, Naomi Motoyoshi, Tadashi Itagaki, Shuhei Miyakawa, Kuniaki Okamoto, Kaori Fukuzawa and Hiroko Kobayashi*,

{"title":"New Catalytic Residues and Catalytic Mechanism of the RNase T1 Family","authors":"Katsuki Takebe, Mamoru Suzuki, Yumiko Hara, Takuya Katsutani, Naomi Motoyoshi, Tadashi Itagaki, Shuhei Miyakawa, Kuniaki Okamoto, Kaori Fukuzawa and Hiroko Kobayashi*, ","doi":"10.1021/acsbiomedchemau.4c0004610.1021/acsbiomedchemau.4c00046","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00046https://doi.org/10.1021/acsbiomedchemau.4c00046","url":null,"abstract":"The ribonuclease T1 family, including RNase Po1 secreted by Pleurotus ostreatus, exhibits antitumor activity. Here, we resolved the Po1/guanosine-3′-monophosphate complex (3′GMP) structure at 1.75 Å. Structure comparison and fragment molecular orbital (FMO) calculation between the apo form and the Po1/3′GMP complex identified Phe38, Phe40, and Glu42 as the key binding residues. Two types of the RNase/3′GMP complex in RNasePo1 and RNase T1 were homologous to Po1, and FMO calculations elucidated that the biprotonated histidine on the β3 sheet (His36) on the β3 sheet and deprotonated Glu54 on the β4 sheet were advantageous to RNase activity. Moreover, tyrosine (Tyr34) on the β3 sheet was elucidated as a crucial catalytic residues. Mutation of Tyr34 with phenylalanine decreased RNase activity and diminished antitumor efficacy compared to that in the wild type. This suggests the importance of RNase activity in antitumor mechanisms.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00046","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New Catalytic Residues and Catalytic Mechanism of the RNase T1 Family RNase T1 家族的新催化残基和催化机理

ACS Bio & Med Chem Au Pub Date : 2024-09-20 DOI: 10.1021/acsbiomedchemau.4c00046

Katsuki Takebe, Mamoru Suzuki, Yumiko Hara, Takuya Katsutani, Naomi Motoyoshi, Tadashi Itagaki, Shuhei Miyakawa, Kuniaki Okamoto, Kaori Fukuzawa, Hiroko Kobayashi

引用次数: 0

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors 作为 HIV-1 蛋白酶抑制剂的 Darunavir 类似物的设计、合成和生物学评价

IF 3.8

ACS Bio & Med Chem Au Pub Date : 2024-09-19 DOI: 10.1021/acsbiomedchemau.4c0004010.1021/acsbiomedchemau.4c00040

Muhammad Asad Ur Rehman, Hathaichanok Chuntakaruk, Soraat Amphan, Aphinya Suroengrit, Kowit Hengphasatporn, Yasuteru Shigeta, Thanyada Rungrotmongkol, Kuakarun Krusong, Siwaporn Boonyasuppayakorn, Chanat Aonbangkhen and Tanatorn Khotavivattana*,

{"title":"Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors","authors":"Muhammad Asad Ur Rehman, Hathaichanok Chuntakaruk, Soraat Amphan, Aphinya Suroengrit, Kowit Hengphasatporn, Yasuteru Shigeta, Thanyada Rungrotmongkol, Kuakarun Krusong, Siwaporn Boonyasuppayakorn, Chanat Aonbangkhen and Tanatorn Khotavivattana*, ","doi":"10.1021/acsbiomedchemau.4c0004010.1021/acsbiomedchemau.4c00040","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00040https://doi.org/10.1021/acsbiomedchemau.4c00040","url":null,"abstract":"Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1′ and P2′, to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2′ substitution was found to be effective, as seen in 5aa (1.54 nM), 5ad (0.71 nM), 5ac (0.31 nM), 5ae (0.28 nM), and 5af (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly 5ae, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2′ subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors 作为 HIV-1 蛋白酶抑制剂的 Darunavir 类似物的设计、合成和生物学评价

ACS Bio & Med Chem Au Pub Date : 2024-09-19 DOI: 10.1021/acsbiomedchemau.4c00040

Muhammad Asad Ur Rehman, Hathaichanok Chuntakaruk, Soraat Amphan, Aphinya Suroengrit, Kowit Hengphasatporn, Yasuteru Shigeta, Thanyada Rungrotmongkol, Kuakarun Krusong, Siwaporn Boonyasuppayakorn, Chanat Aonbangkhen, Tanatorn Khotavivattana

{"title":"Design, Synthesis, and Biological Evaluation of Darunavir Analogs as HIV-1 Protease Inhibitors","authors":"Muhammad Asad Ur Rehman, Hathaichanok Chuntakaruk, Soraat Amphan, Aphinya Suroengrit, Kowit Hengphasatporn, Yasuteru Shigeta, Thanyada Rungrotmongkol, Kuakarun Krusong, Siwaporn Boonyasuppayakorn, Chanat Aonbangkhen, Tanatorn Khotavivattana","doi":"10.1021/acsbiomedchemau.4c00040","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00040","url":null,"abstract":"Darunavir, a frontline treatment for HIV infection, faces limitations due to emerging multidrug resistant (MDR) HIV strains, necessitating the development of analogs with improved activity. In this study, a combinatorial in silico approach was used to initially design a series of HIV-1 PI analogs with modifications at key sites, P1′ and P2′, to enhance interactions with HIV-1 PR. Fifteen analogs with promising binding scores were selected for synthesis and evaluated for the HIV-1 PR inhibition activity. The variation of P2′ substitution was found to be effective, as seen in 5aa (1.54 nM), 5ad (0.71 nM), 5ac (0.31 nM), 5ae (0.28 nM), and 5af (1.12 nM), featuring halogen, aliphatic, and alkoxy functionalities on the phenyl sulfoxide motif exhibited superior inhibition against HIV-1 PR compared to DRV, with minimal cytotoxicity observed in Vero and 293T cell lines. Moreover, computational studies demonstrated the potential of selected analogs to inhibit various HIV-1 PR mutations, including I54M and I84V. Further structural dynamics and energetic analyses confirmed the stability and binding affinity of promising analogs, particularly 5ae, which showed strong interactions with key residues in HIV-1 PR. Overall, this study underscores the importance of flexible moieties and interaction enhancement at the S2′ subsite of HIV-1 PR in developing effective DRV analogs to combat HIV and other global health issues.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142257770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Directed Evolution of Candidatus Methanomethylophilus alvus Pyrrolysyl-tRNA Synthetase for the Genetic Incorporation of Two Different Noncanonical Amino Acids in One Protein 嗜甲烷甲酵母菌（Candidatus Methanomethylophilus alvus）吡咯氨酰-tRNA 合成酶的定向进化，在一个蛋白质中遗传性地加入两种不同的非顺式氨基酸

ACS Bio & Med Chem Au Pub Date : 2024-08-22 DOI: 10.1021/acsbiomedchemau.4c00028

Chia-Chuan D. Cho, Waye Michelle Leeuwon, Wenshe Ray Liu

{"title":"Directed Evolution of Candidatus Methanomethylophilus alvus Pyrrolysyl-tRNA Synthetase for the Genetic Incorporation of Two Different Noncanonical Amino Acids in One Protein","authors":"Chia-Chuan D. Cho, Waye Michelle Leeuwon, Wenshe Ray Liu","doi":"10.1021/acsbiomedchemau.4c00028","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00028","url":null,"abstract":"The genetic code expansion technique is a powerful chemical biology tool to install noncanonical amino acids (ncAAs) in proteins. As a key enzyme for this technique, pyrrolysyl-tRNA synthetase (PylRS), coupled with its cognate amber suppressor tRNAPyl, has been engineered for the genetic incorporation of more than 200 ncAAs. Using PylRS clones from different archaeal origins, two ncAAs have also been genetically encoded in one protein. In this work, we show that the C41AU mutant of tRNAPyl from Candidatus Methanomethylophilus alvus (CmatRNAPyl) is catalytically inert toward PylRS from Methanosarcina mazei (MmPylRS) but has weak activity toward PylRS from Ca. M. alvus (CmaPylRS). To improve the catalytic efficiency of CmaPylRS toward CmatRNAPyl-C41AU, we conducted a directed evolution of CMaPylRS by randomizing its coding sequence, followed by the screening of active mutant clones. After three rounds of randomization and screening, we identified 4 mutations, Y16F/N57D/E161G/N182I, that improve the catalytic efficiency of CMaPylRS toward CMatRNAPyl-C41AU. This new clone, named R3–14, coupling with CmatRNAPyl-C41AU to recognize an amber codon, has been successfully used together with an evolved MmPylRS clone, coupling with a mutant M. mazei tRNAPyl to recognize an ochre codon, to genetically incorporate two different ncAAs, Nε-(t-butoxycarbonyl)-lysine and Nε-acetyl-lysine, into one model protein.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142204333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Directed Evolution of Candidatus Methanomethylophilus alvus Pyrrolysyl-tRNA Synthetase for the Genetic Incorporation of Two Different Noncanonical Amino Acids in One Protein 嗜甲烷甲酵母菌（Candidatus Methanomethylophilus alvus）吡咯氨酰-tRNA 合成酶的定向进化，在一个蛋白质中遗传性地加入两种不同的非顺式氨基酸

IF 3.8

ACS Bio & Med Chem Au Pub Date : 2024-08-22 DOI: 10.1021/acsbiomedchemau.4c0002810.1021/acsbiomedchemau.4c00028

Chia-Chuan D. Cho, Waye Michelle Leeuwon and Wenshe Ray Liu*,

{"title":"Directed Evolution of Candidatus Methanomethylophilus alvus Pyrrolysyl-tRNA Synthetase for the Genetic Incorporation of Two Different Noncanonical Amino Acids in One Protein","authors":"Chia-Chuan D. Cho, Waye Michelle Leeuwon and Wenshe Ray Liu*, ","doi":"10.1021/acsbiomedchemau.4c0002810.1021/acsbiomedchemau.4c00028","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00028https://doi.org/10.1021/acsbiomedchemau.4c00028","url":null,"abstract":"The genetic code expansion technique is a powerful chemical biology tool to install noncanonical amino acids (ncAAs) in proteins. As a key enzyme for this technique, pyrrolysyl-tRNA synthetase (PylRS), coupled with its cognate amber suppressor tRNAPyl, has been engineered for the genetic incorporation of more than 200 ncAAs. Using PylRS clones from different archaeal origins, two ncAAs have also been genetically encoded in one protein. In this work, we show that the C41AU mutant of tRNAPyl from Candidatus Methanomethylophilus alvus (CmatRNAPyl) is catalytically inert toward PylRS from Methanosarcina mazei (MmPylRS) but has weak activity toward PylRS from Ca. M. alvus (CmaPylRS). To improve the catalytic efficiency of CmaPylRS toward CmatRNAPyl-C41AU, we conducted a directed evolution of CMaPylRS by randomizing its coding sequence, followed by the screening of active mutant clones. After three rounds of randomization and screening, we identified 4 mutations, Y16F/N57D/E161G/N182I, that improve the catalytic efficiency of CMaPylRS toward CMatRNAPyl-C41AU. This new clone, named R3–14, coupling with CmatRNAPyl-C41AU to recognize an amber codon, has been successfully used together with an evolved MmPylRS clone, coupling with a mutant M. mazei tRNAPyl to recognize an ochre codon, to genetically incorporate two different ncAAs, Nε-(t-butoxycarbonyl)-lysine and Nε-acetyl-lysine, into one model protein.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a Polymersome Blood Ammonia Assay Coupled with a Portable Near-Infrared Fluorometer 开发与便携式近红外荧光测定仪相结合的聚合体血氨测定法

IF 3.8

ACS Bio & Med Chem Au Pub Date : 2024-07-30 DOI: 10.1021/acsbiomedchemau.4c0001310.1021/acsbiomedchemau.4c00013

Marie-Lynn Al-Hawat, Justine Caron, Sarah Djebbar and Simon Matoori*,

{"title":"Development of a Polymersome Blood Ammonia Assay Coupled with a Portable Near-Infrared Fluorometer","authors":"Marie-Lynn Al-Hawat, Justine Caron, Sarah Djebbar and Simon Matoori*, ","doi":"10.1021/acsbiomedchemau.4c0001310.1021/acsbiomedchemau.4c00013","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00013https://doi.org/10.1021/acsbiomedchemau.4c00013","url":null,"abstract":"Ammonia is a key biomarker in inborn and acquired liver disease. As clinical point-of-care blood ammonia assays are lacking, we developed a polymersome formulation for point-of-care blood ammonia sensing combined with a portable fluorometer. A pH-sensitive near-infrared (NIR) fluorescent dye was identified, which showed a strong fluorescence increase at acidic pH values. Building on reports on ammonia-selective PS-b-PEG polymersomes, these polymersomes were loaded with the NIR dye. These NIR fluorescent polymersomes sensed ammonia in a clinically relevant range in ammonia-spiked fresh whole blood with high linearity (R2 = 0.9948) after 5 min using a conventional tabletop plate reader. Subsequently, the assay was tested with a portable fluorometer. An ammonia-dependent fluorescence increase was detected in ammonia-spiked fresh mouse blood after 5 min using the portable fluorometer. The NIR dye-loaded PS-b-PEG polymersomes rapidly sensed ammonia with high linearity in whole blood. This assay was successfully combined with a portable fluorometer and only required 3 μL of blood. These findings motivate a further development and clinical translation of this point-of-care blood ammonia assay.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a Polymersome Blood Ammonia Assay Coupled with a Portable Near-Infrared Fluorometer 开发与便携式近红外荧光测定仪相结合的聚合体血氨测定法

ACS Bio & Med Chem Au Pub Date : 2024-07-30 DOI: 10.1021/acsbiomedchemau.4c00013

Marie-Lynn Al-Hawat, Justine Caron, Sarah Djebbar, Simon Matoori

{"title":"Development of a Polymersome Blood Ammonia Assay Coupled with a Portable Near-Infrared Fluorometer","authors":"Marie-Lynn Al-Hawat, Justine Caron, Sarah Djebbar, Simon Matoori","doi":"10.1021/acsbiomedchemau.4c00013","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00013","url":null,"abstract":"Ammonia is a key biomarker in inborn and acquired liver disease. As clinical point-of-care blood ammonia assays are lacking, we developed a polymersome formulation for point-of-care blood ammonia sensing combined with a portable fluorometer. A pH-sensitive near-infrared (NIR) fluorescent dye was identified, which showed a strong fluorescence increase at acidic pH values. Building on reports on ammonia-selective PS-b-PEG polymersomes, these polymersomes were loaded with the NIR dye. These NIR fluorescent polymersomes sensed ammonia in a clinically relevant range in ammonia-spiked fresh whole blood with high linearity (R2 = 0.9948) after 5 min using a conventional tabletop plate reader. Subsequently, the assay was tested with a portable fluorometer. An ammonia-dependent fluorescence increase was detected in ammonia-spiked fresh mouse blood after 5 min using the portable fluorometer. The NIR dye-loaded PS-b-PEG polymersomes rapidly sensed ammonia with high linearity in whole blood. This assay was successfully combined with a portable fluorometer and only required 3 μL of blood. These findings motivate a further development and clinical translation of this point-of-care blood ammonia assay.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141870566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses Selagibenzophenone B 及其衍生物：通过体外和硅学分析发现的拓扑异构酶 I/II 双重抑制剂 SelB-1

IF 3.8

ACS Bio & Med Chem Au Pub Date : 2024-07-26 DOI: 10.1021/acsbiomedchemau.4c0002710.1021/acsbiomedchemau.4c00027

Serhat Dönmez, Ringaile Lapinskaite, Hazal Nazlican Atalay, Esra Tokay, Feray Kockar, Lukas Rycek*, Mehmet Özbil* and Tugba Boyunegmez Tumer*,

{"title":"Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses","authors":"Serhat Dönmez, Ringaile Lapinskaite, Hazal Nazlican Atalay, Esra Tokay, Feray Kockar, Lukas Rycek*, Mehmet Özbil* and Tugba Boyunegmez Tumer*, ","doi":"10.1021/acsbiomedchemau.4c0002710.1021/acsbiomedchemau.4c00027","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00027https://doi.org/10.1021/acsbiomedchemau.4c00027","url":null,"abstract":"The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, SelB-1 selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, SelB-1 showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound’s strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, SelB-1 did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that SelB-1 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142011011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses Selagibenzophenone B 及其衍生物：通过体外和硅学分析发现的拓扑异构酶 I/II 双重抑制剂 SelB-1

ACS Bio & Med Chem Au Pub Date : 2024-07-26 DOI: 10.1021/acsbiomedchemau.4c00027

Serhat Dönmez, Ringaile Lapinskaite, Hazal Nazlican Atalay, Esra Tokay, Feray Kockar, Lukas Rycek, Mehmet Özbil, Tugba Boyunegmez Tumer

{"title":"Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses","authors":"Serhat Dönmez, Ringaile Lapinskaite, Hazal Nazlican Atalay, Esra Tokay, Feray Kockar, Lukas Rycek, Mehmet Özbil, Tugba Boyunegmez Tumer","doi":"10.1021/acsbiomedchemau.4c00027","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00027","url":null,"abstract":"The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, SelB-1 selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, SelB-1 showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound’s strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, SelB-1 did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that SelB-1 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0