Pub Date : 2024-07-27DOI: 10.1016/j.bmc.2024.117863
We designed and synthesized two novel photocaged peroxide compounds, N5TBHP and N6TBHP, featuring nitrogen-containing fused ring coumarin skeletons. Notably, a tetrahydroquinoline fused coumarin derivative, N6TBHP demonstrated significantly higher photocleavage efficiency under visible light at 455 nm compared to N5TBHP, which contains an indoline fused coumarin. This process effectively releases the oxidative stress inducer tert-butylhydroperoxide (TBHP). Additionally, N6TBHP exhibits high resistance to glutathione (GSH), and its UV spectral analysis suggests enhanced intracellular stability due to reduced reactivity with GSH through self-assembly. Furthermore, N6TBHP can release an optimal amount of TBHP into cells under visible light irradiation with minimal cell damage. These properties position N6TBHP as a promising tool for advancing research in intracellular redox signaling.
{"title":"Design and synthesis of visible light-activatable photocaged peroxides for optical control of ROS-mediated cellular signaling","authors":"","doi":"10.1016/j.bmc.2024.117863","DOIUrl":"10.1016/j.bmc.2024.117863","url":null,"abstract":"<div><p>We designed and synthesized two novel photocaged peroxide compounds, <strong>N5TBHP</strong> and <strong>N6TBHP</strong>, featuring nitrogen-containing fused ring coumarin skeletons. Notably, a tetrahydroquinoline fused coumarin derivative, <strong>N6TBHP</strong> demonstrated significantly higher photocleavage efficiency under visible light at 455 nm compared to <strong>N5TBHP</strong>, which contains an indoline fused coumarin. This process effectively releases the oxidative stress inducer <em>tert</em>-butylhydroperoxide (TBHP). Additionally, <strong>N6TBHP</strong> exhibits high resistance to glutathione (GSH), and its UV spectral analysis suggests enhanced intracellular stability due to reduced reactivity with GSH through self-assembly. Furthermore, <strong>N6TBHP</strong> can release an optimal amount of TBHP into cells under visible light irradiation with minimal cell damage. These properties position <strong>N6TBHP</strong> as a promising tool for advancing research in intracellular redox signaling.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141839323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-24DOI: 10.1016/j.bmc.2024.117849
The search for new agents targeting different forms of cell death is an important research focus for developing new and potent antitumor therapies. As a contribution to this endeavor, we have designed and synthesized a series of new substituted 3,4-dihydro-2H-1,4-benzoxazine derivatives. These compounds have been evaluated for their efficacy against MCF-7 breast cancer and HCT-116 colon cancer cell lines. Overall, substituting this heterocycle led to improved antiproliferative activity compared to the unsubstituted derivative 1. The most active compounds, 2b and 4b, showed IC50 values of 2.27 and 3.26 μM against MCF-7 cells and 4.44 and 7.63 μM against HCT-116 cells, respectively. To investigate the mechanism of action of the target compounds, the inhibition profile of 8 kinases involved in cell signaling was studied highlighting residual activity on HER2 and JNK1 kinases. 2b and 4b showed a consistent binding mode to both receptor kinases, establishing significant interactions with known and catalytically important domains and residues. Compounds 2b and 4b exhibit potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. This dual capability increases their versatility in the treatment of different stages or types of tumors, providing greater flexibility in clinical applications.
{"title":"New substituted benzoxazine derivatives as potent inducers of membrane permeability and cell death","authors":"","doi":"10.1016/j.bmc.2024.117849","DOIUrl":"10.1016/j.bmc.2024.117849","url":null,"abstract":"<div><p>The search for new agents targeting different forms of cell death is an important research focus for developing new and potent antitumor therapies. As a contribution to this endeavor, we have designed and synthesized a series of new substituted 3,4-dihydro-2<em>H</em>-1,4-benzoxazine derivatives. These compounds have been evaluated for their efficacy against MCF-7 breast cancer and HCT-116 colon cancer cell lines. Overall, substituting this heterocycle led to improved antiproliferative activity compared to the unsubstituted derivative <strong>1</strong>. The most active compounds, <strong>2b</strong> and <strong>4b</strong>, showed IC<sub>50</sub> values of 2.27 and 3.26 μM against MCF-7 cells and 4.44 and 7.63 μM against HCT-116 cells, respectively. To investigate the mechanism of action of the target compounds, the inhibition profile of 8 kinases involved in cell signaling was studied highlighting residual activity on HER2 and JNK1 kinases. <strong>2b</strong> and <strong>4b</strong> showed a consistent binding mode to both receptor kinases, establishing significant interactions with known and catalytically important domains and residues. Compounds <strong>2b</strong> and <strong>4b</strong> exhibit potent cytotoxic activity by disrupting cell membrane permeability, likely triggering both inflammatory and non-inflammatory cell death mechanisms. This dual capability increases their versatility in the treatment of different stages or types of tumors, providing greater flexibility in clinical applications.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002633/pdfft?md5=957c129ae6a4438866f1d600c96a9e3b&pid=1-s2.0-S0968089624002633-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-24DOI: 10.1016/j.bmc.2024.117835
Achieving effective intracellular delivery of therapeutic molecules such as antibodies (IgG) is a challenge in biomedical research and pharmaceutical development. Conjugation of IgG with a cell-penetrating peptide is a rational approach. Here, not only the efficacy of the conjugates in internalizing into cells, but also the physicochemical property of the conjugates allowing their solubilized states in solution without forming aggregates are critical. In this study, we have shown that the first requirement can be addressed using a cell-permeable attenuated cationic amphiphilic lytic (CP-ACAL) peptide, L17ER4. The second requirement can be addressed by ligation of IgG to L17ER4 using sortase A, where the use of a linker of appropriate chain length is also important. For evaluation, the intracellular delivery efficacy was studied using conjugate structures with different orientations and conjugation modes of L17ER4 in ligation to a model protein, green fluorescent protein fused to a nuclear localization signal (NLS-EGFP). The effect of tetraarginine positioning in the L17ER4 sequence was also investigated. Following these studies, an optimized peptide sequence containing L17ER4 was ligated to an anti-green fluorescent protein (GFP) IgG bearing a sortase A recognition sequence. Treatment of the cells with the conjugate of anti-GFP IgG and L17ER4 resulted in a high efficiency of cytosolic translocation of the conjugate and the binding to the target protein in the cell without significant aggregate formation. The feasibility of the d-form of L17ER4 as a CP-ACAL was also confirmed.
{"title":"An approach for the intracellular delivery of IgG via enzymatic ligation with a cell-permeable attenuated cationic amphiphilic lytic peptide","authors":"","doi":"10.1016/j.bmc.2024.117835","DOIUrl":"10.1016/j.bmc.2024.117835","url":null,"abstract":"<div><p>Achieving effective intracellular delivery of therapeutic molecules such as antibodies (IgG) is a challenge in biomedical research and pharmaceutical development. Conjugation of IgG with a cell-penetrating peptide is a rational approach. Here, not only the efficacy of the conjugates in internalizing into cells, but also the physicochemical property of the conjugates allowing their solubilized states in solution without forming aggregates are critical. In this study, we have shown that the first requirement can be addressed using a cell-permeable attenuated cationic amphiphilic lytic (CP-ACAL) peptide, L17ER4. The second requirement can be addressed by ligation of IgG to L17ER4 using sortase A, where the use of a linker of appropriate chain length is also important. For evaluation, the intracellular delivery efficacy was studied using conjugate structures with different orientations and conjugation modes of L17ER4 in ligation to a model protein, green fluorescent protein fused to a nuclear localization signal (NLS-EGFP). The effect of tetraarginine positioning in the L17ER4 sequence was also investigated. Following these studies, an optimized peptide sequence containing L17ER4 was ligated to an anti-green fluorescent protein (GFP) IgG bearing a sortase A recognition sequence. Treatment of the cells with the conjugate of anti-GFP IgG and L17ER4 resulted in a high efficiency of cytosolic translocation of the conjugate and the binding to the target protein in the cell without significant aggregate formation. The feasibility of the <span>d</span>-form of L17ER4 as a CP-ACAL was also confirmed.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002499/pdfft?md5=a143563ceffb0c6b7397c18bc5104b8f&pid=1-s2.0-S0968089624002499-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-23DOI: 10.1016/j.bmc.2024.117856
Mitochondrial G-quadruplexes are components that are potentially involved in regulating mitochondrial function and play crucial roles in the replication and transcription of mitochondrial genes. Consequently, it is imperative to develop probes that can detect mitochondrial G-quadruplexes to understand their functions and mechanisms. In this study, a triphenylamine fluorescent probe, TPPE, which has excellent cytocompatibility and does not affect the natural state of G-quadruplexes, was designed and demonstrated to localize primarily to the mitochondria. Owing to the unique binding mode between TPPE and G-quadruplexes, TPPE was able to distinguish G-quadruplexes from other substances due to the higher fluorescence lifetime and quantum yield. On the basis of the photon counts determined via fluorescence lifetime imaging microscopy, we analyzed the differences in the numbers of mitochondrial G-quadruplexes in various cell lines. We observed reductions in the number of mitochondrial G-quadruplexes during apoptosis, ferroptosis and glycolysis inhibition. This study shows the great potential of using TPPE to track and analyze mitochondrial G-quadruplexes and presents a novel perspective in the development of probes to detect mitochondrial G-quadruplexes in live cells.
{"title":"Development of a high quantum yield probe for detection of mitochondrial G-quadruplexes in live cells based on fluorescence lifetime imaging microscopy","authors":"","doi":"10.1016/j.bmc.2024.117856","DOIUrl":"10.1016/j.bmc.2024.117856","url":null,"abstract":"<div><p>Mitochondrial G-quadruplexes are components that are potentially involved in regulating mitochondrial function and play crucial roles in the replication and transcription of mitochondrial genes. Consequently, it is imperative to develop probes that can detect mitochondrial G-quadruplexes to understand their functions and mechanisms. In this study, a triphenylamine fluorescent probe, <strong>TPPE</strong>, which has excellent cytocompatibility and does not affect the natural state of G-quadruplexes, was designed and demonstrated to localize primarily to the mitochondria. Owing to the unique binding mode between <strong>TPPE</strong> and G-quadruplexes, <strong>TPPE</strong> was able to distinguish G-quadruplexes from other substances due to the higher fluorescence lifetime and quantum yield. On the basis of the photon counts determined via fluorescence lifetime imaging microscopy, we analyzed the differences in the numbers of mitochondrial G-quadruplexes in various cell lines. We observed reductions in the number of mitochondrial G-quadruplexes during apoptosis, ferroptosis and glycolysis inhibition. This study shows the great potential of using <strong>TPPE</strong> to track and analyze mitochondrial G-quadruplexes and presents a novel perspective in the development of probes to detect mitochondrial G-quadruplexes in live cells.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-23DOI: 10.1016/j.bmc.2024.117844
Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12–39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.
{"title":"Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors","authors":"","doi":"10.1016/j.bmc.2024.117844","DOIUrl":"10.1016/j.bmc.2024.117844","url":null,"abstract":"<div><p>Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (<strong>12</strong>–<strong>39</strong>) as another type of reversible MAGL inhibitors, exemplified by <strong>± 34</strong>, which displayed good MAGL inhibition with a pIC<sub>50</sub> of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative <strong>± 34</strong>, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1016/j.bmc.2024.117848
A new total synthesis of the natural δ-lactone cleistenolide (1) and its (6S)-stereoisomer 2 was achieved starting from d-glucose. Key steps in the synthesis of 1 involved: oxidative cleavage of the C1–C2 bond in partially protected d-glucose derivative (20), and chain extension of resulting aldehyde 20a with a single C2 fragment using (Z)-selective Wittig olefination. Synthesis of 2 involves the following key steps: periodate cleavage of the C5–C6 bond in the commercially available monoacetone d-glucose (24), followed by C2 chain elongation by using the (Z)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (3 – 18). Compounds 3 – 7 were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead 1 against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-O-cinnamoyl derivative 3 and 4,6-di-O-benzyl derivative 17, with submicromolar IC50 values (0.76 and 0.67 μM, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis.
{"title":"Synthesis and antiproliferative activity of (−)-cleistenolide, (6S)-cleistenolide and 4-substituted cleistenolide analogues","authors":"","doi":"10.1016/j.bmc.2024.117848","DOIUrl":"10.1016/j.bmc.2024.117848","url":null,"abstract":"<div><p>A new total synthesis of the natural δ-lactone cleistenolide (<strong>1</strong>) and its (6<em>S</em>)-stereoisomer <strong>2</strong> was achieved starting from <span>d</span>-glucose. Key steps in the synthesis of <strong>1</strong> involved: oxidative cleavage of the C<sub>1</sub>–<em>C</em><sub>2</sub> bond in partially protected <span>d</span>-glucose derivative (<strong>20</strong>), and chain extension of resulting aldehyde <strong>20a</strong> with a single <em>C</em><sub>2</sub> fragment using (<em>Z</em>)-selective Wittig olefination. Synthesis of <strong>2</strong> involves the following key steps: periodate cleavage of the C<sub>5</sub>–C<sub>6</sub> bond in the commercially available monoacetone <span>d</span>-glucose (<strong>24</strong>), followed by <em>C</em><sub>2</sub> chain elongation by using the (<em>Z</em>)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (<strong>3</strong> – <strong>18</strong>). Compounds <strong>3</strong> – <strong>7</strong> were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead <strong>1</strong> against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-<em>O</em>-cinnamoyl derivative <strong>3</strong> and 4,6-di-O-benzyl derivative <strong>17</strong>, with submicromolar IC<sub>50</sub> values (0.76 and 0.67 μM, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141786738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1016/j.bmc.2024.117842
The decline of antibiotics efficacy worldwide has recently reached a critical point urging for the development of new strategies to regain upper hand on multidrug resistant bacterial strains. In this context, the raise of photodynamic therapy (PDT), initially based on organic photosensitizers (PS) and more recently on organometallic PS, offers promising perspectives. Many PS exert their biological effects through the generation of reactive oxygen species (ROS) able to freely diffuse into and to kill surrounding bacteria. Hijacking of the bacterial iron-uptake systems with siderophore-PS conjugates would specifically target pathogens. Here, we report the synthesis of unprecedented conjugates between the siderophore desferrioxamine B (DFOB) and an antibacterial iridium(III) PS. Redox properties of the new conjugates have been determined at excited states and compared to that of an antibacterial iridium PS previously reported by our groups. Tested on nosocomial pathogen Pseudomonas aeruginosa and other bacteria, these conjugates demonstrated significant inhibitory activity when activated with blue LED light. Ir(III) conjugate and iridium free DFOB-2,2′-dipyridylamine ligands were crystallized in complex with FoxA, the outer membrane transporter involved in DFOB uptake in P. aeruginosa and revealed details of the binding mode of these unprecedented conjugates.
{"title":"Synthesis and antibacterial properties under blue LED light of conjugates between the siderophore desferrioxamine B (DFOB) and an Iridium(III) complex","authors":"","doi":"10.1016/j.bmc.2024.117842","DOIUrl":"10.1016/j.bmc.2024.117842","url":null,"abstract":"<div><p>The decline of antibiotics efficacy worldwide has recently reached a critical point urging for the development of new strategies to regain upper hand on multidrug resistant bacterial strains. In this context, the raise of photodynamic therapy (PDT), initially based on organic photosensitizers (PS) and more recently on organometallic PS, offers promising perspectives. Many PS exert their biological effects through the generation of reactive oxygen species (ROS) able to freely diffuse into and to kill surrounding bacteria. Hijacking of the bacterial iron-uptake systems with siderophore-PS conjugates would specifically target pathogens. Here, we report the synthesis of unprecedented conjugates between the siderophore desferrioxamine B (DFOB) and an antibacterial iridium(III) PS. Redox properties of the new conjugates have been determined at excited states and compared to that of an antibacterial iridium PS previously reported by our groups. Tested on nosocomial pathogen <em>Pseudomonas aeruginosa</em> and other bacteria, these conjugates demonstrated significant inhibitory activity when activated with blue LED light. Ir(III) conjugate and iridium free DFOB-2,2′-dipyridylamine ligands were crystallized in complex with FoxA, the outer membrane transporter involved in DFOB uptake in <em>P. aeruginosa</em> and revealed details of the binding mode of these unprecedented conjugates.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002566/pdfft?md5=1e00832bf69aa3f3a83d7fe3f662ab0e&pid=1-s2.0-S0968089624002566-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141853389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1016/j.bmc.2024.117846
The coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spread worldwide for more than 3 years. Although the hospitalization rate and mortality have decreased dramatically due to wide vaccination effort and improved treatment options, the disease is still a global health issue due to constant viral mutations, causing negative impact on social and economic activities. In addition, long COVID and complications arising from COVID-19 weeks after infection have become a concern for public health experts. Therefore, better treatments for COVID-19 are still needed. Herein, we describe a class of macrocyclic peptidomimetic compounds that are potent inhibitors of SARS-Cov-2 3CL protease (3CLpro). Significantly, some of the compounds showed a higher stability against human liver microsomes (HLM t1/2 > 180 min) and may be suitable for oral administration without the need for a pharmacokinetic (PK) boosting agent such as ritonavir.
{"title":"Discovery of macrocyclic covalent inhibitors for severe acute respiratory syndrome coronavirus 2 3CL protease","authors":"","doi":"10.1016/j.bmc.2024.117846","DOIUrl":"10.1016/j.bmc.2024.117846","url":null,"abstract":"<div><p>The coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spread worldwide for more than 3 years. Although the hospitalization rate and mortality have decreased dramatically due to wide vaccination effort and improved treatment options, the disease is still a global health issue due to constant viral mutations, causing negative impact on social and economic activities. In addition, long COVID and complications arising from COVID-19 weeks after infection have become a concern for public health experts. Therefore, better treatments for COVID-19 are still needed. Herein, we describe a class of macrocyclic peptidomimetic compounds that are potent inhibitors of SARS-Cov-2 3CL protease (3CL<sup>pro</sup>). Significantly, some of the compounds showed a higher stability against human liver microsomes (HLM t<sub>1/2</sub> > 180 min) and may be suitable for oral administration without the need for a pharmacokinetic (PK) boosting agent such as ritonavir.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141851454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-22DOI: 10.1016/j.bmc.2024.117843
This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure–activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.
{"title":"Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma","authors":"","doi":"10.1016/j.bmc.2024.117843","DOIUrl":"10.1016/j.bmc.2024.117843","url":null,"abstract":"<div><p>This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control <strong>DCZ0415</strong>, the most active compounds <strong>C16</strong>, <strong>C18</strong>, <strong>C20</strong> and <strong>C32</strong> exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC<sub>50</sub> values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound <strong>C20</strong> is a potent inhibitor of TRIP13, <strong>C20</strong> also showed good antitumor activity <em>in vivo</em> on BALB/c nude mice xenografted with MM tumor cells. An initial structure–activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}