MedChemComm最新文献

{"title":"Evaluating the therapeutic potential of genetically engineered probiotic Zbiotics (ZB183) for non-alcoholic steatohepatitis (NASH) management via modulation of the cGAS-STING pathway†","authors":"Maha Saad, Walaa Ibrahim, Amany Helmy Hasanin, Aya Magdy Elyamany and Marwa Matboli","doi":"10.1039/D4MD00477A","DOIUrl":"10.1039/D4MD00477A","url":null,"abstract":"<p >NAFLD/NASH has emerged as a global health concern with no FDA-approved treatment, necessitating the exploration of novel therapeutic elements for NASH. Probiotics are known as an important adjunct therapy in NASH. Zbiotics (ZB183) is the first commercially available genetically engineered probiotic. Herein, we aimed to evaluate the potential therapeutic effects of Zbiotics administration on NASH management by modulating the cGAS-STING-signaling pathway-related RNA network. <em>In silico</em> data analysis was performed and three DEGs (MAPK3/EDN1/TNF) were selected with their epigenetic modulators (miR-6888-5p miRNA, and lncRNA RABGAP1L-DT-206). The experimental design included NASH induction with an HSHF diet in Wistar rats and Zbiotics administration in NASH rats in comparison to statin treatment. Liver functions and lipid profile were assessed. Additionally, the expression levels of the constructed molecular network were assessed using RT-PCR. Moreover, the Zbiotics effects in NASH were further validated with histopathological examination of liver and colon samples. Also, immunohistochemistry staining of hepatic TNF-α and colonic occludin was assessed. Oral administration of Zbiotics for four weeks downregulated the expression of the cGAS-STING-related network (MAPK3/EDN1/TNF/miR-6888-5p miRNA/lncRNA RABGAP1L-DT-206) in NASH models. Zbiotics also ameliorated hepatic inflammation and steatosis, as evidenced by a notable improvement in NAS score and decreased hepatic TNF-α levels. Furthermore, Zbiotics exhibited favorable effects on colon health, including increased crypt length, reduced inflammatory cell infiltration, and restoration of colonic mucosa occludin expression. In conclusion, our findings suggest that Zbiotics has potential therapeutic effects on NASH <em>via</em> modulating the gut–liver axis and the cGAS-STING signaling pathway.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3817-3836"},"PeriodicalIF":3.597,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252050","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":"DC-derived whole cell cytokine nano-regulator for remodelling extracellular matrix and synergizing tumor immunotherapy†","authors":"Jingsong Lu, Ying Li, Xiaohan Gao, Sumei Chen, Zeping Jin, Xiaoxiao Guo, Wensheng Xie, Zhenhu Guo, Yen Wei and Lingyun Zhao","doi":"10.1039/D4MD00496E","DOIUrl":"10.1039/D4MD00496E","url":null,"abstract":"<p >A smart dendritic cell (DC)-derived whole cell cytokine (DWC) nano-regulator of TCPs was developed for tumor cytokine-immunotherapy. The DWCs were purified from activated DC-cultured media and applied as a nano-dosage form. It was found that TCPs could remodel extracellular matrices <em>via</em> the elimination of fibronectin and type I collagen (Col-I) in tumor tissues, as well as the inhibition of α-SMA expression in cancer associated fibroblasts (CAFs). Furthermore, after local TCP treatment, significant tumor inhibition could be achieved combined with radiotherapy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4090-4099"},"PeriodicalIF":3.597,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353062","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":"Replacement of nitro function by free boronic acid in non-steroidal anti-androgens†","authors":"Petr Šlechta, Roman Viták, Pavel Bárta, Kateřina Koucká, Monika Berková, Diana Žďárová, Andrea Petríková, Jiří Kuneš, Vladimír Kubíček, Martin Doležal, Radek Kučera and Marta Kučerová-Chlupáčová","doi":"10.1039/D4MD00343H","DOIUrl":"10.1039/D4MD00343H","url":null,"abstract":"<p >A new series of potential flutamide-like antiandrogens has been designed and synthesized to treat prostate cancer. This new series results from our research, which has been aimed at discovering new compounds that can be used for androgen deprivation treatment. The antiandrogens were designed and synthesized by varying the acyl part, linker, and substitution of the benzene ring in the 4-nitro-3-trifluoromethylanilide scaffold of non-steroidal androgens. In addition, the characteristic feature of the nitro group was replaced by a boronic acid functionality. Compound <strong>9a</strong> was found to be more effective against LAPC-4 than the standard antiandrogens flutamide, hydroxyflutamide, and bicalutamide. Moreover, it exhibited lower toxicity against the non-cancerous cell line HK-2. The initial <em>in silico</em> study did not show evidence of covalent bonding to the androgen receptor, which was confirmed by an NMR binding experiment with arginine methyl ester. The structure–activity relationships discovered in this study could provide directions for further research on non-steroidal antiandrogens.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4018-4038"},"PeriodicalIF":3.597,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353067","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":"Strong in vitro anticancer activity of copper(ii) and zinc(ii) complexes containing naturally occurring lapachol: cellular effects in ovarian A2780 cells†‡","authors":"Sara Stocchetti, Ján Vančo, Jan Belza, Zdeněk Dvořák and Zdeněk Trávníček","doi":"10.1039/D4MD00543K","DOIUrl":"10.1039/D4MD00543K","url":null,"abstract":"<p >Copper(<small>II</small>) and zinc(<small>II</small>) complexes with lapachol (HLap) of the composition [M(Lap)<small>₂</small>(N–N)] and [Cu(Lap)(H<small>₂</small>O)(terpy)]NO<small>₃</small> (<strong>4</strong>), where M = Cu (<strong>1–3</strong>) or Zn (for <strong>5–7</strong>), and N–N stands for bathophenanthroline (<strong>1</strong> and <strong>5</strong>), 5-methyl-1,10-phenanthroline (<strong>2</strong> and <strong>6</strong>), 2,2′-bipyridine (<strong>3</strong>), 2,2′;6′,2′′-terpyridine (terpy, <strong>4</strong>) and 1,10-phenanthroline (<strong>7</strong>), were synthesised and characterised. Complexes <strong>1–5</strong> revealed strong <em>in vitro</em> antiproliferative effects against A2780, A2780R, MCF-7, PC-3, A549 and HOS human cancer lines and MRC-5 normal cells, with IC<small>₅₀</small> values above 0.5 μM, and reasonable selectivity index (SI), with SI &gt; 3.8 for IC<small>₅₀</small>(MRC-5)/IC<small>₅₀</small>(A2780). Considerable time-dependent cytotoxicity in A2780 cells was observed for complexes <strong>6</strong> and <strong>7</strong>, with IC<small>₅₀</small> &gt; 50 μM (24 h) to <em>ca.</em> 4 μM (48 h). Cellular effects of complexes <strong>1</strong>, <strong>5</strong> and <strong>7</strong> in A2780 cells were investigated by flow cytometry revealing that the most cytotoxic complexes (<strong>1</strong> and <strong>5</strong>) significantly perturbed the mitochondrial membrane potential and the interaction with mitochondrial metabolism followed by the triggering of the intracellular pathway of apoptosis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 12","pages":" 4180-4192"},"PeriodicalIF":3.597,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11451940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142381607","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":"Rationally modified SNX-class Hsp90 inhibitors disrupt extracellular fibronectin assembly without intracellular Hsp90 activity†","authors":"Gciniwe S. Mathenjwa, Abir Chakraborty, Abantika Chakraborty, Ronel Muller, Mathew P. Akerman, Moira L. Bode, Adrienne L. Edkins and Clinton G. L. Veale","doi":"10.1039/D4MD00501E","DOIUrl":"10.1039/D4MD00501E","url":null,"abstract":"<p >Despite Hsp90's well documented promise as a target for developing cancer chemotherapeutics, its inhibitors have struggled to progress through clinical trials. This is, in part, attributed to the cytoprotective compensatory heat shock response (HSR) stimulated through intracellular Hsp90 inhibition. Beyond its intracellular role, secreted extracellular Hsp90 (eHsp90) interacts with numerous pro-oncogenic extracellular clients. This includes fibronectin, which in the tumour microenvironment enhances cell invasiveness and metastasis. Through the rational modification of known Hsp90 inhibitors (SNX2112 and SNX25a) we developed four Hsp90 inhibitory compounds, whose alterations restricted their interaction with intracellular Hsp90 and did not stimulate the HSR. Two of the modified cohort (compounds <strong>10</strong> and <strong>11</strong>) were able to disrupt the assembly of the extracellular fibronectin network at non-cytotoxic concentrations, and thus represent promising new tool compounds for studying the druggability of eHsp90 as a target for inhibition of tumour invasiveness and metastasis.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 3609-3615"},"PeriodicalIF":3.597,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00501e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252006","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":"Design and synthesis of novel multi-target tetrabromophthalimides as CBS and Topo-II inhibitors and DNA intercalators†","authors":"Marwa Abdel-Motaal, Dalal Ali Aldakhili, Ayman B. Farag, Ayman Abo Elmaaty, Marwa Sharaky, Nadia A. Mohamed, Saad Shaaban, Abdullah Yahya Abdullah Alzahrani and Ahmed A. Al-Karmalawy","doi":"10.1039/D4MD00585F","DOIUrl":"10.1039/D4MD00585F","url":null,"abstract":"<p >Microtubules are highly dynamic structures and constitute a crucial component of the cellular cytoskeleton. Besides, topoisomerases (Topo) play a fundamental role in maintaining the appropriate structure and organization of DNA. On the other hand, dual mechanism drug candidates for cancer treatment primarily aim to enhance the efficacy of cancer treatment and potentially overcome drug resistance. Hence, this work was tailored to design and synthesize new multi-target tetrabromophthalimide derivatives (<strong>2a–2k</strong>) that are capable of inhibiting the colchicine binding site (CBS) and topoisomerase II (Topo-II). The conducted <em>in vitro</em> studies showed that compound <strong>2f</strong> showed the lowest IC<small>₅₀</small> value (6.7 μg mL<small>⁻¹</small>) against the MDA-MB-468 cancer cell line. Additionally, compound <strong>2f</strong> prompted upregulation of pro-apoptotic markers (caspases 3, 7, 8, and 9, Bax and p53). Moreover, some anti-apoptotic proteins (MMP2, MMP9, and BCL-2) were downregulated by compound <strong>2f</strong> treatment. Besides, the colchicine binding assay showed that compounds <strong>2f</strong> and <strong>2k</strong> displayed promising inhibitory potential with IC<small>₅₀</small> values of 1.92 and 4.84 μg mL<small>⁻¹</small>, respectively, in comparison with colchicine (1.55 μg mL<small>⁻¹</small>). Furthermore, the Topo-II inhibition assay displayed the prominent inhibitory potential of compound <strong>2f</strong> with an IC<small>₅₀</small> value of 15.75 μg mL<small>⁻¹</small>, surpassing the IC<small>₅₀</small> of etoposide (20.82 μg mL<small>⁻¹</small>). Cell cycle analysis revealed that compound <strong>2f</strong> induced cell cycle arrest at both the G0–G1 and G2–M phases. The new candidates were docked against both the CBS (PDB ID: 5XIW) and Topo-II (PDB ID: 5CDP) targets to investigate their binding interactions and affinities as well. Accordingly, the synthesized compounds could serve as promising multi-target anticancer candidates with eligible apoptotic activity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3800-3816"},"PeriodicalIF":3.597,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252042","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":"Pyridinyl 4-(2-oxoalkylimidazolidin-1-yl)benzenesulfonates and their hydrochloride salts as novel water soluble antimitotic prodrugs bioactivated by cytochrome P450 1A1 in breast cancer cells†","authors":"Vincent Ouellette, Chahrazed Bouzriba, Atziri Corin Chavez Alvarez, Quentin Bruxelles, Geneviève Hamel-Côté and Sébastien Fortin","doi":"10.1039/D4MD00476K","DOIUrl":"10.1039/D4MD00476K","url":null,"abstract":"<p >We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC<small>₅₀</small>: 0.03–3.3 μM) and high selectivity (8–&gt;1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with <em>in vitro</em> hepatic half-lives (55–120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for <em>in vivo</em> studies.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3728-3745"},"PeriodicalIF":3.597,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252043","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":"Stachydrine, a pyrrole alkaloid with promising therapeutic potential against metabolic syndrome and associated organ dysfunction","authors":"Semim Akhtar Ahmed, Prasenjit Manna and Jagat Chandra Borah","doi":"10.1039/D4MD00425F","DOIUrl":"10.1039/D4MD00425F","url":null,"abstract":"<p >Metabolic syndrome is a multifaceted condition marked by interconnected risk factors, significantly increasing the risk of serious diseases like cardiovascular disease, type 2 diabetes, and stroke. Effective management often demands new medications due to complexity of the conditions and limitations of current treatments. Natural compounds are increasingly recognized in drug discovery due to their vast chemical diversity, commercial availability, low cost, and minimal side effects. One such compound is stachydrine (STA), also known as proline betaine or <em>N</em>-dimethyl proline. This simple pyrrole alkaloid is a major constituent of the genus <em>Leonurus</em> and the family Lamiaceae, and it shows promise due to its potential therapeutic properties. A comprehensive review of the literature, sourced from databases such as PubMed, Scopus, SciFinder, and Google Scholar, has provided extensive information on the sources, chemistry, biosynthesis, derivatives, molecular targets, biological activities, bioavailability, and toxicity of STA. This review highlights numerous <em>in vitro</em> and <em>in vivo</em> studies that demonstrate the effectiveness of STA in various therapeutic areas, including anti-obesity, neuroprotective, nephroprotective, and cardiovascular protection, among others. The wide range of biological activities of STA is attributed to its influence on multiple molecular targets and signaling pathways, such as ACE/AngII/AT1R-TGFβ1, NF-κB, JAK/STAT, AKT/ERK, AMPK/CAMKKβ/LKB1, CaMKII/PLN, <em>etc.</em> which are critical in the development and progression of metabolic syndrome. Additionally, this review addresses limitations related to the pharmacokinetics and bioavailability of STA. Overall, the findings underscore the potential of STA as a therapeutic agent for metabolic syndrome and related disorders, suggesting that further clinical investigation is warranted to fully understand and utilize its benefits.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3652-3673"},"PeriodicalIF":3.597,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252046","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":"Preventing SARS-CoV-2 infection using Fv-antibodies targeting the proprotein convertase (PPC) cleavage site","authors":"Jaeyong Jung, Jeong Soo Sung, Soonil Kwon, Hyung Eun Bae, Min-Jung Kang, Joachim Jose, Misu Lee and Jae-Chul Pyun","doi":"10.1039/D4MD00552J","DOIUrl":"10.1039/D4MD00552J","url":null,"abstract":"<p >Fv-antibodies targeting the proprotein convertase (PPC) region of the SARS-CoV-2 spike protein (SP) were screened from an Fv-antibody library to inhibit SARS-CoV-2 infection. Two selected Fv-antibodies were expressed as soluble recombinant proteins, and their binding affinities were assessed using a surface plasmon resonance biosensor. The binding regions of these Fv-antibodies corresponded to the cleavage sites of furin (S1/S2) and transmembrane serine protease 2 (TMPRSS2, S2′). The neutralizing activities of the two Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses carrying the SP of four different SARS-CoV-2 variants: wild-type (D614), delta (B.1.617.2), omicron (BA.2), and omicron (BA.4/5).</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 11","pages":" 3704-3710"},"PeriodicalIF":3.597,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142252045","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":"Design, synthesis and biological evaluation of a novel PSMA–PI3K small molecule drug conjugate†","authors":"Shouguo Peng, Haixia Li, Weilu Cui, Tianning Xiong, Jiaqi Hu, Haixiang Qi, Songwen Lin, Deyu Wu, Ming Ji and Heng Xu","doi":"10.1039/D4MD00246F","DOIUrl":"10.1039/D4MD00246F","url":null,"abstract":"<p >Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA–PI3K small molecule drug conjugate <strong>1</strong>. Conjugate <strong>1</strong> demonstrates potent inhibition against PI3K with an IC<small>₅₀</small> value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate <strong>1</strong> also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further <em>in vivo</em> evaluation shows that conjugate <strong>1</strong> has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 10","pages":" 3485-3494"},"PeriodicalIF":3.597,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154861","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}