RSC medicinal chemistry最新文献

{"title":"Developing peptide-based fusion inhibitors as an antiviral strategy utilizing coronin 1 as a template.","authors":"Manbit Subhadarsi Panda, Bushra Qazi, Vaishali Vishwakarma, Gourab Prasad Pattnaik, Sourav Haldar, Hirak Chakraborty","doi":"10.1039/d4md00523f","DOIUrl":"https://doi.org/10.1039/d4md00523f","url":null,"abstract":"<p><p>Enveloped viruses enter the host cells by endocytosis and subsequently fuse with the endosomal membranes, or fuse with the plasma membrane at the cell surface. The crucial stage of viral infection, regardless of the route taken to enter the host cell, is membrane fusion. The present work aims to develop a peptide-based fusion inhibitor that prevents membrane fusion by modifying the properties of the participating membranes, without targeting a protein. This would allow us to develop a fusion inhibitor that might work against a larger spectrum of enveloped viruses as it does not target any specific viral fusion protein. With this goal in mind, we have designed a novel peptide by modifying a native sequence derived from coronin 1, a phagosomal protein, that helps to avoid lysosomal degradation of mycobacterium-loaded phagosomes. The designed peptide, mTG-23, inhibits ∼30-40% fusion between small unilamellar vesicles containing varying amounts of cholesterol by modulating the biophysical properties of the participating bilayers. As a proof of principle, we have further demonstrated that the mTG-23 inhibits Influenza A virus infection in A549 and MDCK cells (with ∼EC₅₀ of 20.45 μM and 21.55 μM, respectively), where viral envelope and endosomal membrane fusion is a crucial step. Through a gamut of biophysical and biochemical methods, we surmise that mTG-23 inhibits viral infection by inhibiting viral envelope and endosomal membrane fusion. We envisage that the proposed antiviral strategy can be extended to other viruses that employ a similar modus operandi, providing a novel pan-antiviral approach.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New anti-ovarian cancer quinolone derivatives acting by modulating microRNA processing machinery.","authors":"Tommaso Felicetti, Nicola Di Iacovo, Maria Agnese Della Fazia, Danilo Piobbico, Stefania Pieroni, Martina Pacetti, Jialing Yu, Yilun Sun, Serena Massari, Maria Letizia Barreca, Stefano Sabatini, Oriana Tabarrini, Violetta Cecchetti, Fei Wang, Yves Pommier, Mariangela Morlando, Giuseppe Servillo, Giuseppe Manfroni","doi":"10.1039/d4md00649f","DOIUrl":"10.1039/d4md00649f","url":null,"abstract":"<p><p>MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI₅₀ values 13.52-31.04 μM) and CC_{50 Wi-38} = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (<i>K</i> _D = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11467779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel curcumin-based analogues as potential VEGFR2 inhibitors with promising metallic loading nanoparticles: synthesis, biological evaluation, and molecular modelling investigation†","authors":"Asmaa S. A. Yassen, Sherief M. Abdel-Wahab, Khaled M. Darwish, Mohamed S. Nafie, Reda F. A. Abdelhameed, Gharieb S. El-Sayyad, Ahmed I. El-Batal, Khadiga M. Attia, Hosam A. Elshihawy and Ranza Elrayess","doi":"10.1039/D4MD00574K","DOIUrl":"10.1039/D4MD00574K","url":null,"abstract":"<p >VEGFR2 inhibition has been established as a therapeutic approach for managing cancer. A series of curcumin-based analogues were designed, synthesized, and screened for their anticancer activity against MCF-7 and HepG-2 cell lines and WISH normal cells. Compounds <strong>4b</strong>, <strong>4d</strong>, <strong>4e</strong>, and <strong>4f</strong> showed potent cytotoxicity against MCF-7 with IC<small>₅₀</small> values of 0.49, 0.14, 0.01, and 0.32 μM, respectively, compared to curcumin (IC<small>₅₀</small> = 13.8 μM) and sorafenib (IC<small>₅₀</small> = 2.13 μM). Interestingly, compound <strong>4e</strong>, the most active compound, exhibited potent VEGFR2 inhibition with an IC<small>₅₀</small> value of 11.6 nM (96.5% inhibition) compared to sorafenib with an IC<small>₅₀</small> value of 30 nM (94.8% inhibition). Additionally, compound <strong>4e</strong> significantly induced apoptotic cell death in MCF-7 cells by 41.1% compared to a control group (0.8%), halting cell division during the G2/M phase by 39.8% compared to the control (21.7%). Molecular docking-coupled dynamics simulations highlighted the bias of the VEGFR2 pocket towards compound <strong>4e</strong> compared to other synthesized compounds. Predicting superior binding affinities and relevant interactions with the pocket's key residues recapitulated <em>in vitro</em> findings towards higher inhibition activity for compound <strong>4e</strong>. Furthermore, compound <strong>4e</strong> with adequate pharmacokinetic and drug-likeness profiles in terms of ADME and safety characteristics can serve as a promising clinical candidate for future lead optimization and development. Notably, <strong>4e</strong>–Fe<small>₂</small>O<small>₃</small>-humic acid NPs exhibited potent cytotoxicity with IC<small>₅₀</small> values of 2.41 and 13.4 ng mL<small>⁻¹</small> against MCF-7 and HepG-2 cell lines, respectively. Hence, compound <strong>4e</strong> and its Fe<small>₂</small>O<small>₃</small>-humic acid-NPs could be further developed as promising anti-breast cancer agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4039-4067"},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353066","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}

{"title":"Assessing the biocompatibility and stability of CeO2 nanoparticle conjugates with azacrowns for use as radiopharmaceuticals†","authors":"Sofia Khabirova, Mikhail Menshikov-Tonyan, Gleb Aleshin, Anastasia Prikhodko, Daniil Kozlov, Evgeny Anokhin, Konstantin Babeshkin, Nikolay Titchenko, Anastasia Zubenko, Anna Shchukina, Yuri Fedorov and Stepan Kalmykov","doi":"10.1039/D4MD00515E","DOIUrl":"10.1039/D4MD00515E","url":null,"abstract":"<p >The application of nanoparticles is promising for the purposes of nuclear medicine due to the possibilities of using them as vectors and transporters of radionuclides. In this study, we have successfully synthesised conjugates of CeO<small>₂</small> nanoparticles and azacrown ligands. Then, the radiolabelling conditions with radionuclides <small>⁶⁵</small>Zn, <small>⁴⁴</small>Sc and <small>²⁰⁷</small>Bi were selected and the kinetic stability of the complexes in biologically significant media was evaluated. Optimum conditions for CeO<small>₂</small>-APTES-L and CeO<small>₂</small>-APTES-DOTA labelling were found: 0.1 g l<small>⁻¹</small> conjugate and 10<small>⁻⁹</small> M metal cations at 90 °C for complexes with [<small>⁶⁵</small>Zn]Zn<small>²⁺</small>, [<small>⁴⁴</small>Sc]Sc<small>³⁺</small> and [<small>²⁰⁷</small>Bi]Bi<small>³⁺</small>. CeO<small>₂</small>-APTES-L-<small>⁴⁴</small>Sc (radiochemical purity more than 90%) was stable in fetal bovine serum. The obtained results enabled us to choose the most promising complex for biomedical applications for carrying out <em>in vitro</em> and <em>in vivo</em> biodistribution research. Nanoceria and its derivative showed no obvious toxicity to human endothelial cells EA.hy926. Then, the <em>in vivo</em> stability of the studied scandium complex was demonstrated. Taken together, our studies show that functionalised cerium oxide nanoparticles lead to stable radiolabelled nanosystems that may be used for targeted drug delivery, diagnosis and treatment of oncological diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4100-4110"},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353060","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}

{"title":"Generation and capture of naphthoquinonynes: a new frontier in the development of trypanocidal quinones <i>via</i> aryne chemistry.","authors":"Laura P R Figueroa, Renato L de Carvalho, Renata G Almeida, Esther R S Paz, Emilay B T Diogo, Maria H Araujo, Warley S Borges, Victor F S Ramos, Rubem F S Menna-Barreto, James M Wood, John F Bower, Eufrânio N da Silva Júnior","doi":"10.1039/d4md00558a","DOIUrl":"https://doi.org/10.1039/d4md00558a","url":null,"abstract":"<p><p>The regioselective synthesis of functionalized naphthoquinones <i>via</i> the formation and capture of naphthoquinonynes has been used to prepare trypanocidal compounds. The target compounds are functionalized on the aromatic ring, leaving the quinoidal ring intact. Using this technique, eighteen functionalized naphthoquinones were succesfull obtained, divided in two main groups: the first scope using <i>N</i>-nucleophiles, and the second scope using pyridine <i>N</i>-oxides, with yields up to 74%. Evaluation against bloodstream trypomastigotes of <i>T. cruzi</i> has identified fourteen compounds that are more potent than benznidazole (Bz); for instance, compounds 29b-I and 30b, with IC₅₀/24 h values of 10.5 and 10.1 μM, respectively, are approximately 10-fold more active than Bz. This study provides the first examples of the application of naphthoquinonyne chemistry for the synthesis of new compounds with potent trypanocidal activities.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11539365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrophobic CPP/HDO conjugates: a new frontier in oligonucleotide-warheaded PROTAC delivery†","authors":"Miyako Naganuma, Nobumichi Ohoka, Motoharu Hirano, Daishi Watanabe, Genichiro Tsuji, Takao Inoue and Yosuke Demizu","doi":"10.1039/D4MD00546E","DOIUrl":"10.1039/D4MD00546E","url":null,"abstract":"<p >Proteolysis-targeting chimeras (PROTACs) have emerged as a potent strategy for inducing targeted degradation of proteins, offering promising therapeutic potential to treat diseases such as cancer. However, oligonucleotide-based PROTACs face significant delivery challenges because of their anionic nature and chemical instability. To address these issues, we developed a novel hydrophobic cell-penetrating peptide (CPP) and heteroduplex oligonucleotide (HDO)-conjugated PROTAC, <strong>CPP/HDO-PROTAC</strong>, to enhance intracellular delivery and degradation efficiency. <strong>CPP/HDO-PROTAC</strong> was designed to enter the cell through the activity of the conjugated hydrophobic CPP and release decoy oligonucleotide-based PROTACs by RNase H-mediated RNA strand breaks. Our findings demonstrated that <strong>CPP/HDO-PROTAC</strong> binds to the estrogen receptor α (ERα) with higher affinity than previous constructs, significantly degrades ERα in MCF-7 human breast cancer cells and inhibits cell proliferation at 10 μM. This research highlights the potential of <strong>CPP/HDO-PROTAC</strong> as a viable method for delivering and activating decoy oligonucleotide-based PROTACs within cells, overcoming the limitations of traditional transfection methods and paving the way for their clinical application.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 11","pages":" 3695-3703"},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473771","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}

{"title":"Mannich reaction mediated derivatization of chromones and their biological evaluations as putative multipotent ligands for the treatment of Alzheimer's disease†","authors":"Naveen Kumar, Kailash Jangid, Vinay Kumar, Bharti Devi, Tania Arora, Jayapriya Mishra, Vijay Kumar, Ashish Ranjan Dwivedi, Jyoti Parkash, Jasvinder Singh Bhatti and Vinod Kumar","doi":"10.1039/D4MD00550C","DOIUrl":"10.1039/D4MD00550C","url":null,"abstract":"<p >Alzheimer's disease (AD) is a complex neurological disorder and multiple pathways are associated with its pathology. Currently available single-targeting drugs are found to be ineffective for the treatment of AD, and most of these drugs provide symptomatic relief. The multi-target directed ligand strategy is proposed as an effective approach for the treatment of AD. Herein, we report the design and synthesis of a series of 2-phenyl substituted chromone derivatives and their evaluation against AChE, MAO-B, and β amyloid self-aggregation inhibition. In the series, <strong>NS-</strong><strong>4</strong> and <strong>NS-</strong><strong>13</strong> were identified as the potent leads against all the specified targets. <strong>NS-</strong><strong>4</strong> and <strong>NS-</strong><strong>13</strong> exhibited balanced multipotent activities against AChE with IC<small>₅₀</small> values of 3.09 μM, and 0.625 μM and against MAO-B with IC<small>₅₀</small> values of 19.64 μM and 12.31 μM, respectively. These compounds also displayed 28.5% and 32.2% self-aggregation inhibition potential against Aβ<small>_1–42</small>, respectively. All the compounds were found to be selective for AChE over BuChE. Additionally, <strong>NS-</strong><strong>4</strong> also exhibited potent BuChE inhibition with an IC<small>₅₀</small> value of 1.95 μM. Moreover, <strong>NS-</strong><strong>4</strong> and <strong>NS-</strong><strong>13</strong> reduced intracellular ROS levels up to 65% against SH-SY5Y cells at 25 μM concentration. The lead compounds were found to be neuroprotective and exhibited no cytotoxicity even at 25 μM concentration. In enzyme kinetic inhibition studies, these compounds showed mixed-type inhibition to AChE. In the computational studies, binding interactions, and orientations of the ligands at the active site of the enzymes were analyzed and these lead compounds were found to be thermodynamically stable inside the active cavity for up to 100 ns.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4206-4221"},"PeriodicalIF":4.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473773","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}

{"title":"Unveiling the anticancer potential of plumbagin: targeting pyruvate kinase M2 to induce oxidative stress and apoptosis in hepatoma cells","authors":"Jun Wu, Zhenjiang Ding, Jingwen Tu, Alsiddig Osama, Qiuying Nie, Wenqing Cai and Baoxin Zhang","doi":"10.1039/D4MD00519H","DOIUrl":"10.1039/D4MD00519H","url":null,"abstract":"<p >Pyruvate kinase M2 (PKM2), a crucial enzyme in the glycolysis pathway, is commonly documented as being overexpressed in cancer cells. Inhibiting PKM2, a strategy to mitigate cancer cell-dependent glycolysis, has demonstrated efficacy in anticancer treatment. In this study, plumbagin, which was originally extracted from the plant <em>Plumbago zeylanica</em> L., was discovered as a novel PKM2 inhibitor and it could bind to PKM2 to inhibit the enzymatic activity. Treatment with plumbagin in HepG2 cells resulted in the decrease of PKM2 expression, which in turn reduced the protein kinase function. The mRNA levels of its downstream genes, such as <em>LDHA</em> and <em>MYC</em>, were suppressed. Additionally, plumbagin downregulated the expression of intracellular antioxidant proteins, which induced oxidative stress and mitochondrial damage, ultimately triggering apoptosis. Moreover, plumbagin also reduced the migration and proliferation of HepG2 cells. This study offered valuable insights into the molecular mechanism of plumbagin and advocated for the exploration of PKM2 inhibitors as viable possibilities for anticancer therapeutics.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4126-4137"},"PeriodicalIF":4.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372761","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}

{"title":"Inhibition of SARS-CoV-2 3CLpro by chemically modified tyrosinase from Agaricus bisporus†","authors":"David Aguilera-Rodriguez, David Ortega-Alarcon, Angela Vazquez-Calvo, Veronica Ricci, Olga Abian, Adrian Velazquez-Campoy, Antonio Alcami and Jose M. Palomo","doi":"10.1039/D4MD00289J","DOIUrl":"10.1039/D4MD00289J","url":null,"abstract":"<p >Antiviral compounds are crucial to controlling the SARS-CoV-2 pandemic. Approved drugs have been tested for their efficacy against COVID-19, and new pharmaceuticals are being developed as a complementary tool to vaccines. In this work, a cheap and fast purification method for natural tyrosinase from <em>Agaricus bisporus</em> (AbTyr) fresh mushrooms was developed to evaluate the potential of this enzyme as a therapeutic protein <em>via</em> the inhibition of SARS-CoV-2 3CLpro protease activity <em>in vitro</em>. AbTyr showed a mild inhibition of 3CLpro. Thus, different variants of this protein were synthesized through chemical modifications, covalently binding different tailor-made glycans and peptides to the amino terminal groups of the protein. These new tyrosinase conjugates were purified and characterized through circular dichroism and fluorescence spectroscopy analyses, and their stability was evaluated under different conditions. Subsequently, all these tyrosinase conjugates were tested for 3CLpro protease inhibition. From them, the conjugate between tyrosinase and a dextran-aspartic acid (6 kDa) polymer showed the highest inhibition, with an IC<small>₅₀</small> of 2.5 μg ml<small>⁻¹</small> and IC<small>₉₀</small> of 5 μg ml<small>⁻¹</small>, with no cytotoxicity activity by polymer insertion. Finally, SARS-CoV-2 virus infection was studied. It was found that this new AbTyr-Dext6000 protein showed an 80% decrease in viral load. These results show the capacity of these tyrosinase bioconjugates as potential therapeutic proteins, opening the possibility of extension and applicability against other different viruses.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 12","pages":" 4159-4167"},"PeriodicalIF":4.1,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sidechain structure–activity relationships of cyclobutane-based small molecule αvβ3 antagonists†","authors":"Adam Throup, Manar Saleh Zraikat, Andrew Gordon, Shohreh Jafarinejad Soumehsaraei, Kathrin D. Haase, Laurence H. Patterson, Patricia A. Cooper, Katherine Hanlon, Paul M. Loadman, Mark Sutherland, Steven D. Shnyder and Helen M. Sheldrake","doi":"10.1039/D4MD00306C","DOIUrl":"10.1039/D4MD00306C","url":null,"abstract":"<p >The integrin family of cell surface extracellular matrix binding proteins are key to several physiological processes involved in tissue development, as well as cancer proliferation and dissemination. They are therefore attractive targets for drug discovery with cancer and non-cancer applications. We have developed a new integrin antagonist chemotype incorporating a functionalised cyclobutane ring as the central scaffold in an arginine–glycine–aspartic acid mimetic structure. Here, we report the synthesis of cyclobutanecarboxylic acids and cyclobutylamines with tetrahydronaphthyridine and aminopyridine arginine mimetic sidechains and masked carboxylic acid aspartic acid mimetic sidechains of varying length. Effective αvβ3 antagonists and new aspartic acid mimetics were identified in cell-based adhesion and invasion assays. A lead compound selected based on <em>in vitro</em> activity (IC<small>₅₀</small> &lt; 1 μM), stability (<em>t</em><small>_1/2</small> &gt; 80 minutes) and synthetic tractability was well-tolerated <em>in vivo</em>. These results show the promise of this synthetic approach for developing αvβ3 antagonists and provide a firm foundation to progress into advanced preclinical evaluation prior to progression towards the clinic. Additionally, they highlight the use of functionalised cyclobutanes as metabolically stable core structures and a straightforward and robust method for their synthesis. This important contribution to the medicinal chemists' toolbox paves the way for increased use of cyclobutanes in drug discovery.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" 10","pages":" 3616-3624"},"PeriodicalIF":4.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00306c?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}