MedChemComm最新文献

{"title":"Benzenesulfonamide decorated dihydropyrimidin(thi)ones: carbonic anhydrase profiling and antiproliferative activity†","authors":"Hakan Aslan, Gioele Renzi, Andrea Angeli, Ilaria D'Agostino, Roberto Ronca, Maria Luisa Massardi, Camilla Tavani, Simone Carradori, Marta Ferraroni, Paolo Governa, Fabrizio Manetti, Fabrizio Carta and Claudiu T. Supuran","doi":"10.1039/D4MD00101J","DOIUrl":"10.1039/D4MD00101J","url":null,"abstract":"<p >In the last decades, carbonic anhydrases (CAs) have become the top investigated innovative pharmacological targets and, in particular, isoforms IX and XII have been widely studied due to the evidence of their overexpression in hypoxic tumors. The frantic race to find new anticancer agents places the quick preparation of large libraries of putative bioactive compounds as the basis of a successful drug discovery and development programme. In this context, multi-component and, in general, one-step reactions are becoming very popular and, among them, Biginelli's reaction gave clean and easy-to-isolate products. Thus, we synthesized a series of Biginelli's products (<strong>10–17a–b</strong>) and similar derivatives (<strong>20–21</strong>) bearing the benzenesulfonamide moiety, which is known to inhibit CA enzymes. Through the stopped-flow technique, we were able to assess their ability to inhibit the targeted CAs IX and XII in the nanomolar range with promising selectivity over the physiologically relevant isoforms I and II. Crystallography studies and docking simulations helped us to gain insight into the interaction patterns established in the enzyme–inhibitor complex. From a chemical similarity-based screening of in-house libraries of compounds, a diphenylpyrimidine (<strong>23</strong>) emerged. The surprisingly potent inhibitory activity of <strong>23</strong> for CAs IX and XII along with its strong antiproliferative effect on two (triple-negative breast cancer MDA-MB-231 and glioblastoma U87MG) cell lines laid the foundation for further investigation, again confirming the key role of CAs in cancer.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 1929-1941"},"PeriodicalIF":3.597,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00101j?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140625091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrazolopyridine-based kinase inhibitors for anti-cancer targeted therapy†","authors":"Pallabi Halder, Anubhav Rai, Vishal Talukdar, Parthasarathi Das and Naga Rajiv Lakkaniga","doi":"10.1039/D4MD00003J","DOIUrl":"10.1039/D4MD00003J","url":null,"abstract":"<p >The need for effective cancer treatments continues to be a challenge for the biomedical research community. In this case, the advent of targeted therapy has significantly improved therapeutic outcomes. Drug discovery and development efforts targeting kinases have resulted in the approval of several small-molecule anti-cancer drugs based on ATP-mimicking heterocyclic cores. Pyrazolopyridines are a group of privileged heterocyclic cores in kinase drug discovery, which are present in several inhibitors that have been developed against various cancers. Notably, selpercatinib, glumetinib, camonsertib and olverembatinib have either received approval or are in late-phase clinical studies. This review presents the success stories employing pyrazolopyridine scaffolds as hinge-binding cores to address various challenges in kinase-targeted drug discovery research.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1452-1470"},"PeriodicalIF":3.597,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carltonine-derived compounds for targeted butyrylcholinesterase inhibition†","authors":"Filip Pidany, Jana Kroustkova, Jaroslav Jenco, Katerina Hradiska Breiterova, Lubica Muckova, Lucie Novakova, Jiri Kunes, Jakub Fibigar, Tomas Kucera, Martin Novak, Ales Sorf, Martina Hrabinova, Lenka Pulkrabkova, Jiri Janousek, Ondrej Soukup, Daniel Jun, Jan Korabecny and Lucie Cahlikova","doi":"10.1039/D4MD00060A","DOIUrl":"10.1039/D4MD00060A","url":null,"abstract":"<p >The investigation into human butyrylcholinesterase (<em>h</em>BChE) inhibitors as therapeutic agents for Alzheimer's disease (AD) holds significant promise, addressing both symptomatic relief and disease progression. In the pursuit of novel drug candidates with a selective BChE inhibition pattern, we focused on naturally occurring template structures, specifically Amaryllidaceae alkaloids of the carltonine-type. Herein, we explored a series of compounds implementing an innovative chemical scaffold built on the 3- and 4-benzyloxy-benzylamino chemotype. Notably, compounds <strong>28</strong> (<em>h</em>BChE IC<small>₅₀</small> = 0.171 ± 0.063 μM) and <strong>33</strong> (<em>h</em>BChE IC<small>₅₀</small> = 0.167 ± 0.018 μM) emerged as top-ranked <em>h</em>BChE inhibitors. <em>In silico</em> simulations elucidated the binding modes of these compounds within <em>h</em>BChE. CNS availability was predicted using the BBB score algorithm, corroborated by <em>in vitro</em> permeability assessments with the most potent derivatives. Compound <strong>33</strong> was also inspected for aqueous solubility, microsomal and plasma stability. Chemoinformatics analysis validated these <em>h</em>BChE inhibitors for oral administration, indicating favorable gastrointestinal absorption in compliance with Lipinski's and Veber's rules. Safety assessments, crucial for the chronic administration typical in AD treatment, were conducted through cytotoxicity testing on human neuroblastoma (SH-SY5Y) and hepatocellular carcinoma (HepG2) cell lines.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1601-1625"},"PeriodicalIF":3.597,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00060a?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-cancer activity and mechanism of flurbiprofen organoselenium compound RY-1-92 in non-small cell lung cancer†","authors":"Bo Cui, Xianda Cheng, Xin Zhang, Lili Chen, Wenqian Pang, Yue Liu, Zhe Yang, Hui Li, Xianran He, Xiaolong Li and Xiuli Bi","doi":"10.1039/D4MD00058G","DOIUrl":"10.1039/D4MD00058G","url":null,"abstract":"<p >Lung cancer is one of the malignancies with the highest incidence and mortality rates worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer types. In this study, the anti-cancer activities of a novel flurbiprofen organic selenium compound, RY-1-92, on NSCLC cells and a mouse model and the underlying molecular mechanisms were explored. We found that compound RY-1-92 can significantly inhibit the viability, colony formation and migration of A549, NCI-H460 lung cancer cells. Flow cytometry analysis showed that RY-1-92 also can lead to G2/M cell cycle arrest and apoptosis induced in lung cancer cells. Further, RY-1-92 can decrease the tumor size in the Lewis lung cancer tumor-bearing mouse model. The protein levels of cell cycle-related proteins CDK1/cyclinB1 were decreased, while the apoptosis-related protein BAX was increased dramatically after RY-1-92 treatment <em>in vitro</em> and <em>in vivo</em>. Impressively, it was found that TRPV1 might act as a potential molecular target of RY-1-92 using the SEA search server. Furthermore, down-regulation on TRPV1 and its downstream associated factors including p-AKT protein and MAPK signaling pathway-related proteins after RY-1-92 treatment was observed in A549, NCI-H460 lung cancer cells. Taken together, our findings shed light on the potential of RY-1-92 as a novel small molecular drug for NSCLC, and it is of great significance for its further in-depth research and development.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1737-1745"},"PeriodicalIF":3.597,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helical sulfonyl-γ-AApeptides for the inhibition of HIV-1 fusion and HIF-1α signaling","authors":"Xue Zhao, Heng Liu, Justin C. Zhang and Jianfeng Cai","doi":"10.1039/D4MD00110A","DOIUrl":"10.1039/D4MD00110A","url":null,"abstract":"<p >Synthetic helical peptidic foldamers show promising applications in chemical biology and biomedical sciences by mimicking protein helical segments. Sulfonyl-γ-AApeptide helices developed by our group exhibit good chemodiversity, predictable folding structures, proteolytic resistance, favorable cell permeability, and enhanced bioavailability. Herein, in this minireview, we highlight two recent examples of homogeneous left-handed sulfonyl-γ-AApeptide helices to modulate protein–protein interactions (PPIs). One is sulfonyl-γ-AApeptides as anti-HIV-1 fusion inhibitors mimicking the helical C-terminal heptad repeat (CHR), which show excellent anti-HIV-1 activities through tight binding with the N-terminal heptad repeat (NHR) and inhibiting the formation of the 6-helical bundle (HB) structure. Another example is helical sulfonyl-γ-AApeptides disrupting hypoxia-inducible factor 1α (HIF-1α) and p300 PPI, thus selectively inhibiting the relevant signaling cascade. We hope these findings could help to elucidate the principles of the structural design of sulfonyl-γ-AApeptides and inspire their future applications in PPI modulations.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1418-1423"},"PeriodicalIF":3.597,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140589066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of fragments targeting SMYD3 using highly sensitive kinetic and multiplexed biosensor-based screening†","authors":"Edward A. FitzGerald, Daniela Cederfelt, Bjarte Aarmo Lund, Nadine E. M. Myers, He Zhang, Doreen Dobritzsch and U. Helena Danielson","doi":"10.1039/D4MD00093E","DOIUrl":"10.1039/D4MD00093E","url":null,"abstract":"<p >A 1056-membered fragment library has been screened against SMYD3 using a novel multiplexed experimental design implemented in a grating coupled interferometry (GCI)-based biosensor. SMYD3 is a prospective target for anticancer drugs and the focus has initially been on discovery of inhibitors of its lysine methyl transferase activity. However, it has multiple protein interaction partners and several potential roles in carcinogenesis. It therefore remains unclear what mode of action ligands targeting the protein should have. Our goal was therefore to identify new ligands and discriminate hits that interact with the active site and those that interact with other sites. In addition, we were interested in selecting hits based on kinetic features rather than affinity. Screening was done in parallel against SMYD3 alone or SMYD3 with the active site blocked by a tight binding inhibitor. Hit selection was primarily based on dissociation rates. In total, 20 fragments were selected as hits, of which half apparently targeted the active site and half targeted other sites. Twelve of the hits were selected for structural analysis using X-ray crystallography in order to identify binding sites and modes of binding. Four of the hits were successfully identified in crystal structures with SMYD3; the others did not show any electron densities for ligands in the crystals. Although it might be possible to optimize the crystallography approach for a better success rate, it was clear that the sensitivity and time resolution of the biosensor assay was exceptional and enabled kinetic rate constants to be estimated for fragments. Fragments are typically considered to interact too rapidly for such quantification to be possible. This approach consequently represents a paradigm shift. In addition, the multiplexed approach allows ligands targeting different sites to be rationally selected already in the fragment library screening stage.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 1982-1990"},"PeriodicalIF":3.597,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00093e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140801341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Live cell screening to identify RNA-binding small molecule inhibitors of the pre-let-7–Lin28 RNA–protein interaction†","authors":"Sydney L. Rosenblum, Dalia M. Soueid, George Giambasu, Steve Vander Roest, Alexander Pasternak, Erin F. DiMauro, Vladimir Simov and Amanda L. Garner","doi":"10.1039/D4MD00123K","DOIUrl":"10.1039/D4MD00123K","url":null,"abstract":"<p >Dysregulation of the networking of RNA-binding proteins (RBPs) and RNAs drives many human diseases, including cancers, and the targeting of RNA–protein interactions (RPIs) has emerged as an exciting area of RNA-targeted drug discovery. Accordingly, methods that enable the discovery of cell-active small molecule modulators of RPIs are needed to propel this emerging field forward. Herein, we describe the application of live-cell assay technology, RNA interaction with protein-mediated complementation assay (RiPCA), for high-throughput screening to identify small molecule inhibitors of the pre-let-7d–Lin28A RPI. Utilizing a combination of RNA-biased small molecules and virtual screening hits, we discovered an RNA-binding small molecule that can disrupt the pre-let-7–Lin28 interaction demonstrating the potential of RiPCA for advancing RPI-targeted drug discovery.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1539-1546"},"PeriodicalIF":3.597,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00123k?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140316348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coumarin–furo[2,3-d]pyrimidone hybrid molecules targeting human liver cancer cells: synthesis, anticancer effect, EGFR inhibition and molecular docking studies†","authors":"Tianshuai Wang, Yumeng Gao, Fengxu Wu, Lun Luo, Junkai Ma and Yanggen Hu","doi":"10.1039/D3MD00668A","DOIUrl":"10.1039/D3MD00668A","url":null,"abstract":"<p >The design, synthesis and investigation of antitumor activities of some coumarin–furo[2,3-<em>d</em>]pyrimidone hybrid molecules are reported. <em>In vitro</em>, HepG2 cells were used to investigate the cytotoxicity of <strong>6a–n</strong> and <strong>10a–n</strong>. The results demonstrated that coupling a furopyrimidone scaffold with coumarin through a hydrazide linker can effectively improve their synergistic anticancer activity. The coumarin–furo[2,3-<em>d</em>]pyrimidone combination <strong>10a</strong> exhibited significant inhibitory activity against HepG2 cells with IC<small>₅₀</small> = 7.72 ± 1.56 μM, which is better than those of gefitinib and sorafenib. It is worth mentioning that the coumarin–furo[2,3-<em>d</em>]pyrimidone combination <strong>10a</strong> showed excellent inhibition of the EGFR enzymatic activity with IC<small>₅₀</small> = 1.53 μM and 90% inhibition at 10 μM concentration. <em>In silico</em> investigation predicts the possibility of direct binding between the new coumarin–furo[2,3-<em>d</em>]pyrimidone hybrid molecules and the EGFR. The results suggest that coumarin–furo[2,3-<em>d</em>]pyrimidone hybrid molecules are potential antitumor agents targeting human liver cancer cells.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1565-1577"},"PeriodicalIF":3.597,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140588943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in vivo evaluation of novel chromeno[2,3-d]pyrimidinones as therapeutic agents for triple negative breast cancer†","authors":"Luísa Carvalho, Fábio Pedroso de Lima, Mónica Cerqueira, Ana Silva, Olívia Pontes, Sofia Oliveira-Pinto, Sara Guerreiro, Marta D. Costa, Sara Granja, Patrícia Maciel, Adhemar Longatto-Filho, Fátima Baltazar, Fernanda Proença and Marta Costa","doi":"10.1039/D3MD00682D","DOIUrl":"10.1039/D3MD00682D","url":null,"abstract":"<p >Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and the limited therapeutic options show poor efficacy in patients, associated to severe side effects and development of resistance. Considering that chromene-based scaffolds proved to be attractive candidates for cancer therapy, herein we prepared new chromeno[2,3-<em>d</em>]pyrimidinone derivatives by a simple two step procedure, starting from the reaction of cyanoacetamide and a salicylaldehyde. A cell viability screening in several breast cancer cell lines allowed to identify two promising compounds with IC<small>₅₀</small> values in the low micromolar range for TNBC cells. These chromenes inhibited cell proliferation, induced cell cycle arrest and triggered cell death through apoptosis. <em>In vivo</em> studies revealed a safe profile in invertebrate and vertebrate animal models and confirmed their capacity to inhibit tumor growth in the CAM model, inducing significant tumor regression after 4 days of treatment. The two compounds identified in this study are promising drug candidates for TNBC treatment and valuable hits for future optimization, using the versatile synthetic platform that was developed.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1362-1380"},"PeriodicalIF":3.597,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140167260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based virtual screening of unbiased and RNA-focused libraries to identify new ligands for the HCV IRES model system†","authors":"Elisabeth Kallert, Laura Almena Rodriguez, Jan-Åke Husmann, Kathrin Blatt and Christian Kersten","doi":"10.1039/D3MD00696D","DOIUrl":"10.1039/D3MD00696D","url":null,"abstract":"<p >Targeting RNA including viral RNAs with small molecules is an emerging field. The hepatitis C virus internal ribosome entry site (HCV IRES) is a potential target for translation inhibitor development to raise drug resistance mutation preparedness. Using RNA-focused and unbiased molecule libraries, a structure-based virtual screening (VS) by molecular docking and pharmacophore analysis was performed against the HCV IRES subdomain IIa. VS hits were validated by a microscale thermophoresis (MST) binding assay and a Förster resonance energy transfer (FRET) assay elucidating ligand-induced conformational changes. Ten hit molecules were identified with potencies in the high to medium micromolar range proving the suitability of structure-based virtual screenings against RNA-targets. Hit compounds from a 2-guanidino-quinazoline series, like the strongest binder, compound <strong>8b</strong> with an EC<small>₅₀</small> of 61 μM, show low molecular weight, moderate lipophilicity and reduced basicity compared to previously reported IRES ligands. Therefore, it can be considered as a potential starting point for further optimization by chemical derivatization.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 1527-1538"},"PeriodicalIF":3.597,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d3md00696d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140316436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}