Circulating free messenger RNAs (cfmRNAs) in serum have emerged as potential noninvasive biomarkers for cancer diagnosis, including gastric cancer (GC). This study utilized RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify a training set of 100 differentially expressed genes (DEGs) specific to GC patients. Employing a support vector machine (SVM) classification, we narrowed down the candidate gene set to 23, which was further refined to 4 genes-DMBX1, EVX1, MAL, and PIWIL1-after validation through reverse transcription quantitative polymerase chain reaction (RT-qPCR). The diagnostic performance of mRNA panels, particularly the combinations of DMBX1 with EVX1 and EVX1 with PIWIL1, was exceptional, achieving area under the curve (AUC) values of 0.800, sensitivities of 90.0%, and specificities of 80.0%. The accuracy of these biomarkers was corroborated through various machine learning algorithms, underscoring their robust diagnostic potential. The findings of this study are poised to significantly influence clinical practice by providing robust tools for early GC detection. As these biomarkers undergo further investigation and validation, they hold promise to become integral to the diagnostic for GC.
{"title":"Serum Circulating mRNA Panel for the Early Detection of Gastric Cancer: A Potential Biomarker Test.","authors":"Da Han, Xinyu Peng, Xiaoyan Teng, Qian Ma","doi":"10.1002/cmdc.202400523","DOIUrl":"https://doi.org/10.1002/cmdc.202400523","url":null,"abstract":"<p><p>Circulating free messenger RNAs (cfmRNAs) in serum have emerged as potential noninvasive biomarkers for cancer diagnosis, including gastric cancer (GC). This study utilized RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify a training set of 100 differentially expressed genes (DEGs) specific to GC patients. Employing a support vector machine (SVM) classification, we narrowed down the candidate gene set to 23, which was further refined to 4 genes-DMBX1, EVX1, MAL, and PIWIL1-after validation through reverse transcription quantitative polymerase chain reaction (RT-qPCR). The diagnostic performance of mRNA panels, particularly the combinations of DMBX1 with EVX1 and EVX1 with PIWIL1, was exceptional, achieving area under the curve (AUC) values of 0.800, sensitivities of 90.0%, and specificities of 80.0%. The accuracy of these biomarkers was corroborated through various machine learning algorithms, underscoring their robust diagnostic potential. The findings of this study are poised to significantly influence clinical practice by providing robust tools for early GC detection. As these biomarkers undergo further investigation and validation, they hold promise to become integral to the diagnostic for GC.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bernhard Wünsch, Giuliana Costanzo, Giuseppe Cosentino, Lorella Pasquinucci, Emanuele Amata, Dirk Schepmann
Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8‒13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki = 58 nM and 20 nM).
{"title":"Two-step synthesis of enantiomerically pure morphans from (R)-carvone.","authors":"Bernhard Wünsch, Giuliana Costanzo, Giuseppe Cosentino, Lorella Pasquinucci, Emanuele Amata, Dirk Schepmann","doi":"10.1002/cmdc.202400596","DOIUrl":"https://doi.org/10.1002/cmdc.202400596","url":null,"abstract":"<p><p>Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8‒13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki = 58 nM and 20 nM).</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ingrid Wilt, Adrian Demeritte, Alexander Kim, Weiwei Wang, William M Wuest
Ubiquinone mimics known as quinone outside inhibitors (QoIs) are one of the most prominent fungicides used to protect crops in the agricultural industry. Due to chemotype similarities with known QoIs, peniciaculin A, a triaryl natural product, was proposed to exhibit similar broad spectrum antifungal activity against phytopathogens. Instability of the tertiary alcohol and phenol motif, however, prompted exploration of the antifungal properties of simplified analogues to probe possible overlap in mechanism of action between the natural product and QoIs. Peniciaculin A inspired analogues mimicking known QoI scaffolds displayed broad spectrum antifungal activity while those containing scaffolds dissimilar to QoIs possessed negligible bioactivity. These activity profiles suggest peniciaculin A is likely acting as a QoI.
被称为醌外抑制剂(QoIs)的泛醌模拟物是农业领域用于保护农作物的最重要的杀真菌剂之一。由于与已知 QoIs 的化学型相似,有人提出三芳基天然产物 peniciaculin A 对植物病原体具有类似的广谱抗真菌活性。然而,叔醇和苯酚基团的不稳定性促使人们探索简化类似物的抗真菌特性,以探究天然产物和 QoIs 之间可能存在的作用机制重叠。模仿已知 QoI 骨架的青霉素 A 灵感类似物显示出广谱抗真菌活性,而那些含有与 QoI 不同骨架的类似物的生物活性则微乎其微。这些活性特征表明,青霉素 A 很可能是一种 QoI。
{"title":"Leveraging Natural Product-inspired Antifungals to Investigate the Mechanism of Action of Peniciaculin A.","authors":"Ingrid Wilt, Adrian Demeritte, Alexander Kim, Weiwei Wang, William M Wuest","doi":"10.1002/cmdc.202400500","DOIUrl":"https://doi.org/10.1002/cmdc.202400500","url":null,"abstract":"<p><p>Ubiquinone mimics known as quinone outside inhibitors (QoIs) are one of the most prominent fungicides used to protect crops in the agricultural industry. Due to chemotype similarities with known QoIs, peniciaculin A, a triaryl natural product, was proposed to exhibit similar broad spectrum antifungal activity against phytopathogens. Instability of the tertiary alcohol and phenol motif, however, prompted exploration of the antifungal properties of simplified analogues to probe possible overlap in mechanism of action between the natural product and QoIs. Peniciaculin A inspired analogues mimicking known QoI scaffolds displayed broad spectrum antifungal activity while those containing scaffolds dissimilar to QoIs possessed negligible bioactivity. These activity profiles suggest peniciaculin A is likely acting as a QoI.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Rodríguez-Luévano, Julio C Almanza-Pérez, Rolffy Ortiz-Andrade, Samuel Lara-González, Rosa Santillán, Gabriel Navarrete-Vázquez, Abraham Giacoman-Martínez, Roberto C Lazzarini-Lechuga, Elihú Bautista, Sergio Hidalgo-Figueroa
This work describes a first attempt of palindromic design for dual compounds that act simultaneously on peroxisome proliferator-activated receptor gamma (PPARg) and G-protein-coupled receptor 40 (GPR40) for the treatment of type 2 diabetes. The compounds were synthesized by multi-step chemical reactions and the relative mRNA expression levels of PPARg, GPR40, and GLUT-4 were measured in cultured C2C12 muscle cells and RIN-m5f b-pancreatic cells. In addition, insulin secretion and GLUT-4 translocation were measured. Compound 2 displayed a moderate increase in the mRNA expression of PPARg and GPR40. However, the translocation of the GLUT-4 transporter was 400% with a similar effect to pioglitazone. The in vivo effect of compound 2 was determined at 25 mg/kg single dose using a normoglycemic and non-insulin dependent diabetes mellitus (NIDDM) rat models. Compound 2 showed basal plasma glucose in diabetic rats with feed intake, which is associated with the moderate release of insulin measured in cells. Surprisingly, the glucose does not decrease in normoglycemic rats. Compound 2 maintained significant interactions with the GPR40 and PPARg receptors during molecular dynamics. Altogether, the results demonstrate that compound 2, with a palindromic design, simultaneously activates PPARg and GPR40 receptors without inducing hypoglycemia.
{"title":"Discovery of Palindrome Dual PPARγ-GPR40 Agonists for Treating Type 2 Diabetes.","authors":"Ana Rodríguez-Luévano, Julio C Almanza-Pérez, Rolffy Ortiz-Andrade, Samuel Lara-González, Rosa Santillán, Gabriel Navarrete-Vázquez, Abraham Giacoman-Martínez, Roberto C Lazzarini-Lechuga, Elihú Bautista, Sergio Hidalgo-Figueroa","doi":"10.1002/cmdc.202400492","DOIUrl":"https://doi.org/10.1002/cmdc.202400492","url":null,"abstract":"<p><p>This work describes a first attempt of palindromic design for dual compounds that act simultaneously on peroxisome proliferator-activated receptor gamma (PPARg) and G-protein-coupled receptor 40 (GPR40) for the treatment of type 2 diabetes. The compounds were synthesized by multi-step chemical reactions and the relative mRNA expression levels of PPARg, GPR40, and GLUT-4 were measured in cultured C2C12 muscle cells and RIN-m5f b-pancreatic cells. In addition, insulin secretion and GLUT-4 translocation were measured. Compound 2 displayed a moderate increase in the mRNA expression of PPARg and GPR40. However, the translocation of the GLUT-4 transporter was 400% with a similar effect to pioglitazone. The in vivo effect of compound 2 was determined at 25 mg/kg single dose using a normoglycemic and non-insulin dependent diabetes mellitus (NIDDM) rat models. Compound 2 showed basal plasma glucose in diabetic rats with feed intake, which is associated with the moderate release of insulin measured in cells. Surprisingly, the glucose does not decrease in normoglycemic rats. Compound 2 maintained significant interactions with the GPR40 and PPARg receptors during molecular dynamics. Altogether, the results demonstrate that compound 2, with a palindromic design, simultaneously activates PPARg and GPR40 receptors without inducing hypoglycemia.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Athar Nakisa, Lorenzo F Sempere, Xi Chen, Linda T Qu, Daniel Woldring, Howard C Crawford, Xuefei Huang
Carbohydrate antigen 19-9 (CA 19-9) also known as sialyl Lewis A is a tetrasaccharide overexpressed on a wide range of cancerous cells, which has been detected at elevated levels in sera of patients with various types of malignancies, most prominently pancreatic ductal adenocarcinoma. After its identification in 1979, multiple studies have highlighted the significant roles of CA 19-9 in cancer progression, including facilitating extravasation and eventually metastases, proliferation of cancer cells, and suppression of the immune system. Therefore, CA 19-9 has been considered an attractive target for cancer diagnosis, prognosis, and therapy. This review discusses the synthesis of CA 19-9 antigen, elicitation of antibodies through vaccination, development of anti-CA 19-9 monoclonal antibodies, and their applications as imaging tracers and therapeutics for a variety of CA 19-9-positive cancer.
碳水化合物抗原 19-9(CA 19-9)又称 sialyl Lewis A,是一种在多种癌细胞上过度表达的四糖,在各类恶性肿瘤(最常见的是胰腺导管腺癌)患者的血清中检测到其含量升高。自 1979 年发现 CA 19-9 后,多项研究都强调了它在癌症进展过程中的重要作用,包括促进癌细胞外渗并最终转移、癌细胞增殖以及抑制免疫系统。因此,CA 19-9 被认为是癌症诊断、预后和治疗的一个有吸引力的靶点。本综述将讨论 CA 19-9 抗原的合成、通过疫苗接种激发抗体、抗 CA 19-9 单克隆抗体的开发,以及它们作为成像示踪剂和治疗各种 CA 19-9 阳性癌症的应用。
{"title":"Tumor-Associated Carbohydrate Antigen 19-9 (CA 19-9), a Promising Target for Antibody-Based Detection, Diagnosis, and Immunotherapy of Cancer.","authors":"Athar Nakisa, Lorenzo F Sempere, Xi Chen, Linda T Qu, Daniel Woldring, Howard C Crawford, Xuefei Huang","doi":"10.1002/cmdc.202400491","DOIUrl":"https://doi.org/10.1002/cmdc.202400491","url":null,"abstract":"<p><p>Carbohydrate antigen 19-9 (CA 19-9) also known as sialyl Lewis A is a tetrasaccharide overexpressed on a wide range of cancerous cells, which has been detected at elevated levels in sera of patients with various types of malignancies, most prominently pancreatic ductal adenocarcinoma. After its identification in 1979, multiple studies have highlighted the significant roles of CA 19-9 in cancer progression, including facilitating extravasation and eventually metastases, proliferation of cancer cells, and suppression of the immune system. Therefore, CA 19-9 has been considered an attractive target for cancer diagnosis, prognosis, and therapy. This review discusses the synthesis of CA 19-9 antigen, elicitation of antibodies through vaccination, development of anti-CA 19-9 monoclonal antibodies, and their applications as imaging tracers and therapeutics for a variety of CA 19-9-positive cancer.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There is a great deal of research interest in the design of alternative metallodrugs to Pt(II)-derivatives for cancer treatment. The low solubility of such drugs in biological mediums leading to poor bioavailability is the major hurdle of several metal-based anticancer agents. These issues have recently been addressed by designing bio-active ligands based on metal-containing anticancer agents. Conjugating with bioactive ligands has significantly improved the bioavailability of the metallodrugs and their cancer cell targeting ability. One such naturally available bioactive ligand is curcumin. Until recently, several curcumin-based anticancer metallodrugs have been developed and successfully demonstrated for their anticancer studies. In this article, we aim to highlight, the synthesis, structure, and anticancer properties of various Zn(II)-curcumin-based coordination complexes. The effect of introducing different functional groups, targeting ligands, and photo-active ligands on the anticancer potential of such complexes has been mentioned in detail. The current status and future perspective on curcumin-based metallodrugs for cancer treatment have also been stated.
{"title":"Zn(II)-curcumin complexes-based anticancer agents.","authors":"Sankarasekaran Shanmugaraju, Rajdeep Mondal, Muthukumar Keerthana, Nanjan Pandurangan","doi":"10.1002/cmdc.202400558","DOIUrl":"https://doi.org/10.1002/cmdc.202400558","url":null,"abstract":"<p><p>There is a great deal of research interest in the design of alternative metallodrugs to Pt(II)-derivatives for cancer treatment. The low solubility of such drugs in biological mediums leading to poor bioavailability is the major hurdle of several metal-based anticancer agents. These issues have recently been addressed by designing bio-active ligands based on metal-containing anticancer agents. Conjugating with bioactive ligands has significantly improved the bioavailability of the metallodrugs and their cancer cell targeting ability. One such naturally available bioactive ligand is curcumin. Until recently, several curcumin-based anticancer metallodrugs have been developed and successfully demonstrated for their anticancer studies. In this article, we aim to highlight, the synthesis, structure, and anticancer properties of various Zn(II)-curcumin-based coordination complexes. The effect of introducing different functional groups, targeting ligands, and photo-active ligands on the anticancer potential of such complexes has been mentioned in detail. The current status and future perspective on curcumin-based metallodrugs for cancer treatment have also been stated.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jan Voldřich, Marika Matoušová, Markéta Šmídková, Helena Mertlikova-Kaiserova
Ion channels represent a druggable family of transmembrane pore-forming proteins with important (patho)physiological functions. While electrophysiological measurement (manual patch clamp) remains the only direct method for detection of ion currents, it is a labor-intensive technique. Although automated patch clamp instruments have become available to date, their high costs limit their use to large pharma companies or commercial screening facilities. Therefore, fluorescence-based assays are particularly important for initial screening of compound libraries. Despite their numerous disadvantages, they are highly amenable to high-throughput screening and in many cases, no sophisticated instrumentation or materials are required. These features predispose them for implementation in early phases of drug discovery pipelines (hit identification), even in an academic environment. This review summarizes the advantages and pitfalls of individual methodological approaches for identification of ion channel modulators employing fluorescent probes (i.e., membrane potential and ion flux assays) with emphasis on practical aspects of their adaptation to high-throughput format.
{"title":"Fluorescence-Based HTS Assays for Ion Channel Modulation in Drug Discovery Pipelines.","authors":"Jan Voldřich, Marika Matoušová, Markéta Šmídková, Helena Mertlikova-Kaiserova","doi":"10.1002/cmdc.202400383","DOIUrl":"https://doi.org/10.1002/cmdc.202400383","url":null,"abstract":"<p><p>Ion channels represent a druggable family of transmembrane pore-forming proteins with important (patho)physiological functions. While electrophysiological measurement (manual patch clamp) remains the only direct method for detection of ion currents, it is a labor-intensive technique. Although automated patch clamp instruments have become available to date, their high costs limit their use to large pharma companies or commercial screening facilities. Therefore, fluorescence-based assays are particularly important for initial screening of compound libraries. Despite their numerous disadvantages, they are highly amenable to high-throughput screening and in many cases, no sophisticated instrumentation or materials are required. These features predispose them for implementation in early phases of drug discovery pipelines (hit identification), even in an academic environment. This review summarizes the advantages and pitfalls of individual methodological approaches for identification of ion channel modulators employing fluorescent probes (i.e., membrane potential and ion flux assays) with emphasis on practical aspects of their adaptation to high-throughput format.</p>","PeriodicalId":147,"journal":{"name":"ChemMedChem","volume":null,"pages":null},"PeriodicalIF":3.6,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142102575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prof. Dr. Ciro Milite, Giuliana Sarno, Ida Pacilio, Dr. Agostino Cianciulli, Dr. Monica Viviano, Dr. Giulia Iannelli, Erica Gazzillo, Dr. Alessandra Feoli, Dr. Alessandra Cipriano, Prof. Dr. Maria Giovanna Chini, Prof. Dr. Sabrina Castellano, Prof. Dr. Giuseppe Bifulco, Prof. Dr. Gianluca Sbardella
The front cover picture shows that the introduction of a NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group (in cyan sticks) to mask the S-alanine amido group turns PRMT4 inhibitors (in orange sticks) into cell-permeable prodrugs, that after in cell activation (magenta) are able to inhibit PRMT4 (yellow green) and reduce arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155). More details can be found in the Research Article by Maria Giovanna Chini, Sabrina Castellano, and co-workers. Cover design by Gianluca Sbardella.