Pub Date : 2024-06-21DOI: 10.1016/j.bmcl.2024.129843
Minsun Chang , Sung-Hak Lee , Ho Jun Kim , Jong-Sung Koh , Aeri Kim
{"title":"Retraction notice to “Corrigendum to “Preclinical metabolism of LB42908, a novel farnesyl transferase inhibitor, and its effects on the cytochrome P450 isozyme activities” [Bioorg. Med. Chem. Lett. 22 (2012), 3067–3071]” [Bioorg. Med. Chem. Lett. 24 (2014) 1862]","authors":"Minsun Chang , Sung-Hak Lee , Ho Jun Kim , Jong-Sung Koh , Aeri Kim","doi":"10.1016/j.bmcl.2024.129843","DOIUrl":"https://doi.org/10.1016/j.bmcl.2024.129843","url":null,"abstract":"","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0960894X24002452/pdfft?md5=bfd84a171d334d912114a6a159af379b&pid=1-s2.0-S0960894X24002452-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141483149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-21DOI: 10.1016/j.bmcl.2024.129857
Hiroaki Matoba , Kouhei Oba , Huanlin Li , Yuta Mizuno , Qianqian Wang , Makoto Yoritate , Mariko Aso , Mikiko Sodeoka , Minoru Yoshida , Yoko Yashiroda , Go Hirai
We have synthesized 10 analogs of oxylipins, which are nitrogen signaling factors (NSFs) that mediate cell-to-cell communication in the fission yeast Schizosaccharomyces pombe, and evaluated their structure–activity relationships with the aim of developing molecular probes for NSFs. We found that the OH or OAc group at C10 could be replaced with a compact amide (17) or carbamate (19). Introducing an alkyne as a detection tag at C10 led to decreased, though still sufficient, activity. Introducing an alkyne at the C18 position showed a similar trend, suggesting tolerance is relatively low even for compact functional groups such as alkynes. Although introduction of a diazirine moiety as a photoreactive group at the C5 position decreased the activity, we found that introducing diazirine at the C13 position was acceptable, and compound 38 exhibited potent NSF activity. These findings will be helpful in the development of molecular probes for NSFs.
{"title":"Structure–activity relationship study of nitrogen signaling factors","authors":"Hiroaki Matoba , Kouhei Oba , Huanlin Li , Yuta Mizuno , Qianqian Wang , Makoto Yoritate , Mariko Aso , Mikiko Sodeoka , Minoru Yoshida , Yoko Yashiroda , Go Hirai","doi":"10.1016/j.bmcl.2024.129857","DOIUrl":"10.1016/j.bmcl.2024.129857","url":null,"abstract":"<div><p>We have synthesized 10 analogs of oxylipins, which are nitrogen signaling factors (NSFs) that mediate cell-to-cell communication in the fission yeast <em>Schizosaccharomyces pombe</em>, and evaluated their structure–activity relationships with the aim of developing molecular probes for NSFs. We found that the OH or OAc group at C10 could be replaced with a compact amide (<strong>17</strong>) or carbamate (<strong>19</strong>). Introducing an alkyne as a detection tag at C10 led to decreased, though still sufficient, activity. Introducing an alkyne at the C18 position showed a similar trend, suggesting tolerance is relatively low even for compact functional groups such as alkynes. Although introduction of a diazirine moiety as a photoreactive group at the C5 position decreased the activity, we found that introducing diazirine at the C13 position was acceptable, and compound <strong>38</strong> exhibited potent NSF activity. These findings will be helpful in the development of molecular probes for NSFs.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141441864","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 : 2024-06-21DOI: 10.1016/j.bmcl.2024.129853
Mary Sravani Galla , Nandini B. Kale , Anamika Sharma , Aditya Hajare , Chandraiah Godugu , Nagula Shankaraiah
Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC50 concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC50 of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.
{"title":"Development of chromone-thiazolidine-2,4-dione Knoevenagel conjugates as apoptosis inducing agents","authors":"Mary Sravani Galla , Nandini B. Kale , Anamika Sharma , Aditya Hajare , Chandraiah Godugu , Nagula Shankaraiah","doi":"10.1016/j.bmcl.2024.129853","DOIUrl":"10.1016/j.bmcl.2024.129853","url":null,"abstract":"<div><p>Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on <em>in vitro</em> cancer cell lines revealed the presence of compounds <strong>8a</strong>, <strong>8k</strong>, <strong>8l</strong>, and <strong>8n</strong>, which were found to have good to moderate anti-proliferative activity (with an IC<sub>50</sub> concentration less than 10 µM). Among them, <strong>8l</strong> depicted the highest cytotoxicity on the A549 cell line with an IC<sub>50</sub> of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of <strong>8l</strong>, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound <strong>8l</strong> reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141441863","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 : 2024-06-20DOI: 10.1016/j.bmcl.2024.129855
Yutong Chen , Kazumitsu Onizuka , Fumi Nagatsugi
The role of G-quadruplex (G4) in cellular processes can be investigated by the covalent modification of G4-DNA using alkylating reagents. Controllable alkylating reagents activated by external stimuli can react elegantly and selectively. Herein, we report a chemical activation system that can significantly boost the reaction rate of methylamine-protected vinyl-quinazolinone (VQ) derivative for the alkylation of G4‐DNA. The two screened activators can transform low-reactive VQ-NHR’ to highly reactive intermediates following the Michael addition mechanism. This approach expands the toolbox of activable G4 alkylating reagents.
{"title":"Michael addition-activated alkylation of G-quadruplex DNA with methylamine-protected vinyl-quinazolinone derivatives","authors":"Yutong Chen , Kazumitsu Onizuka , Fumi Nagatsugi","doi":"10.1016/j.bmcl.2024.129855","DOIUrl":"10.1016/j.bmcl.2024.129855","url":null,"abstract":"<div><p>The role of G-quadruplex (G4) in cellular processes can be investigated by the covalent modification of G4-DNA using alkylating reagents. Controllable alkylating reagents activated by external stimuli can react elegantly and selectively. Herein, we report a chemical activation system that can significantly boost the reaction rate of methylamine-protected vinyl-quinazolinone (VQ) derivative for the alkylation of G4‐DNA. The two screened activators can transform low-reactive VQ-NHR’ to highly reactive intermediates following the Michael addition mechanism. This approach expands the toolbox of activable G4 alkylating reagents.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141440079","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}
Alzheimer’s disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure–activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (2, IC50 = 1.22 μM), although the potency was increased by 2′ substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (2, IC50 = 0.0021 μM), and the electron-withdrawing group and 2′ and 3′ substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds 14–35 revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R2). Increasing the linker length and introduction of a methoxy group (R2) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of 33 and 24 with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.
{"title":"Structure-activity relationship of dual inhibitors containing maleimide and imidazole motifs against glutaminyl cyclase and glycogen synthase kinase-3β","authors":"Dingjun Wei , Jiaxin Cai , Feixia Qin , Qingqing Zhou , Wei Xiong , Chenshu Xu , Chenyang Li , Haiqiang Wu","doi":"10.1016/j.bmcl.2024.129851","DOIUrl":"10.1016/j.bmcl.2024.129851","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a major cause of dementia and one of the most common chronic diseases affecting the aging population. Because AD is considered a public health priority, there is a critical need to discover novel and effective agents for the treatment of this condition. In view of the known contribution of up-regulated glutaminyl cyclase (QC) and glycogen synthase kinase-3β (GSK-3β) to the initiation of AD, we previously evaluated a series of dual inhibitors containing maleimide and imidazole motifs as potential anti-AD agents. Here, we assessed another series of hybrids containing maleimide and imidazole motifs to gain an in-depth understanding of the structure–activity relationship (SAR). Based on the primary screening, the introduction of 5-methyl imidazole at one side of the molecule did not enhance the QC-specific inhibitory activity of these hybrids (<strong>2</strong>, IC<sub>50</sub> = 1.22 μM), although the potency was increased by 2′ substitution on the maleimide motif at the other side of the molecule. Interestingly, compounds containing 5-methyl imidazole exhibited stronger GSK-3β-specific inhibitory activity (<strong>2</strong>, IC<sub>50</sub> = 0.0021 μM), and the electron-withdrawing group and 2′ and 3′ substitution were favorable. Further investigation of substitutions on the maleimide motif in compounds <strong>14</strong>–<strong>35</strong> revealed that QC-specific inhibition in the presence of piperidine was improved by introduction of a methoxy group (R<sup>2</sup>). Increasing the linker length and introduction of a methoxy group (R<sup>2</sup>) also increased the GSK-3β-specific inhibitory potency. These findings were further confirmed by molecular docking analysis of <strong>33</strong> and <strong>24</strong> with QC and GSK-3β. Overall, these hybrids exhibited enhanced inhibitory potency against both QC and GSK-3β, highlighting an important strategy for improving the potency of hybrids as dual-targeting anti-AD agents.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436477","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}
For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine 11 drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine 10. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid–gemcitabine conjugate 16 was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.
{"title":"Cysteinylprolyl ester-mediated drug release from a lipid–drug conjugate","authors":"Takashi Tsuji, Hayato Inazuki, Daishiro Kobayashi, Junya Hayashi, Masaya Denda, Akira Otaka","doi":"10.1016/j.bmcl.2024.129850","DOIUrl":"10.1016/j.bmcl.2024.129850","url":null,"abstract":"<div><p>For small-molecule drugs, lipidation via a cleavable linkage can extend half-life in circulation through interaction with albumin. Here we modified the cysteinylprolyl ester (CPE) system used in peptide thioester synthesis, which normally requires basic conditions, for use as an self-immolative linker and release device for a lipid-gemcitabine conjugate. To improve release under physiological conditions for medical application, a methyl group at the α-position of cysteine on the CPE unit was incorporated in anticipation of the Thorpe-Ingold effect. As a result, Ac-Gly-(α-Me)Cys(SH)-Pro-gemcitabine <strong>11</strong> drastically promoted the release of gemcitabine in comparison with Ac-Gly-Cys(SH)-Pro-gemcitabine <strong>10</strong>. Furthermore, in the presence of bovine serum albumin and/or 2-mercaptoethanesulfonic acid, the gentle and continuous release of gemcitabine from the lipid–gemcitabine conjugate <strong>16</strong> was achieved. In addition to gemcitabine, this method could allow high clearance drugs, including nucleic acid and prostacyclin derivatives, to maintain their biological activity long enough to become effective.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326975","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}
Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.
{"title":"Discovery of a potent orally available pyrazolopyridone derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor","authors":"Shuichi Hagihara, Kouhei Ishizawa, Kana Soga, Takashi Honjo, Shigeki Takai, Yuko Kawano, Manami Kikuchi, Akiko Nishidate, Fumi Matsumoto, Mikako Murase, Naohiro Hashimoto, Chiduko Sasaki, Ikuko Miyaguchi, Okimasa Okada, Tomoya Akashi, Shinji Nakayama, Yuko Ogasawara, Junichi Endo","doi":"10.1016/j.bmcl.2024.129849","DOIUrl":"10.1016/j.bmcl.2024.129849","url":null,"abstract":"<div><p>Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative <strong>13a</strong>, and confirmed its in vivo efficacy.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320121","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}
We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors.
This study identified furopyridine derivatives 7 and 8 with high BD1 inhibitory activity and high selectivity over BD2. Compound 7 was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.
我们采用表型药物发现策略,以 T 细胞中的成本刺激分子为重点,探索具有免疫耐受的新型免疫抑制剂,并获得了三唑硫氮杂卓衍生物。它们的作用机制是抑制溴结构域和末端外结构域(BET)家族,正如我们之前所报道的那样。选择性抑制 BET 家族的第一个溴结构域(BD1)有望发挥与 BET 抑制剂类似的抗肿瘤和免疫抑制作用。本研究发现呋喃吡啶衍生物 7 和 8 具有很高的 BD1 抑制活性和对 BD2 的高选择性。化合物 7 具有口服生物利用度,并在脂多糖诱导模型中表现出抗炎活性。
{"title":"Discovery of a potent, orally available furopyridine derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor","authors":"Shuichi Hagihara, Kouhei Ishizawa, Manami Kikuchi, Yuko Kawano, Akiko Nishidate, Fumi Matsumoto, Naohiro Hashimoto, Chiduko Sasaki, Ikuko Miyaguchi, Okimasa Okada, Tomoya Akashi, Shinji Nakayama, Yuko Ogasawara, Junichi Endo","doi":"10.1016/j.bmcl.2024.129848","DOIUrl":"10.1016/j.bmcl.2024.129848","url":null,"abstract":"<div><p>We explored novel immunosuppressive agents with immune tolerance using a phenotypic drug discovery strategy, focusing on costimulatory molecules in T cells, and obtained triazolothienodiazepine derivatives. Their mechanism of action is to inhibit the bromodomain and extra-terminal domain (BET) family, as we have previously reported. Selective inhibition of the first bromodomain (BD1) of the BET family is expected to exert antitumor and immunosuppressive effects, similar to BET inhibitors.</p><p>This study identified furopyridine derivatives <strong>7</strong> and <strong>8</strong> with high BD1 inhibitory activity and high selectivity over BD2. Compound <strong>7</strong> was found to be orally bioavailable and exhibited anti-inflammatory activity in a lipopolysaccharide-induced model.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141320122","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 : 2024-06-09DOI: 10.1016/j.bmcl.2024.129847
Xiaoqian Chen , Yuyang Guo , Rui Wang
2′-5′-Adenosine linked nucleic acids are crucial components in living cells that play significant roles, including participating in antiviral defense mechanisms by facilitating the breakdown of viral genetic material. In this report, we present a chemical derivatization method employing 5-fluoro-2-pyridinoyl-imidazole as the acylation agent, a strategy that can be effectively combined with advanced analytical tools, including Nuclear Magnetic Resonance spectroscopy and Liquid Chromatography-Mass Spectrometry, to enhance the characterization and detection capabilities. This marks the first instance of a simple method designed to detect 2′-5′-adenosine linked nucleic acids. The new method is characterized by its time-saving nature, simplicity, and relative accuracy compared to previous methods.
{"title":"Detecting 2′-5′-adenosine linked nucleic acids via acylation of secondary hydroxy functionality","authors":"Xiaoqian Chen , Yuyang Guo , Rui Wang","doi":"10.1016/j.bmcl.2024.129847","DOIUrl":"10.1016/j.bmcl.2024.129847","url":null,"abstract":"<div><p>2′-5′-Adenosine linked nucleic acids are crucial components in living cells that play significant roles, including participating in antiviral defense mechanisms by facilitating the breakdown of viral genetic material. In this report, we present a chemical derivatization method employing 5-fluoro-2-pyridinoyl-imidazole as the acylation agent, a strategy that can be effectively combined with advanced analytical tools, including Nuclear Magnetic Resonance spectroscopy and Liquid Chromatography-Mass Spectrometry, to enhance the characterization and detection capabilities. This marks the first instance of a simple method designed to detect 2′-5′-adenosine linked nucleic acids. The new method is characterized by its time-saving nature, simplicity, and relative accuracy compared to previous methods.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299617","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 : 2024-06-08DOI: 10.1016/j.bmcl.2024.129846
Baji Baba Shaik , Rajshekhar Karpoormath
Over the past 2000 years, tuberculosis (TB) has been responsible for more deaths than any other infectious disease. In recent years, there has been a recovery of research and development (R&D) efforts focused on TB drugs. This is driven by the pressing need to combat the global spread of the disease and develop improved therapies for both drug-sensitive and drug-resistant strains. Many new TB drug candidates have recently entered clinical trials, marking the beginning of a rebirth in this area after decades of neglect. The problem is that very few of the hundreds of compounds identified each year as potential anti-TB drugs really make it to the clinical development stage. This perspective focuses on the primary obstacles and approaches involved in the development of new medications for TB. This will help medicinal chemists better understand TB drug challenges and develop novel drug candidates.
{"title":"Key challenges in TB drug discovery: A perspective","authors":"Baji Baba Shaik , Rajshekhar Karpoormath","doi":"10.1016/j.bmcl.2024.129846","DOIUrl":"10.1016/j.bmcl.2024.129846","url":null,"abstract":"<div><p>Over the past 2000 years, tuberculosis (TB) has been responsible for more deaths than any other infectious disease. In recent years, there has been a recovery of research and development (R&D) efforts focused on TB drugs. This is driven by the pressing need to combat the global spread of the disease and develop improved therapies for both drug-sensitive and drug-resistant strains. Many new TB drug candidates have recently entered clinical trials, marking the beginning of a rebirth in this area after decades of neglect. The problem is that very few of the hundreds of compounds identified each year as potential anti-TB drugs really make it to the clinical development stage. This perspective focuses on the primary obstacles and approaches involved in the development of new medications for TB. This will help medicinal chemists better understand TB drug challenges and develop novel drug candidates.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2024-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141299618","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}