Bioorganic & Medicinal Chemistry最新文献

{"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}

{"title":"Advancements in platinum-based anticancer drug development: A comprehensive review of strategies, discoveries, and future perspectives","authors":"Debsankar Sahoo ,&nbsp;Priya Deb ,&nbsp;Tamal Basu ,&nbsp;Srishti Bardhan ,&nbsp;Sayan Patra ,&nbsp;Pradip K. Sukul","doi":"10.1016/j.bmc.2024.117894","DOIUrl":"10.1016/j.bmc.2024.117894","url":null,"abstract":"<div><p>Platinum-based anticancer drugs have been at the forefront of cancer chemotherapy, with cisplatin emerging as a pioneer in the treatment of various malignancies. This review article provides a comprehensive overview of the evolution of platinum-based anticancer therapeutics, focusing on the development of cisplatin, platinum(IV) prodrugs, and the integration of photodynamic therapy (PDT) for enhanced cancer treatment results. The first section of the review delves into the historical context and molecular mechanisms underlying the success of cisplatin, highlighting its DNA binding properties and subsequent interference with cellular processes. Despite its clinical efficacy, the inherent limitations, including dose-dependent toxicities and acquired resistance, accelerated the exploration of novel platinum derivatives. This led to the emergence of platinum(IV) prodrugs, designed to overcome resistance mechanisms and enhance selectivity through targeted drug delivery. The subsequent section provides an in-depth analysis of the principles of design and structural modifications employed in the development of platinum(IV) prodrugs. The transitions to the incorporation of photodynamic therapy (PDT) stands out as a synergistic approach to platinum-based anticancer treatment. The photophysical properties of platinum complexes are discussed in the context of their potential application in PDT, emphasizing on combined cytotoxic effects of platinum-based drugs and light-induced reactive oxygen species generation. This dual-action approach holds great promise for overcoming the limitations of traditional chemotherapy as well as producing superior therapeutic outcomes. Overall, the present report explores the latest developments in the development and use of platinum complexes, highlighting novel strategies such combination treatments, targeted delivery methods, and the generation of multifunctional complexes. It also provides a comprehensive overview of the current landscape while proposing future directions for the development of next-generation platinum-based anticancer therapeutics.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117894"},"PeriodicalIF":3.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142099188","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":"Discovery, synthesis and SAR of 2-acyl-1-biarylmethyl pyrazolidines, dual orexin receptor antagonists designed as fast and short-acting sleeping drugs","authors":"Jean-Philippe Surivet,&nbsp;Melanie Kessler,&nbsp;Catherine Vaillant,&nbsp;Hamed Aissaoui,&nbsp;Olivier Bezençon,&nbsp;Louise Busch,&nbsp;Manon Kiry,&nbsp;Urs Lüthi,&nbsp;Nicolas Marck,&nbsp;Florence Masse,&nbsp;Jens-Uwe Peters,&nbsp;Catherine Sweatman,&nbsp;Aude Weigel,&nbsp;Christopher Kohl","doi":"10.1016/j.bmc.2024.117892","DOIUrl":"10.1016/j.bmc.2024.117892","url":null,"abstract":"<div><p>Dual orexin receptor antagonists (DORAs) are approved for the treatment of sleep onset and/or sleep maintenance insomnia. In the present disclosure, we report the discovery of a new class of DORAs designed to treat sleep disorders requiring a fast onset and a short duration of action (&lt;4 h). We used early human pharmacokinetic-pharmacodynamic (PK-PD) predictions and <em>in vivo</em> experiments to identify DORAs eliciting this specific hypnotic profile. A high-throughput screening campaign revealed hits based on a rarely precedented tricyclic pyrazolidine scaffold. After unsuccessful structure–activity-relationship (SAR) studies on this hit series, a scaffold hopping exercise, aimed at reducing the molecular complexity of the tricyclic scaffold, resulted in the discovery of the 2-acyl-1-biarylmethylpyrazolidine series. SAR studies on this achiral series gave rise to the lead compound DORA <strong>42</strong>. <em>In vitro</em> and <em>in vivo</em> parameters of DORA <strong>42</strong>, and its PK-PD simulation for human use are detailed.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117892"},"PeriodicalIF":3.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136402","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":"Amine-bearing hydrocarbon cross-links: Tailoring helix stability, hydrophilicity, and synthetic adaptability in peptides","authors":"Duc V.H. Tran,&nbsp;Thanh K. Pham,&nbsp;Young-Woo Kim","doi":"10.1016/j.bmc.2024.117893","DOIUrl":"10.1016/j.bmc.2024.117893","url":null,"abstract":"<div><p>This study comprehensively explored the helix-stabilizing effects of amine-bearing hydrocarbon cross-links (ABXs), revealing their context-dependent nature influenced by various structural parameters. Notably, we identified a 9-atom ABX as a robust helix stabilizer, showcasing versatile synthetic adaptability while preserving peptide water solubility. Future investigations are imperative to fully exploit this system’s potential and enrich our chemical toolkit for designing innovative peptide-based biomolecules.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117893"},"PeriodicalIF":3.3,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142077472","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":"177Lu-labeling of nuclear localization sequence (NLS)-grafted HER2-receptor affine peptide","authors":"Sushree Arpitabala Yadav ,&nbsp;V. Kusum Vats ,&nbsp;Rohit Sharma ,&nbsp;Nitish Chauhan ,&nbsp;Mahesh Subramanian ,&nbsp;Amit Das ,&nbsp;Drishty Satpati","doi":"10.1016/j.bmc.2024.117883","DOIUrl":"10.1016/j.bmc.2024.117883","url":null,"abstract":"<div><p>Tagging of cell permeable nuclear localization sequence (NLS) with receptor targeting peptide vectors is an attractive strategy for selectively targeted translocation of therapeutic cargoes. The present study aimed at grafting nuclear localization sequence (NLS) onto breast cancer targeting rL-A9 peptide. Molecular docking analysis revealed higher binding affinity of the peptide, DOTA-NLS-rL-A9 (−26.1 kJ/mol) towards HER2 receptor in comparison to DOTA-rL-A9 peptide (−22.2 kJ/mol). Confocal microscopy data suggested significantly enhanced cellular internalization of NLS-tagged peptide. The engineered HER2-selective, DOTA-NLS-rL-A9 peptide scaffold was radiolabeled with Lu-177 for intracellular delivery of the theranostic radionuclide into tumor cells. [¹⁷⁷Lu]Lu-DOTA-NLS-rL-A9 exhibited significantly enhanced binding affinity (4.58 ± 1.77 nM) towards human breast carcinoma SKBR3 cells and cellular internalization (85 % at 24 h) compared to its original analog, [¹⁷⁷Lu]Lu-DOTA-rL-A9. <em>In vivo</em> biodistribution studies showed consistent retention of [¹⁷⁷Lu]Lu-DOTA-NLS-rL-A9 in the tumor with negligible washout of radioactivity (∼4.1 % ID/g at 48 h). Prolonged tumor activity with rapid off-target tissue clearance resulted in significantly high tumor-to-background ratios. The radiopeptide, [¹⁷⁷Lu]Lu-DOTA-NLS-rL-A9 thus, being precisely confined into HER2-expressing tumor cells and exhibiting favourable pharmacokinetic features is an efficient candidate for further screening.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"112 ","pages":"Article 117883"},"PeriodicalIF":3.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047780","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}