Bioorganic & Medicinal Chemistry最新文献

{"title":"Sydnone-based prosthetic groups for radioiodination","authors":"Ludovic Le Saux ,&nbsp;Ferid Haddad ,&nbsp;Jean-François Gestin ,&nbsp;Romain Eychenne ,&nbsp;François Guérard","doi":"10.1016/j.bmc.2024.117904","DOIUrl":"10.1016/j.bmc.2024.117904","url":null,"abstract":"<div><p>The potential of Strained-Promoted Sydnone-Alkyne Cycloaddition (SPSAC) for radioiodination was evaluated with model cyclooctyne-conjugated peptides. Starting with a series of sydnones with varying N₃ and C₄ substitution, a preliminary kinetic study with non-radioactive iodinated compounds highlighted the superiority of an arylsydnone substituted by a chlorine atom in C₄ position. Interestingly, reaction rate up to 11 times higher than using an azide was achieved with the best system. Access to ¹²⁵I-labelled sydnones was granted with high efficiency from arylboronic acid precursors by copper catalyzed nucleophilic substitution. Application of SPSAC on the model peptide in radiotracer conditions showed the same trend than in non-radioactive kinetic study and complete reactions could be achieved within less than an hour for the best systems. These results are favorable for use in the production of radiopharmaceuticals with heavy halogens and increase the diversity of available bioorthogonal reaction for nuclear imaging and therapy.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"113 ","pages":"Article 117904"},"PeriodicalIF":3.3,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624003183/pdfft?md5=b267cfb011400737ad9b2cc8d49eb982&pid=1-s2.0-S0968089624003183-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel inhibitors of bromodomain and extra-terminal domain trigger cell death in breast cancer cell lines","authors":"Minna Rahnasto-Rilla,&nbsp;Tatu Puumalainen,&nbsp;Vilma Karttunen,&nbsp;Santosh Kumar Adla,&nbsp;Maija Lahtela-Kakkonen","doi":"10.1016/j.bmc.2024.117884","DOIUrl":"10.1016/j.bmc.2024.117884","url":null,"abstract":"<div><p>Small molecule inhibitors targeting the bromodomain and extra-terminal domain (BET) family proteins have emerged as a promising class of anti-cancer drugs. Nevertheless, the clinical advancement of these agents has been significantly hampered by challenges related to their potency, oral bioavailability, or toxicity. In this study, virtual screening approaches were employed to discover novel inhibitors of the bromodomain-containing protein 4 (BRD4) by analyzing their comparable chemical structural features to established BRD4 inhibitors. Several of these compounds exhibited inhibitory effects on BRD4 activity ranging from 60 % to 70 % at 100 µM concentrations, while one compound also exhibited an 84 % inhibition of Sirtuin 2 (SIRT2) activity. Furthermore, a subset of structurally diverse compounds from the BRD4 inhibitors was selected to investigate their anti-cancer properties in both 2D and 3D cell cultures. These compounds exhibited varying effects on cell numbers depending on the specific cell line, and some of them induced cell cycle arrest in the G0/G1 phase in breast cancer (MDA-MB-231) cells. Moreover, all the compounds studied reduced the sizes of spheroids, and the most potent compound exhibited a 90 % decrease in growth at a concentration of 10 µM in T47D cells. These compounds hold potential as epigenetic regulators for future studies.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117884"},"PeriodicalIF":3.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089624002980/pdfft?md5=57cf7b2f4e2061ac12305d00eba67f4e&pid=1-s2.0-S0968089624002980-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of alpha-Gal C-disaccharides","authors":"Alex Ann,&nbsp;Steven Truong,&nbsp;Jiwani Peters,&nbsp;David R. Mootoo","doi":"10.1016/j.bmc.2024.117903","DOIUrl":"10.1016/j.bmc.2024.117903","url":null,"abstract":"<div><p>The synthesis of C-disaccharides of α-<span>d</span>-galactopyranosyl-(1 → 3)-<span>d</span>-galactopyranose (α-Gal), potential tools for studying the biology of α-Gal glycans, is described. The synthetic strategy, centers on the reaction of two easily available precursors 1,2-O-isopropylidene-<span>d</span>-glyceraldehyde and an α-C-glactosyl-<em>E</em>-crotylboronate, which affords a mixture of two diastereomeric anti-crotylation products. The stereoselectivity of this reaction was controlled with (<em>R</em>)- and (S)-TRIP catalysts, and the appropriate diastereomer was transformed to C-linked disaccharides of α-Gal, in which the aglycone segment comprised O-, C- and S-glycoside entities that can enable glycoconjugate synthesis.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117903"},"PeriodicalIF":3.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in the design of small molecular drugs with acrylamides covalent warheads","authors":"Luxia Liang ,&nbsp;Ze Zhang ,&nbsp;Qidong You ,&nbsp;Xiaoke Guo","doi":"10.1016/j.bmc.2024.117902","DOIUrl":"10.1016/j.bmc.2024.117902","url":null,"abstract":"<div><p>In the development of covalent inhibitors, acrylamides warhead is one of the most popular classes of covalent warheads. In recent years, researchers have made different structural modifications to acrylamides warheads, resulting in the creation of fluorinated acrylamide warheads and cyano acrylamide warheads. These new warheads exhibit superior selectivity, intracellular accumulation, and pharmacokinetic properties. Additionally, although ketoamide warheads have been applied in the design of covalent inhibitors for viral proteins, it has not received sufficient attention. Combined with the studies in kinase inhibitors and antiviral drugs, this review presents the structural features and the progression of acrylamides warheads, offering a perspective on future research and development in this field.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117902"},"PeriodicalIF":3.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and antibacterial activities of heterocyclic ring-fused 20(S)-protopanaxadiol derivatives","authors":"De-Jie Zhang ,&nbsp;Zi-Qi Yuan ,&nbsp;Yan-Xin Yue ,&nbsp;Min Zhang ,&nbsp;Wen-Juan Wu ,&nbsp;Cai-Guang Yang ,&nbsp;Wen-Wei Qiu","doi":"10.1016/j.bmc.2024.117901","DOIUrl":"10.1016/j.bmc.2024.117901","url":null,"abstract":"<div><p>Multidrug-resistant (MDR) bacterial infections are becoming a life-threatening issue in public health; therefore, it is urgent to develop novel antibacterial agents for treating infections caused by MDR bacteria. The 20(S)-protopanaxadiol (PPD) derivative <strong>9</strong> was identified as a novel antibacterial hit compound in screening of our small synthetic natural product-like (NPL) library. A series of novel PPD derivatives with heterocyclic rings fused at the C-2 and C-3 positions of the A-ring were synthesized and their antibacterial activities against <em>Staphylococcus aureus</em> (<em>S. aureus</em>) Newman strain and MDR <em>S. aureus</em> strains (USA300, NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, XJ017, and XJ036) were evaluated. Among these compounds, quinoxaline derivative <strong>56</strong> (SH617) exhibited the highest activity with MICs of 0.5–4 μg/mL against the <em>S. aureus</em> Newman strain and the eight MDR <em>S. aureus</em> strains. Its antibacterial activity was comparable to that of the positive control, vancomycin. In the zebrafish, <strong>56</strong> revealed no obvious toxicity even at a high administered dose. <em>In vivo</em>, following a lethal infection induced by USA300 strains in zebrafish, <strong>56</strong> exhibited significantly increased survival rates in a dose-dependent manner.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117901"},"PeriodicalIF":3.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142128910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, classification, and adverse effects of NSAIDs: A review on recent advancements","authors":"Minhajul Arfeen ,&nbsp;Ashish Srivastava ,&nbsp;Noopur Srivastava ,&nbsp;Riaz A. Khan ,&nbsp;Suliman A. Almahmoud ,&nbsp;Hamdoon A. Mohammed","doi":"10.1016/j.bmc.2024.117899","DOIUrl":"10.1016/j.bmc.2024.117899","url":null,"abstract":"<div><p>Inflammation is a hallmark of many diseases, including cancer, neurodegenerative diseases like Alzheimer’s, type II diabetes, rheumatoid arthritis, and asthma. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been a cornerstone in the management of various inflammatory, pain, and fever-related conditions. As a result, NSAIDs have found their applications in new therapeutic areas. NSAIDs are known to act by inhibiting the cyclooxygenase (COX) pathway. In recent years, new strategies have been proposed to counter inflammation and develop safer COX inhibitors. This review discusses the design of new COX inhibitors, the derivatization of conventional NSAIDs, and their biological applications. The review also presents an integrated classification of NSAIDs incorporating both traditional chemical-based and function-based approaches, including a brief overview of the NSAIDs of natural origins. Additionally, the review addresses adverse effects associated with different NSAIDs, including effects associated with cardiovascular, renal, and hepatic complications emphasizing the need for the development of new and safer COX inhibitors.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117899"},"PeriodicalIF":3.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facile incorporation of non-canonical heme ligands in myoglobin through chemical protein synthesis","authors":"Kewei Yi,&nbsp;Peng Wang,&nbsp;Chunmao He","doi":"10.1016/j.bmc.2024.117900","DOIUrl":"10.1016/j.bmc.2024.117900","url":null,"abstract":"<div><p>The incorporation of non-canonical amino acids (ncAAs) into the metal coordination environments of proteins has endowed metalloproteins with enhanced properties and novel activities, particularly in hemoproteins. In this work, we disclose a scalable synthetic strategy that enables the production of myoglobin (Mb) variants with non-canonical heme ligands, i.e., HoCys and f4Tyr. The ncAA-containing Mb* variants (with H64V/V68A mutations) were obtained through two consecutive native chemical ligations and a subsequent desulfurization step, with overall isolated yield up to 28.6 % in over 10-milligram scales. After refolding and heme <em>b</em> cofactor reconstitution, the synthetic Mb* variants showed typical electronic absorption bands. When subjected to the catalysis of the cyclopropanation of styrene, both synthetic variants, however, were not as competent as the His-ligated Mb*. We envisioned that the synthetic method reported herein would be useful for incorporating a variety of ncAAs with diverse structures and properties into Mb for varied purposes.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117900"},"PeriodicalIF":3.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and biological evaluation of a novel PAK1 degrader for the treatment of triple negative breast cancer","authors":"Yi Du ,&nbsp;Xiya Chen ,&nbsp;Weiji Chen ,&nbsp;Gang Chen ,&nbsp;Xiaoling Cheng ,&nbsp;Hailing Wang ,&nbsp;Ling Guo ,&nbsp;Chenyang Li ,&nbsp;Dahong Yao","doi":"10.1016/j.bmc.2024.117896","DOIUrl":"10.1016/j.bmc.2024.117896","url":null,"abstract":"<div><p>Triple-negative breast cancer is one of the most malignant subtypes in clinical practice, and it is urgent to find new therapies. The p21-activated kinase I (PAK1) has been considered to be an attractive therapeutic target for TNBC. In this study, we designed and synthesized a series of novel PROTAC PAK1 degraders by conjugating VHL or CRBN ligase ligands to PAK1 inhibitors which are connected by alkyl chains or PEG chains. The most promising compound, <strong>19s</strong>, can significantly degrade PAK1 protein at concentrations as low as 0.1 μM, and achieves potent anti-proliferative activity with an IC₅₀ value of 1.27 μM in MDA-MB-231 cells. Additionally, <strong>19s</strong> exhibits potent anti-migration activity <em>in vitro</em> and induces rapid tumor regression <em>in vivo</em>. Collectively, these findings document that <strong>19s</strong> is a potent and novel PAK1 degrader with promising potential for TNBC treatment.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117896"},"PeriodicalIF":3.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel gold-based complex GC7 suppresses cancer cell proliferation via impacting energy metabolism mediated by mitochondria","authors":"Qingbin Cui ,&nbsp;Wenwen Ding ,&nbsp;Bingling Luo,&nbsp;Wenhua Lu,&nbsp;Peng Huang,&nbsp;Shijun Wen","doi":"10.1016/j.bmc.2024.117897","DOIUrl":"10.1016/j.bmc.2024.117897","url":null,"abstract":"<div><p>Due to their pivotal roles in regulating energy metabolism and apoptosis, mitochondria in cancer cells have been considered a vulnerable and feasible target. Many anticancer agents, e.g., metal-based compounds, are found to target and disturb mitochondria primarily, which may lead to the disturbance of energy metabolism and, more importantly, the initiation of apoptosis. In this work, a gold-based complex 7 (<strong>GC7</strong>) was synthesized and evaluated in a series of different cancer cell lines. The anticancer efficacies of <strong>GC7</strong> on cell viability, apoptosis, and colony formation were determined. Cellular thioredoxin reductase (TrxR) activity, oxygen consumption rate (OCR), glucose uptake, and lactate production following <strong>GC7</strong> treatment were evaluated and analyzed. The Jeko-1 and A549 xenograft models were used to assess <strong>GC7</strong>’s tumor-suppressing effects. The results showed that <strong>GC7</strong> possessed a broad-spectrum anticancer effect, with IC₅₀ values ranging from 0.43 to 1.2 μM in multiple cancer cell lines, which was more potent than gold-based auranofin (∼2–6 folds). <strong>GC7</strong> (0.3 and 1 μM) efficiently induced apoptosis of Jeko-1, A549, and HCT116 cells, and it suppressed the sphere formation of cancer stem cells GSC11 and GSC23 cells at 0.1 μM, and it completely eliminated colony at 0.3 μM. The preliminary mechanistic study showed that <strong>GC7</strong> inhibited cellular TrxR activity, suppressed mitochondrial OCR, reduced mitochondrial membrane potential (MMP), decreased glucose uptake, and possibly suppressed glycolysis to reduce lactate production. <strong>GC7</strong> was predicted to have a similar yet slightly different pharmacokinetic profile as auranofin. Finally, <strong>GC7</strong> (20 mg/kg, oral, 5/week, or 3 mg/kg, IP, 3/week) significantly inhibited tumor growth. In conclusion, <strong>GC7</strong> showed great potential in suppressing cancer cell proliferation, probably via inhibiting TrxR and impacting mitochondria-mediated energy metabolism.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117897"},"PeriodicalIF":3.3,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proximal fleximer analogues of 2′-deoxy-2′-fluoro-2′-methyl purine nucleos(t)ides: Synthesis and preliminary pharmacokinetic and antiviral evaluation","authors":"Charles D. Waters III ,&nbsp;Evan Carlyle ,&nbsp;Viviana Smart ,&nbsp;Apurv Rege ,&nbsp;Charles J. Bieberich ,&nbsp;Katherine L. Seley-Radtke","doi":"10.1016/j.bmc.2024.117898","DOIUrl":"10.1016/j.bmc.2024.117898","url":null,"abstract":"<div><p>In this study, proximal fleximer nucleos(t)ide analogues of Bemnifosbuvir were synthesized and evaluated for their potential to serve as antiviral therapeutics. The final parent flex-nucleoside and ProTide modified flex-nucleoside analogues were tested against several viral families including flaviviruses, filoviruses, and coronaviruses. Modest activity against Zaire Ebola virus was observed at 30 μM for compound ProTide modified analogue. Neither compound exhibited activity for any of the other viruses tested. The parent flex-nucleoside analogue was screened for toxicity in CD-1 mice and showed no adverse effects up to 300 mg/kg, the maximum concentration tested.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117898"},"PeriodicalIF":3.3,"publicationDate":"2024-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}