Pub Date : 2024-09-07DOI: 10.1016/j.bioorg.2024.107810
Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, LG-12, was developed and radiolabeled with 131I to obtain the chemically and biologically identical radiopharmaceutical [131I]LG-12, which aimed to improve the antitumor effect by combination of LG-12 and [131I]LG-12. LG-12 showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [131I]LG-12 could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [131I]LG-12 and LG-12 could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.
{"title":"Synthesis and immunotherapy efficacy of a PD-L1 small-molecule inhibitor combined with its 131I-iodide labelled isostructural compound","authors":"","doi":"10.1016/j.bioorg.2024.107810","DOIUrl":"10.1016/j.bioorg.2024.107810","url":null,"abstract":"<div><p>Although antibody-based immune checkpoint blockades have been successfully used in antitumor immunotherapy, the low response rate is currently the main problem. In this work, a small-molecule programmed cell death-ligand (PD-L1) inhibitor, <strong>LG-12</strong>, was developed and radiolabeled with <sup>131</sup>I to obtain the chemically and biologically identical radiopharmaceutical [<sup>131</sup>I]<strong>LG-12</strong>, which aimed to improve the antitumor effect by combination of <strong>LG-12</strong> and [<sup>131</sup>I]<strong>LG-12</strong>. <strong>LG-12</strong> showed high inhibitory activity to PD-1/PD-L1 interaction. The results of cell uptake and biodistribution studies indicated that [<sup>131</sup>I]<strong>LG-12</strong> could specifically bind to PD-L1 in B16-F10 tumors. It could induce immunogenic cell death and the release of high mobility group box 1 and calreticulin. The combination of [<sup>131</sup>I]<strong>LG-12</strong> and <strong>LG-12</strong> could significantly inhibit tumor growth and resulted in enhanced antitumor immune response. This PD-L1 small-molecule inhibitor based combination strategy has great potential for tumor treatment.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1016/j.bioorg.2024.107808
Epidermal growth factor receptor exon 20 insertions (EGFR Ex20ins) driver mutations in non–small cell lung cancer (NSCLC) is insensitive to EGFR tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to develop more novel strategy to address the limitations of existing therapies targeting EGFR-mutated NSCLC. Lupalbigenin (LB), a flavonoid compound extracted from Derris scandens, has shown preclinical activity in lung cancer. However, the activity of LB in Ex20ins-driven tumors has not yet been elucidated. In this study, a series of stable BaF/3 cell-line that contains a high proportion (>90 %) of EGFR-eGFP Ex20ins were generated using an IL3-deprivation method. Ba/F3 cell models harboring dissimilar Ex20ins were used to characterize the antineoplastic mechanism of LB. Molecular docking confirmed that the LB could effectively bind to key target EGFR. The in vitro anticancer activity of LB was investigated in engineered Ba/F3 cells bearing diverse uncommon EGFR mutations. LB was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines. Mechanistic studies disclosed that LB repressed EGFR phosphorylation and downstream survival pathways in Ba/F3 cells expressing EGFR Ex20ins, resulting in caspase activation by activating the intrinsic apoptotic pathway. Further analyses showed that LB significantly induced G0/G1 cell cycle arrest and apoptosis in cells. LB also reduced the protein expression levels of CDK4, CDK6, CDK8, cyclin D1, cyclin A2, and Bcl2 and promoted the expression of cytochrome C, p27, and p53. In summary, we explored the possible potential targets of LB through network pharmacology and verified the target using in vitro experiments. Furthermore, our results demonstrated that LB showed potential anti-Ex20ins cancer activity through suppression of the EGFR and ERK1/2 signaling pathway in Ba/F3 cells bearing two to three amino acid insertion mutations. These findings suggested that LB might be valuable for further investigation as a potential candidate in the treatment of associated diseases.
{"title":"Discovery of flavonoid-containing compound Lupalbigenin as anti-NSCLC cancer agents via suppression of EGFR and ERK1/2 pathway","authors":"","doi":"10.1016/j.bioorg.2024.107808","DOIUrl":"10.1016/j.bioorg.2024.107808","url":null,"abstract":"<div><p>Epidermal growth factor receptor exon 20 insertions (EGFR Ex20ins) driver mutations in non–small cell lung cancer (NSCLC) is insensitive to EGFR tyrosine kinase inhibitors (TKIs). Therefore, it is necessary to develop more novel strategy to address the limitations of existing therapies targeting EGFR-mutated NSCLC. Lupalbigenin (LB), a flavonoid compound extracted from <em>Derris scandens</em>, has shown preclinical activity in lung cancer. However, the activity of LB in Ex20ins-driven tumors has not yet been elucidated. In this study, a series of stable BaF/3 cell-line that contains a high proportion (>90 %) of EGFR-eGFP Ex20ins were generated using an IL3-deprivation method. Ba/F3 cell models harboring dissimilar Ex20ins were used to characterize the antineoplastic mechanism of LB. Molecular docking confirmed that the LB could effectively bind to key target EGFR. The in vitro anticancer activity of LB was investigated in engineered Ba/F3 cells bearing diverse uncommon EGFR mutations. LB was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines. Mechanistic studies disclosed that LB repressed EGFR phosphorylation and downstream survival pathways in Ba/F3 cells expressing EGFR Ex20ins, resulting in caspase activation by activating the intrinsic apoptotic pathway. Further analyses showed that LB significantly induced G0/G1 cell cycle arrest and apoptosis in cells. LB also reduced the protein expression levels of CDK4, CDK6, CDK8, cyclin D1, cyclin A2, and Bcl2 and promoted the expression of cytochrome C, p27, and p53. In summary, we explored the possible potential targets of LB through network pharmacology and verified the target using in vitro experiments. Furthermore, our results demonstrated that LB showed potential anti-Ex20ins cancer activity through suppression of the EGFR and ERK1/2 signaling pathway in Ba/F3 cells bearing two to three amino acid insertion mutations. These findings suggested that LB might be valuable for further investigation as a potential candidate in the treatment of associated diseases.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1016/j.bioorg.2024.107813
A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both in vitro and in vivo. Among them, compound III-4 demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC50 value of 2.9 nM and a KD value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3+ T cells assay, III-4 relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-γ, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 μg/mL). Moreover, compound III-5, an ester prodrug derived from III-4, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound III-5 holds promise as an inhibitor of the PD-1/PD-L1 interaction for cancer immunotherapy.
{"title":"Design, synthesis, and antitumor activity evaluation of 1,2,3-triazole derivatives as potent PD-1/PD-L1 inhibitors","authors":"","doi":"10.1016/j.bioorg.2024.107813","DOIUrl":"10.1016/j.bioorg.2024.107813","url":null,"abstract":"<div><p>A series of 1,2,3-triazole derivatives targeting the PD-1/PD-L1 pathway were designed, synthesized, and evaluated both <em>in vitro</em> and <em>in vivo</em>. Among them, compound <strong>III-4</strong> demonstrated exceptional inhibitory activity against the interaction of PD-1/PD-L1 and showed great binding affinity with hPD-L1, with an IC<sub>50</sub> value of 2.9 nM and a <em>K</em><sub>D</sub> value of 3.33 nM. In the co-culture of Hep3B/OS-8/hPD-L1 cells and CD3<sup>+</sup> T cells assay, <strong>III-4</strong> relieved the inhibition of PD-L1 on PD-1 and promoted the expression of IFN-<em>γ</em>, which shared a comparable effect to that of the PD-1 monoclonal antibody Pembrolizumab (5 <em>μ</em>g/mL). Moreover, compound <strong>III-5</strong>, an ester prodrug derived from <strong>III-4</strong>, demonstrated significant antitumor effects in the hPD-L1-MC38 C57BL/6 mouse model (TGI: 49.6 %) by oral administration. These findings suggest that compound <strong>III-5</strong> holds promise as an inhibitor of the PD-1/PD-L1 interaction for cancer immunotherapy.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1016/j.bioorg.2024.107809
Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson’s and Alzheimer’s. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound 5c (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, 5j, 5h, and 5e. The most potent compound of this series 5j (4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine), exhibited EC50 of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that 5j is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of 5j (20 mg/kg, p.o) in C57BL/6j mice showed that 5j is readily absorbed via oral route of dosing and also enters into the brain (plasma Tmax: 1 h, Cmax: 51.10 ± 13.51 ng/ml; Brain Tmax: 0.5 h, Cmax: 22.54 ± 4.08 ng/ml). We further determined the in-vivo effect of 5j on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that 5j (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, i.p.). Furthermore, 5j did not exhibit any cytotoxicity (up to 10 µM) or in vivo acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that 5j could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.
{"title":"Discovery and structure − activity relationships of 2,4,5-trimethoxyphenyl pyrimidine derivatives as selective D5 receptor partial agonists","authors":"","doi":"10.1016/j.bioorg.2024.107809","DOIUrl":"10.1016/j.bioorg.2024.107809","url":null,"abstract":"<div><p>Dopamine receptors are therapeutic targets for the treatment of various neurological and psychiatric disorders, including Parkinson’s and Alzheimer’s. Previously, PF-06649751 (tavapadon), PF-2562 and PW0464 have been discovered as potent and selective G protein-biased D1/D5 receptor agonists with optimal pharmacokinetic properties. However, no selective D5R agonist has been reported yet. In this context, we designed and synthesized forty non-catecholamines-based pyrimidine derivatives and identified four pyrimidine derivatives as selective D5R partial agonists. Using cAMP-based GloSensor assay in transiently transfected HEK293T cells with human D1 or D5 receptors, we discovered that compound <strong>5c</strong> (4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine) exhibited modest D5R agonist activity. This leads us to explore various modifications of this scaffold to improve the D5 agonist potency and efficacy. Using molecular docking, and rational design followed by their evaluation at D1 and D5 receptors for agonist activity, we identified three new derivatives, <strong>5j</strong>, <strong>5</strong><strong>h</strong>, and <strong>5e</strong>. The most potent compound of this series <strong>5j</strong> (<em>4-(4-iodophenyl)-6-(2,4,5-trimethoxyphenyl)pyrimidin-2-amine),</em> exhibited EC<sub>50</sub> of 269.7 ± 6.6 nM. Mice microsomal stability studies revealed that <strong>5j</strong> is quite stable (>70 % at 1 hr). Furthermore, pharmacokinetic analysis of <strong>5j</strong> (20 mg/kg, p.o) in C57BL/6j mice showed that <strong>5j</strong> is readily absorbed via oral route of dosing and also enters into the brain (plasma T<sub>max</sub>: 1 h, C<sub>max</sub>: 51.10 ± 13.51 ng/ml; Brain T<sub>max</sub>: 0.5 h, C<sub>max</sub>: 22.54 ± 4.08 ng/ml). We further determined the <em>in-vivo</em> effect of <strong>5j</strong> on cognition in scopolamine-induced amnesia in C57BL/6j mice. We observed that <strong>5j</strong> (10 mg/kg, p.o) alleviated scopolamine-induced impairment in short-term memory and social recognition, which were blocked by D1/D5 antagonist SCH23390 (0.1 mg/kg, <em>i.p.</em>). Furthermore, <strong>5j</strong> did not exhibit any cytotoxicity (up to 10 µM) or <em>in vivo</em> acute toxicity up to 200 mg/kg (p.o). These results strongly suggest that <strong>5j</strong> could be further developed for treating neurological disorders wherein the D5 receptors play pivotal roles.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.bioorg.2024.107812
Diabetes mellitus can induce liver injury and easily progress to liver fibrosis. However, there is still a lack of effective treatments for diabetes-induced hepatic fibrosis. Cordycepin (COR), a natural nucleoside derived from Cordyceps militaris, has demonstrated remarkable efficacy in treating metabolic diseases and providing hepatoprotective effects. However, its protective effect and underlying mechanism in diabetes-induced liver injury remain unclear. This study utilized a high-fat diet/streptozotocin-induced diabetic mouse model, as well as LX-2 and AML-12 cell models exposed to high glucose and TGF-β1, to explore the protective effects and mechanisms of Cordycepin in liver fibrosis associated with diabetes. The results showed that COR lowered blood glucose levels, enhanced liver function, mitigated fibrosis, and suppressed HSC activation in diabetic mice. Mechanistically, COR attenuated the activation of the Wnt/β-catenin pathway by inhibiting β-catenin nuclear translocation, and β-catenin knockdown further intensified this effect. Meanwhile, COR significantly inhibited SOX9 expression in vivo and in vitro. Knockdown of SOX9 downregulated Wnt3a and β-catenin expression at the protein and gene levels to exacerbate the inhibitory action of COR on HG&TGF-β1-induced HSCs activations. These results indicate SOX9 is involved in the mechanism by which COR deactivates the Wnt/β-catenin pathway in hepatic fibrosis induced by diabetes. Moreover, prolonged half-life time, slower metabolism and higher exposure of COR were observed in diabetes-induced liver injury animal model via pharmacokinetics studies. Altogether, COR holds potential as a therapeutic agent for ameliorating hepatic injury and fibrosis in diabetes by suppressing the activation of the SOX9-mediated Wnt/β-catenin pathway.
{"title":"Cordycepin alleviates diabetes mellitus-associated hepatic fibrosis by inhibiting SOX9-mediated Wnt/β-catenin signal axis","authors":"","doi":"10.1016/j.bioorg.2024.107812","DOIUrl":"10.1016/j.bioorg.2024.107812","url":null,"abstract":"<div><p>Diabetes mellitus can induce liver injury and easily progress to liver fibrosis. However, there is still a lack of effective treatments for diabetes-induced hepatic fibrosis. Cordycepin (COR), a natural nucleoside derived from <em>Cordyceps militaris</em>, has demonstrated remarkable efficacy in treating metabolic diseases and providing hepatoprotective effects. However, its protective effect and underlying mechanism in diabetes-induced liver injury remain unclear. This study utilized a high-fat diet/streptozotocin-induced diabetic mouse model, as well as LX-2 and AML-12 cell models exposed to high glucose and TGF-β1, to explore the protective effects and mechanisms of Cordycepin in liver fibrosis associated with diabetes. The results showed that COR lowered blood glucose levels, enhanced liver function, mitigated fibrosis, and suppressed HSC activation in diabetic mice. Mechanistically, COR attenuated the activation of the Wnt/β-catenin pathway by inhibiting β-catenin nuclear translocation, and β-catenin knockdown further intensified this effect. Meanwhile, COR significantly inhibited SOX9 expression <em>in vivo</em> and <em>in vitro</em>. Knockdown of SOX9 downregulated Wnt3a and β-catenin expression at the protein and gene levels to exacerbate the inhibitory action of COR on HG&TGF-β1-induced HSCs activations. These results indicate SOX9 is involved in the mechanism by which COR deactivates the Wnt/β-catenin pathway in hepatic fibrosis induced by diabetes. Moreover, prolonged half-life time, slower metabolism and higher exposure of COR were observed in diabetes-induced liver injury animal model via pharmacokinetics studies. Altogether, COR holds potential as a therapeutic agent for ameliorating hepatic injury and fibrosis in diabetes by suppressing the activation of the SOX9-mediated Wnt/β-catenin pathway.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.bioorg.2024.107774
In most organisms, the tri-carboxylic acid cycle (TCA cycle) is an essential metabolic system that is involved in both energy generation and carbon metabolism. Its uni-directionality, however, restricts its use in synthetic biology and carbon fixation. Here, it is describing the use of the modified TCA cycle, called the Tri-carboxylic acid Hooked to Ethylene by Enzyme Reactions and Amino acid Synthesis, the reductive tricarboxylic acid branch/4-hydroxybutyryl-CoA/ethylmalonyl-CoA/acetyl-CoA (THETA) cycle, in Escherichia coli for the purposes of carbon fixation and amino acid synthesis. Three modules make up the THETA cycle: (1) pyruvate to succinate transformation, (2) succinate to crotonyl-CoA change, and (3) crotonyl-CoA to acetyl-CoA and pyruvate change. It is presenting each module’s viability in vivo and showing how it integrates into the E. coli metabolic network to support growth on minimal medium without the need for outside supplementation. Enzyme optimization, route redesign, and heterologous expression were used to get over metabolic roadblocks and produce functional modules. Furthermore, the THETA cycle may be improved by including components of the Carbon-Efficient Tri-Carboxylic Acid Cycle (CETCH cycle) to improve carbon fixation. THETA cycle’s promise as a platform for applications in synthetic biology and carbon fixation.
{"title":"Synthetic biology of metabolic cycles for Enhanced CO2 capture and Sequestration","authors":"","doi":"10.1016/j.bioorg.2024.107774","DOIUrl":"10.1016/j.bioorg.2024.107774","url":null,"abstract":"<div><p>In most organisms, the tri-carboxylic acid cycle (TCA cycle) is an essential metabolic system that is involved in both energy generation and carbon metabolism. Its uni-directionality, however, restricts its use in synthetic biology and carbon fixation. Here, it is describing the use of the modified TCA cycle, called the Tri-carboxylic acid Hooked to Ethylene by Enzyme Reactions and Amino acid Synthesis, the reductive tricarboxylic acid branch/4-hydroxybutyryl-CoA/ethylmalonyl-CoA/acetyl-CoA (THETA) cycle, in Escherichia coli for the purposes of carbon fixation and amino acid synthesis. Three modules make up the THETA cycle: (1) pyruvate to succinate transformation, (2) succinate to crotonyl-CoA change, and (3) crotonyl-CoA to acetyl-CoA and pyruvate change. It is presenting each module’s viability in vivo and showing how it integrates into the E. coli metabolic network to support growth on minimal medium without the need for outside supplementation. Enzyme optimization, route redesign, and heterologous expression were used to get over metabolic roadblocks and produce functional modules. Furthermore, the THETA cycle may be improved by including components of the Carbon-Efficient Tri-Carboxylic Acid Cycle (CETCH cycle) to improve carbon fixation. THETA cycle’s promise as a platform for applications in synthetic biology and carbon fixation.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.bioorg.2024.107785
Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using Iodiconazole as the lead compound. Among them, compound 19g is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus, with a MIC80 value of 0.0625 μg/mL. In addition, compounds 19e, 19f, 19g, 19h, 19i and 19k exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC80 values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound 19g had optimal in vitro antifungal activity, we selected 19g for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound 19g on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound 19g on the filamentation of Candida albicans and determined the mechanism of action by sterol composition analysis.
{"title":"Design, synthesis and bioactivity evaluation of triazole antifungal drugs with phenylthiophene structure","authors":"","doi":"10.1016/j.bioorg.2024.107785","DOIUrl":"10.1016/j.bioorg.2024.107785","url":null,"abstract":"<div><p>Invasive fungal infections have high morbidity and mortality rates and have become one of the most serious threats to human health. In the present study, a series of triazole antifungal derivatives with phenylthiophene backbone were obtained by structural modification of the lead compound using <strong>Iodiconazole</strong> as the lead compound. Among them, compound <strong>19g</strong> is a triazole antifungal compound with 4-chloro-2-fluoro phenylthiophene backbone, which showed optimal antifungal activity against <em>Candida albicans</em>, <em>Cryptococcus neoformans</em>, and <em>Aspergillus</em>, with a MIC<sub>80</sub> value of 0.0625 μg/mL. In addition, compounds <strong>19e</strong>, <strong>19f</strong>, <strong>19g</strong>, <strong>19h</strong>, <strong>19i</strong> and <strong>19k</strong> exhibited different levels of inhibitory activity against fluconazole-resistant strains with MIC<sub>80</sub> values ranging from 0.0625 μg/mL to 32 μg/mL. Since compound <strong>19g</strong> had optimal <em>in vitro</em> antifungal activity, we selected <strong>19g</strong> for human liver microsomal stability and CYP enzyme inhibition assays as well as further evaluated the inhibitory activity of compound <strong>19g</strong> on normal and cancerous cells in humans. Finally, we verified the inhibitory effect of compound <strong>19g</strong> on the filamentation of <em>Candida albicans</em> and determined the mechanism of action by sterol composition analysis.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142163926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.bioorg.2024.107804
In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a–i) and pyrazolo[3,4-b]pyridines (10a–i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC50 range: 1.28–3.52 μM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC50 of 0.18 μM. Additionally, 10f induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds’ stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective anticancer agents targeting PIM-1 kinase.
{"title":"Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights","authors":"","doi":"10.1016/j.bioorg.2024.107804","DOIUrl":"10.1016/j.bioorg.2024.107804","url":null,"abstract":"<div><p>In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-<em>a</em>]pyrimidines (<strong>6a–i</strong>) and pyrazolo[3,4-<em>b</em>]pyridines (<strong>10a–i</strong>) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-<em>a</em>]pyrimidines (<strong>6b</strong>, <strong>6c</strong>, <strong>6g</strong>, <strong>6h</strong>, and <strong>6i</strong>) and pyrazolo[3,4-<em>b</em>]pyridine (<strong>10f</strong>) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC<sub>50</sub> range: 1.28–3.52 μM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, <strong>10f</strong>, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC<sub>50</sub> of 0.18 μM. Additionally, <strong>10f</strong> induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds’ stability with PIM-1 kinase. The results highlight these compounds, especially <strong>10f</strong>, as promising selective anticancer agents targeting PIM-1 kinase.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.bioorg.2024.107788
Breast cancer stands as the cancer with the highest incidence and mortality rates among women globally, in which triple-negative breast cancer has been ranked as the most difficult one. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been exhibited notable inhibitory effect on both hormone-dependent breast cancer cells and triple-negative breast cancer cells, but showing very low in vivo effeacy. In order to obtain more effective antitumor derivatives than BZA, we have employed a structurally diverse design and synthesis of 57 novel 2-phenylindole amides for detecting their cytotoxities against triple-negative mammary cancer cell line, CMT-7364. Among them, 21 compounds demonstrated significant inhibitory activity against CMT-7364 cells (IC50 < 20 μM). Notably, compound 49 stood out, displaying both similar tumor cell inhibition (20 % reduce in IC50 value) and higher selectivity (4.6 times higher in SI value), compared to Bazedoxifene. Additionally, compound 49 exhibited desirable antitumor effects in a CMT-7364 cell-derived mouse in vivo model, achieving the best inhibition rate of 43.1 % and establishing strong molecular bonding with GP130. Our findings are also supported by comprehensive SAR and 3D-QSAR analyses. Furthermore, the best potent compound 49 was determined to block the cell cycle of canine breast cancer cells in the G0G1 phase in a time-dependent manner, by inducing apoptosis and autophagy. In conclusion, this work presents a valuable lead compound as a potential GP130 inhibitor against triple-negative breast cancer cell lines, laying the foundation for further antitumor drug development.
{"title":"Structurally diverse design and synthesis of novel 2-phenylindole amide derivatives with anti-canine breast cancer activity","authors":"","doi":"10.1016/j.bioorg.2024.107788","DOIUrl":"10.1016/j.bioorg.2024.107788","url":null,"abstract":"<div><p>Breast cancer stands as the cancer with the highest incidence and mortality rates among women globally, in which triple-negative breast cancer has been ranked as the most difficult one. Bazedoxifene (BZA), a third-generation selective estrogen receptor modulator (SERM), has been exhibited notable inhibitory effect on both hormone-dependent breast cancer cells and triple-negative breast cancer cells, but showing very low <em>in vivo</em> effeacy. In order to obtain more effective antitumor derivatives than BZA, we have employed a structurally diverse design and synthesis of 57 novel 2-phenylindole amides for detecting their cytotoxities against triple-negative mammary cancer cell line, CMT-7364. Among them, 21 compounds demonstrated significant inhibitory activity against CMT-7364 cells (IC<sub>50</sub> < 20 μM). Notably, compound <strong>49</strong> stood out, displaying both similar tumor cell inhibition (20 % reduce in IC<sub>50</sub> value) and higher selectivity (4.6 times higher in SI value), compared to Bazedoxifene. Additionally, compound <strong>49</strong> exhibited desirable antitumor effects in a CMT-7364 cell-derived mouse <em>in vivo</em> model, achieving the best inhibition rate of 43.1 % and establishing strong molecular bonding with GP130. Our findings are also supported by comprehensive SAR and 3D-QSAR analyses. Furthermore, the best potent compound <strong>49</strong> was determined to block the cell cycle of canine breast cancer cells in the G0G1 phase in a time-dependent manner, by inducing apoptosis and autophagy. In conclusion, this work presents a valuable lead compound as a potential GP130 inhibitor against triple-negative breast cancer cell lines, laying the foundation for further antitumor drug development.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.1016/j.bioorg.2024.107803
Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein overexpressed in a variety of tumors, especially in nearly all prostate cancers, which makes it a potentially attractive antigen for targeted cancer therapies. More importantly, PSMA, due to no shedding into circulation and efficient internalization after antibody binding, becomes a potential target for antibody-drug conjugates (ADCs), a valid and emerging paradigm of cancer treatment. Four and eight PSMA-directed ADCs have been or are currently being investigated in clinical trials (three of which failed to confirm the promising results while one is currently being evaluated in an ongoing clinical study) and preclinical studies, respectively, for the treatment of PSMA-positive solid tumors, especially prostate cancer. The present study aims to completely review clinical- and preclinical-stage PSMA-directed ADCs.
{"title":"Clinical and preclinical advances in PSMA-Directed Antibody-Drug conjugates (ADCs): Current status and hope for the future","authors":"","doi":"10.1016/j.bioorg.2024.107803","DOIUrl":"10.1016/j.bioorg.2024.107803","url":null,"abstract":"<div><p>Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein overexpressed in a variety of tumors, especially in nearly all prostate cancers, which makes it a potentially attractive antigen for targeted cancer therapies. More importantly, PSMA, due to no shedding into circulation and efficient internalization after antibody binding, becomes a potential target for antibody-drug conjugates (ADCs), a valid and emerging paradigm of cancer treatment. Four and eight PSMA-directed ADCs have been or are currently being investigated in clinical trials (three of which failed to confirm the promising results while one is currently being evaluated in an ongoing clinical study) and preclinical studies, respectively, for the treatment of PSMA-positive solid tumors, especially prostate cancer. The present study aims to completely review clinical- and preclinical-stage PSMA-directed ADCs.</p></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}