Pub Date : 2024-07-20DOI: 10.1016/j.bmc.2024.117845
SR9009 is an activator of REV-ERBs with diverse biological activities, including improving exercise tolerance and controlling skeletal muscle mass. To optimise the carbamate motif of SR9009, analogues of SR9009 were synthesised and evaluated. All of them showed REV-ERB-α agonist activities. Among them, 5a, 5f, 5 g, 5m, and 5p showed potencies equivalent to or slightly higher than the potency of SR9009 in vitro. These data indicate that the halogenated benzyl group is an indispensable active group in these compounds. 5m, 5p and SR9009 improved exercise tolerance in normal mice in vivo. Additionally, in hyperlipidemic mice, 5m and 5p not only improved exercise tolerance but also lowered blood lipid levels. 5m and 5p displayed stronger hypoglycaemic activity than SR9009.
{"title":"Regulation of exercise ability and glycolipid metabolism by synthetic SR9009 analogues as new REV-ERB-α agonists","authors":"","doi":"10.1016/j.bmc.2024.117845","DOIUrl":"10.1016/j.bmc.2024.117845","url":null,"abstract":"<div><p>SR9009 is an activator of REV-ERBs with diverse biological activities, including improving exercise tolerance and controlling skeletal muscle mass. To optimise the carbamate motif of SR9009, analogues of SR9009 were synthesised and evaluated. All of them showed REV-ERB-α agonist activities. Among them, <strong>5a</strong>, <strong>5f</strong>, <strong>5 g</strong>, <strong>5</strong><strong>m</strong>, and <strong>5p</strong> showed potencies equivalent to or slightly higher than the potency of SR9009 in <em>vitro</em>. These data indicate that the halogenated benzyl group is an indispensable active group in these compounds. <strong>5</strong><strong>m</strong>, <strong>5p</strong> and SR9009 improved exercise tolerance in normal mice in vivo. Additionally, in hyperlipidemic mice, <strong>5</strong><strong>m</strong> and <strong>5p</strong> not only improved exercise tolerance but also lowered blood lipid levels. <strong>5</strong><strong>m</strong> and <strong>5p</strong> displayed stronger hypoglycaemic activity than SR9009.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764587","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 : 2024-07-18DOI: 10.1016/j.bmc.2024.117841
3-Tetrazolyl-β-carbolines were prepared by the Pictet-Spengler approach using a tryptophan analogue as building block, in which the carboxylic acid was replaced by the bioisosteric tetrazole group. Knowing that β-carbolines are often associated with psychopharmacological effects, the study of the 3-tetrazolyl-β-carbolines as potential neuroprotective agents against Parkinson’s disease was investigated. The evaluation of neuroprotective effects against 1-methyl-4-phenylpyridin-1-ium (MPP+)-induced cytotoxicity allowed to identify compounds with relevant neuroprotective activity. One derivative, 3-(1-benzyl-1H-tetrazol-5-yl)-1-(p-dimethylaminophenyl)-β-carboline, stood out for its low cytotoxicity and excellent performance, preventing cell death induced by this neurotoxin. The most promising compounds were also evaluated for their neuroprotective properties against iron (III)-induced cytotoxicity. However, only one 3-tetrazolyl-β-carboline derivative slightly reduced iron-induced cytotoxicity. Overall, the neuroprotective properties of 3-tetrazolyl-β-carbolines have been demonstrated and this finding may contribute to the development of new therapies for Parkinson’s disease.
{"title":"3-Tetrazolyl-β-carboline derivatives as potential neuroprotective agents","authors":"","doi":"10.1016/j.bmc.2024.117841","DOIUrl":"10.1016/j.bmc.2024.117841","url":null,"abstract":"<div><p>3-Tetrazolyl-β-carbolines were prepared by the Pictet-Spengler approach using a tryptophan analogue as building block, in which the carboxylic acid was replaced by the bioisosteric tetrazole group. Knowing that β-carbolines are often associated with psychopharmacological effects, the study of the 3-tetrazolyl-β-carbolines as potential neuroprotective agents against Parkinson’s disease was investigated. The evaluation of neuroprotective effects against 1-methyl-4-phenylpyridin-1-ium (MPP<sup>+</sup>)-induced cytotoxicity allowed to identify compounds with relevant neuroprotective activity. One derivative, 3-(1-benzyl-1<em>H</em>-tetrazol-5-yl)-1-(<em>p</em>-dimethylaminophenyl)-β-carboline, stood out for its low cytotoxicity and excellent performance, preventing cell death induced by this neurotoxin. The most promising compounds were also evaluated for their neuroprotective properties against iron (III)-induced cytotoxicity. However, only one 3-tetrazolyl-β-carboline derivative slightly reduced iron-induced cytotoxicity. Overall, the neuroprotective properties of 3-tetrazolyl-β-carbolines have been demonstrated and this finding may contribute to the development of new therapies for Parkinson’s disease.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002554/pdfft?md5=c7d3bafc405a5f47beb0d4c00db36383&pid=1-s2.0-S0968089624002554-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141853983","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 : 2024-07-15DOI: 10.1016/j.bmc.2024.117839
Peptaibols are a class of short peptides, typically 7 to 20 amino acids long, characterized by noncanonical amino acid residues such as aminoisobutyric acid (Aib). Although the helix length is shorter than the membrane thickness, the 11-residue peptaibol trichorovin-XII (TV-XII) can form ion channels in membranes. Assuming that a higher proportion of isoleucine (Ile) relative to leucine (Leu) residues is crucial for maintaining the ion channel activity of TV-XII, peptide analogs of TV-XII with varying Ile content were designed, synthesized, and evaluated. The secondary structure of all derivatives under hydrophobic conditions was confirmed by CD measurement as an α-helix-like β-bend ribbon spiral structure. The most stable ion channel activity was found in compound 4a with maximum Ile. Furthermore, the C-terminal Ile analog showed greater ion channel activity compared to the Leu analog. This suggests that the choice between Leu and Ile can influence the expression of ion channel activity, which will be crucial for the de novo designed functional peptides.
Peptaibols 是一类短肽,通常长 7 至 20 个氨基酸,以氨基异丁酸(Aib)等非典型氨基酸残基为特征。虽然螺旋长度比膜厚度短,但 11 个残基的 peptaibol trichorovin-XII(TV-XII)可以在膜中形成离子通道。假设异亮氨酸(Ile)相对于亮氨酸(Leu)残基的比例较高是维持 TV-XII 离子通道活性的关键,我们设计、合成并评估了不同 Ile 含量的 TV-XII 肽类似物。通过 CD 测量证实,所有衍生物在疏水条件下的二级结构均为α-螺旋状的β-弯曲带螺旋结构。发现化合物 4a 的离子通道活性最稳定,其 Ile 含量最高。此外,与 Leu 类似物相比,C 端 Ile 类似物显示出更强的离子通道活性。这表明,Leu 和 Ile 之间的选择会影响离子通道活性的表达,这对从头设计功能肽至关重要。
{"title":"Importance of isoleucine residue in ion channel formation ability of 11-residue peptaibols","authors":"","doi":"10.1016/j.bmc.2024.117839","DOIUrl":"10.1016/j.bmc.2024.117839","url":null,"abstract":"<div><p>Peptaibols are a class of short peptides, typically 7 to 20 amino acids long, characterized by noncanonical amino acid residues such as aminoisobutyric acid (Aib). Although the helix length is shorter than the membrane thickness, the 11-residue peptaibol trichorovin-XII (TV-XII) can form ion channels in membranes. Assuming that a higher proportion of isoleucine (Ile) relative to leucine (Leu) residues is crucial for maintaining the ion channel activity of TV-XII, peptide analogs of TV-XII with varying Ile content were designed, synthesized, and evaluated. The secondary structure of all derivatives under hydrophobic conditions was confirmed by CD measurement as an α-helix-like β-bend ribbon spiral structure. The most stable ion channel activity was found in compound <strong>4a</strong> with maximum Ile. Furthermore, the C-terminal Ile analog showed greater ion channel activity compared to the Leu analog. This suggests that the choice between Leu and Ile can influence the expression of ion channel activity, which will be crucial for the <em>de novo</em> designed functional peptides.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141636912","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 : 2024-07-14DOI: 10.1016/j.bmc.2024.117836
Liver cancer is a complex disease that involves various oncoproteins and the inactivation of tumor suppressor proteins (TSPs). Gankyrin is one such oncoprotein, first identified in human hepatocellular carcinoma, that is known to inactivate multiple TSPs, leading to proliferation and metastasis of tumor cells. Despite this, there has been limited development of small molecule gankyrin binders for the treatment of liver cancer. In this study, we are reporting the structure-based design of gankyrin-binding small molecules which inhibit the proliferation of HuH6 and HepG2 cells while also increasing the levels of certain TSPs, such as Rb and p53. Interestingly the first molecule to exhibit inhibition by 3D structure stabilization is seen. These results suggest a possible mechanism for small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of liver cancer.
{"title":"Structural modification of the propyl linker of cjoc42 in combination with sulfonate ester and triazole replacements for enhanced gankyrin binding and anti-proliferative activity","authors":"","doi":"10.1016/j.bmc.2024.117836","DOIUrl":"10.1016/j.bmc.2024.117836","url":null,"abstract":"<div><p>Liver cancer is a complex disease that involves various oncoproteins and the inactivation of tumor suppressor proteins (TSPs). Gankyrin is one such oncoprotein, first identified in human hepatocellular carcinoma, that is known to inactivate multiple TSPs, leading to proliferation and metastasis of tumor cells. Despite this, there has been limited development of small molecule gankyrin binders for the treatment of liver cancer. In this study, we are reporting the structure-based design of gankyrin-binding small molecules which inhibit the proliferation of HuH6 and HepG2 cells while also increasing the levels of certain TSPs, such as Rb and p53. Interestingly the first molecule to exhibit inhibition by 3D structure stabilization is seen. These results suggest a possible mechanism for small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of liver cancer.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141637103","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 : 2024-07-14DOI: 10.1016/j.bmc.2024.117838
Prenylation (isopentenylation), a key post-transcriptional modification with a hydrophobic prenyl group onto the biomacromolecules such as RNA and proteins, influences their localization and function. Prenyltransferases mediate this process, while cytokinin oxidases degrade the prenylated adenosine in plants. This review summarizes current progress in detecting prenylation modifications in RNA across species and their effects on protein synthesis. Advanced methods have been developed to label and study these modifications in vitro and in vivo, despite challenges posed by the inert chemical properties of prenyl groups. Continued advancements in bioorthogonal chemistry promise new tools for understanding the precise biological functions of prenylated RNA modifications and other related proteins.
{"title":"Advances in the investigation of N6-isopentenyl adenosine i6A RNA modification","authors":"","doi":"10.1016/j.bmc.2024.117838","DOIUrl":"10.1016/j.bmc.2024.117838","url":null,"abstract":"<div><p>Prenylation (isopentenylation), a key post-transcriptional modification with a hydrophobic prenyl group onto the biomacromolecules such as RNA and proteins, influences their localization and function. Prenyltransferases mediate this process, while cytokinin oxidases degrade the prenylated adenosine in plants. This review summarizes current progress in detecting prenylation modifications in RNA across species and their effects on protein synthesis. Advanced methods have been developed to label and study these modifications <em>in vitro</em> and <em>in vivo</em>, despite challenges posed by the inert chemical properties of prenyl groups. Continued advancements in bioorthogonal chemistry promise new tools for understanding the precise biological functions of prenylated RNA modifications and other related proteins.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141630376","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 : 2024-07-11DOI: 10.1016/j.bmc.2024.117837
RNA molecules contain diverse modified nucleobases that play pivotal roles in numerous biological processes. Adenosine-to-inosine (A-to-I) RNA editing, one of the most prevalent RNA modifications in mammalian cells, is linked to a multitude of human diseases. To unveil the functions of A-to-I RNA editing, accurate quantification of inosine at specific sites is essential. In this study, we developed an endonuclease-mediated cleavage and real-time fluorescence quantitative PCR method for A-to-I RNA editing (EM-qPCR) to quantitatively analyze A-to-I RNA editing at a single site. By employing this method, we successfully quantified the levels of A-to-I RNA editing on various transfer RNA (tRNA) molecules at position 34 (I34) in mammalian cells with precision. Subsequently, this method was applied to tissues from sleep-deprived mice, revealing a notable alteration in the levels of I34 between sleep-deprived and control mice. The proposed method sets a precedent for the quantitative analysis of A-to-I RNA editing at specific sites, facilitating a deeper understanding of the biological implications of A-to-I RNA editing.
RNA 分子中含有多种修饰的核碱基,它们在许多生物过程中发挥着关键作用。腺苷-肌苷(A-to-I)RNA 编辑是哺乳动物细胞中最常见的 RNA 修饰之一,与多种人类疾病有关。要揭示 A 到 I RNA 编辑的功能,必须对特定位点的肌苷进行精确定量。在这项研究中,我们开发了一种内切酶介导的A-I RNA编辑裂解和实时荧光定量PCR方法(EM-qPCR)来定量分析单个位点的A-I RNA编辑。利用这种方法,我们成功地精确定量了哺乳动物细胞中各种转移 RNA(tRNA)分子第 34 位(I34)上的 A 对 I RNA 编辑水平。随后,我们将这种方法应用于睡眠不足小鼠的组织,结果发现睡眠不足小鼠和对照组小鼠的 I34 水平发生了显著变化。该方法开创了在特定位点定量分析A-to-I RNA编辑的先例,有助于深入了解A-to-I RNA编辑的生物学意义。
{"title":"Site-specific quantification of Adenosine-to-Inosine RNA editing by Endonuclease-Mediated qPCR","authors":"","doi":"10.1016/j.bmc.2024.117837","DOIUrl":"10.1016/j.bmc.2024.117837","url":null,"abstract":"<div><p>RNA molecules contain diverse modified nucleobases that play pivotal roles in numerous biological processes. Adenosine-to-inosine (A-to-I) RNA editing, one of the most prevalent RNA modifications in mammalian cells, is linked to a multitude of human diseases. To unveil the functions of A-to-I RNA editing, accurate quantification of inosine at specific sites is essential. In this study, we developed an endonuclease-mediated cleavage and real-time fluorescence quantitative PCR method for A-to-I RNA editing (EM-qPCR) to quantitatively analyze A-to-I RNA editing at a single site. By employing this method, we successfully quantified the levels of A-to-I RNA editing on various transfer RNA (tRNA) molecules at position 34 (I<sub>34</sub>) in mammalian cells with precision. Subsequently, this method was applied to tissues from sleep-deprived mice, revealing a notable alteration in the levels of I<sub>34</sub> between sleep-deprived and control mice. The proposed method sets a precedent for the quantitative analysis of A-to-I RNA editing at specific sites, facilitating a deeper understanding of the biological implications of A-to-I RNA editing.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141623221","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 : 2024-07-09DOI: 10.1016/j.bmc.2024.117832
Yu Jung Park , Hee Jin Jung , Min Kyung Kang , Jieun Lee , Dahye Yoon , Hye Soo Park , Hye Jin Kim , Ga Young Kim , Dongwan Kang , Yujin Park , Hae Young Chung , Hyung Ryong Moon
Tyrosinase is a metalloenzyme that contains copper(II) ions. We designed and synthesized eight known low-molecular-weight 2-mercaptobenzoxazole (2-MBO) analogs as tyrosinase inhibitors. Our focus was on the mercapto functional group, which interacts with copper ions. Analogs 1–3 exhibited mushroom tyrosinase inhibitory activity at the nanomolar level and demonstrated strong potency with extremely low half-maximal inhibitory concentration (IC50) values of 80–90 nM for l-dopa and 100–240 nM for l-tyrosine. Analogs 2, 4, and 5 showed the most potent anti-melanogenic effects in B16F10 cells, and their mode of action was demonstrated by kinetic analysis. Their anti-melanogenic effects were similar to the tyrosinase inhibition results, suggesting that their anti-melanogenic effects could be attributed to their tyrosinase inhibitory ability. Experiments using copper-chelating activity assays and changes in tyrosinase inhibitory activity with and without CuSO4 demonstrated that 2-MBO analogs inhibit tyrosinase activity by chelating the copper ions of tyrosinase. In conclusion, the 2-MBO analogs show potential as anti-melanogenic agents with potent tyrosinase inhibitory activity.
{"title":"Design, synthesis, and anti-melanogenic efficacy of 2-mercaptobenzoxazoles with nanomolar tyrosinase activity inhibition","authors":"Yu Jung Park , Hee Jin Jung , Min Kyung Kang , Jieun Lee , Dahye Yoon , Hye Soo Park , Hye Jin Kim , Ga Young Kim , Dongwan Kang , Yujin Park , Hae Young Chung , Hyung Ryong Moon","doi":"10.1016/j.bmc.2024.117832","DOIUrl":"10.1016/j.bmc.2024.117832","url":null,"abstract":"<div><p>Tyrosinase is a metalloenzyme that contains copper(II) ions. We designed and synthesized eight known low-molecular-weight 2-mercaptobenzoxazole (2-MBO) analogs as tyrosinase inhibitors. Our focus was on the mercapto functional group, which interacts with copper ions. Analogs <strong>1</strong>–<strong>3</strong> exhibited mushroom tyrosinase inhibitory activity at the nanomolar level and demonstrated strong potency with extremely low half-maximal inhibitory concentration (IC<sub>50</sub>) values of 80–90 nM for <span>l</span>-dopa and 100–240 nM for <span>l</span>-tyrosine. Analogs <strong>2</strong>, <strong>4</strong>, and <strong>5</strong> showed the most potent anti-melanogenic effects in B16F10 cells, and their mode of action was demonstrated by kinetic analysis. Their anti-melanogenic effects were similar to the tyrosinase inhibition results, suggesting that their anti-melanogenic effects could be attributed to their tyrosinase inhibitory ability. Experiments using copper-chelating activity assays and changes in tyrosinase inhibitory activity with and without CuSO<sub>4</sub> demonstrated that 2-MBO analogs inhibit tyrosinase activity by chelating the copper ions of tyrosinase. In conclusion, the 2-MBO analogs show potential as anti-melanogenic agents with potent tyrosinase inhibitory activity.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141602908","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 : 2024-07-09DOI: 10.1016/j.bmc.2024.117834
Currently, no effective treatment exists for premature ovarian failure (POF). To obtain compounds with protective effects against POF, we aimed to design and synthesize a series of spiroheterocyclic protective agents with a focus on minimizing toxicity while enhancing their protective effect against cisplatin-induced POF. This was achieved through systematic modifications of Michael receptors and linkers within the molecular structure of 1,5-diphenylpenta-1,4-dien-3-one analogs. To assess the cytotoxicity and activity of these compounds, we constructed quantitative conformational relationship models using an artificial intelligence random forest algorithm, resulting in R2 values exceeding 0.87. Among these compounds, j2 exhibited optimal protective activity. It significantly increased the survival of cisplatin-injured ovarian granulosa KGN cells, improved post-injury cell morphology, reduced apoptosis, and enhanced cellular estradiol (E2) levels. Subsequent investigations revealed that j2 may exert its protective effect via a novel mechanism involving the activation of the SIRT1/AKT signal pathway. Furthermore, in cisplatin-injured POF in rats, j2 was effective in increasing body, ovarian, and uterine weights, elevating the number of follicles at all levels in the ovary, improving ovarian and uterine structures, and increasing serum E2 levels in rats with cisplatin-injured POF. In conclusion, this study introduces a promising compound j2 and a novel target SIRT1 with substantial protective activity against cisplatin-induced POF.
{"title":"Discovery and evaluation of novel spiroheterocyclic protective agents via a SIRT1 upregulation mechanism in cisplatin-induced premature ovarian failure","authors":"","doi":"10.1016/j.bmc.2024.117834","DOIUrl":"10.1016/j.bmc.2024.117834","url":null,"abstract":"<div><p>Currently, no effective treatment exists for premature ovarian failure (POF). To obtain compounds with protective effects against POF, we aimed to design and synthesize a series of spiroheterocyclic protective agents with a focus on minimizing toxicity while enhancing their protective effect against cisplatin-induced POF. This was achieved through systematic modifications of Michael receptors and linkers within the molecular structure of 1,5-diphenylpenta-1,4-dien-3-one analogs. To assess the cytotoxicity and activity of these compounds, we constructed quantitative conformational relationship models using an artificial intelligence random forest algorithm, resulting in R<sup>2</sup> values exceeding 0.87. Among these compounds, <strong>j2</strong> exhibited optimal protective activity. It significantly increased the survival of cisplatin-injured ovarian granulosa KGN cells, improved post-injury cell morphology, reduced apoptosis, and enhanced cellular estradiol (E2) levels. Subsequent investigations revealed that <strong>j2</strong> may exert its protective effect via a novel mechanism involving the activation of the SIRT1/AKT signal pathway. Furthermore, in cisplatin-injured POF in rats, <strong>j2</strong> was effective in increasing body, ovarian, and uterine weights, elevating the number of follicles at all levels in the ovary, improving ovarian and uterine structures, and increasing serum E2 levels in rats with cisplatin-injured POF. In conclusion, this study introduces a promising compound <strong>j2</strong> and a novel target SIRT1 with substantial protective activity against cisplatin-induced POF.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141637104","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 : 2024-07-09DOI: 10.1016/j.bmc.2024.117833
Serena Fiorito, Chiara Collevecchio, Francesco Epifano, Salvatore Genovese
Prolidase (EC.3.4.13.9) is a Mn+2-dependent dipeptidase that is well known to play a crucial role in several physiological and pathological processes affecting humans. More in particular, this enzyme is involved in the cleavage of proline- and hydroxyproline-containing dipeptides (imidodipeptides), providing a fine regulation of the homeostasis of these two amino acids. Hyperactivity or deficiency of prolidase have been clearly associated to the development and progress of several acute and chronic syndromes (e.g. chronic liver fibrosis, viral and acute hepatitis, cancer, neurological disorders, inflammation, skin diseases, intellectual disability, respiratory infection). Thus, targeting prolidase and modulating its activity is an intriguing field of research with a great therapeutic potential for the next future and for the design of specific and selective drugs. Prolidase can be exploited in two essential ways: as an activator of proline containing prodrugs and by direct interaction. In this latter case, few specific ligands for the title enzyme have been described, but with no reports about their structure–activity relationship. The aim of this comprehensive review is to gather all available information on prolidase targeting so far reported in the literature, to rationalize the observed data and effect into a preliminary structure-relationship picture, to comment about the effectiveness of each reported ligands, and to address future research activities providing new potential and putative natural, semisynthetic, and purely synthetic molecules able to trigger prolidase as the main biological target.
{"title":"Targeting prolidase. A survey of the literature data to depict a structure-activity relationship frame and to address future studies for drug development","authors":"Serena Fiorito, Chiara Collevecchio, Francesco Epifano, Salvatore Genovese","doi":"10.1016/j.bmc.2024.117833","DOIUrl":"10.1016/j.bmc.2024.117833","url":null,"abstract":"<div><p>Prolidase (EC.3.4.13.9) is a Mn<sup>+2</sup>-dependent dipeptidase that is well known to play a crucial role in several physiological and pathological processes affecting humans. More in particular, this enzyme is involved in the cleavage of proline- and hydroxyproline-containing dipeptides (imidodipeptides), providing a fine regulation of the homeostasis of these two amino acids. Hyperactivity or deficiency of prolidase have been clearly associated to the development and progress of several acute and chronic syndromes (e.g. chronic liver fibrosis, viral and acute hepatitis, cancer, neurological disorders, inflammation, skin diseases, intellectual disability, respiratory infection). Thus, targeting prolidase and modulating its activity is an intriguing field of research with a great therapeutic potential for the next future and for the design of specific and selective drugs. Prolidase can be exploited in two essential ways: as an activator of proline containing prodrugs and by direct interaction. In this latter case, few specific ligands for the title enzyme have been described, but with no reports about their structure–activity relationship. The aim of this comprehensive review is to gather all available information on prolidase targeting so far reported in the literature, to rationalize the observed data and effect into a preliminary structure-relationship picture, to comment about the effectiveness of each reported ligands, and to address future research activities providing new potential and putative natural, semisynthetic, and purely synthetic molecules able to trigger prolidase as the main biological target.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141598011","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}
Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed—without scaffold hopping—from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the C-terminus. Structural modifications near the C-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.
环肽作为治疗药物备受关注,因为它们具有口服吸收的潜力,而且容易进入细胞内的强靶点。临床 KRAS 抑制剂 LUNA18 是利用符合我们药物相似性标准的 mRNA 展示文库从最初的命中化合物转化而来的,无需跳支架。在使用 mRNA 展示文库进行药物发现的过程中,命中化合物总是拥有一个与 mRNA 标记相连的位点。在此,我们介绍了利用 X 射线结构对结构-活性关系(SAR)进行的研究,以对与 mRNA 标记相连的位点(相当于 C 端)附近进行化学优化。C 端附近的结构修饰显示了侧链相对较宽的容许范围。此外,我们还表明,单个原子的修改就足以改变药代动力学(PK)曲线。由于在活性方面有四个位置允许侧链修饰,因此可以通过优化侧链结构来灵活调整药代动力学特征。本文所展示的侧链改造结果可能普遍适用于从 mRNA 展示文库中获得的命中物。
{"title":"Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display","authors":"Mirai Kage, Ryuji Hayashi, Atsushi Matsuo, Minoru Tamiya, Shino Kuramoto, Kazuhiro Ohara, Machiko Irie, Aya Chiyoda, Koji Takano, Toshiya Ito, Tomoya Kotake, Ryuuichi Takeyama, Shiho Ishikawa, Kenichi Nomura, Noriyuki Furuichi, Yuya Morita, Satoshi Hashimoto, Hatsuo Kawada, Yoshikazu Nishimura, Keiji Nii, Takuya Shiraishi","doi":"10.1016/j.bmc.2024.117830","DOIUrl":"10.1016/j.bmc.2024.117830","url":null,"abstract":"<div><p>Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed—without scaffold hopping—from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag. Here, we describe our examination of the Structure-Activity Relationship (SAR) using X-ray structures for chemical optimization near the site linked to the mRNA tag, equivalent to the <em>C</em>-terminus. Structural modifications near the <em>C</em>-terminus demonstrated a relatively wide range of tolerance for side chains. Furthermore, we show that a single atom modification is enough to change the pharmacokinetic (PK) profile. Since there are four positions where side chain modification is permissible in terms of activity, it is possible to flexibly adjust the pharmacokinetic profile by structurally optimizing the side chain. The side chain transformation findings demonstrated here may be generally applicable to hits obtained from mRNA display libraries.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562183","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}