MedChemComm最新文献

{"title":"A glimpse into the developments, potential leads and future perspectives of anticancer cobalt complexes","authors":"Azharudin Khursheed, Nuzhat Khursheed, Nusrat Rashid, Waheed Ahmad Khanday, Afzal Hussain, Mohamed F. Alajmi, Samira Amir, Akhtar Hussain Malik, Jahangir Ahmad Rather, Abdul Haleem Wani, Jahangir Ahmad, Iqbal Hussain, Prince Firdous Iqbal and Waseem A. Wani","doi":"10.1039/D5MD00323G","DOIUrl":"10.1039/D5MD00323G","url":null,"abstract":"<p >The unanticipated finding of cisplatin's anticancer properties prompted extensive investigations into different platinum-containing complexes as anticancer agents. However, the side effects and resilience of cancerous cells to platinum complexes triggered investigations on non-platinum anticancer complexes. As a result, several non-platinum complexes have been developed. Among these, the anticancer potential of cobalt complexes has been recognized over the past few decades. Inorganic medicinal chemists are fascinated by cobalt complexes, as these complexes interact with cellular proteins and macromolecules, causing cellular disruption and stopping the division, growth and multiplication of cancer cells. Owing to the increasing interest of researchers in the development of anticancer cobalt complexes, this paper critically reviews the developments in the design and development of these complexes. The results of the <em>in vitro</em> and <em>in vivo</em> investigations of anticancer profiles of cobalt complexes with ligands such as Schiff bases, quinolines, carbonyl groups, polypyridyl ligands, macrocycles, thiosemicarbazones, active pharmaceuticals, natural products, <em>etc.</em> are reviewed. Importantly, the intervention of nanotechnological approaches in amplifying the therapeutic properties of anticancer cobalt complexes is discussed. Besides, the modes of action of anticancer cobalt complexes are highlighted. Moreover, pharmacologically significant cobalt complexes with equal or better anticancer effects than that of standard anticancer agents are identified. Finally, the existing challenges and future perspectives in research on the design and development of anticancer cobalt complexes are discussed.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4003-4043"},"PeriodicalIF":3.597,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627027","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":"Novel mangiferin derivatives attenuate adipogenesis in 3T3-L1 preadipocytes and ameliorate diet induced obesity in C57BL/6J mice†","authors":"Dong-Quan Gu, Yin Li, Liu-Shun Wu, Meng-Ting Lyu, Ying Li, Sheng-Zhuo Huang, Feng-Qing Xu, De-Ling Wu and Wu-Xi Zhou","doi":"10.1039/D5MD00264H","DOIUrl":"10.1039/D5MD00264H","url":null,"abstract":"<p >Mangiferin with a xanthone scaffold exhibited potent anti-obesity activities and thus has attracted interest. However, some shortcomings, including limited solubility and moderate potency, restrict its application. To develop novel and efficient anti-obesity agents, a series of mangiferin (MGF) amino acid derivatives were synthesized, optimized and evaluated for anti-obesity activities <em>in vitro</em> and <em>in vivo</em>. Among these derivatives, <strong>G1</strong> was identified to be a promising compound. <strong>G1</strong> showed better liposolubility compared to MGF. In 3T3-L1 preadipocytes, <strong>G1</strong> significantly inhibited cell differentiation and reduced fat accumulation by increasing inhibitory activity on fatty acid synthase, and triggering G0/G1 phase cell cycle arrest and production of intracellular reactive oxygen species. The intraperitoneal administration of <strong>G1</strong> (30, 60 mg kg<small>⁻¹</small>/2 days) significantly inhibited body, liver and fat tissue weight gain, reduced lipid dysfunction, and ameliorated pathological characteristics in high-fat diet induced C57BL/6J obese mice. These results suggest that compound <strong>G1</strong> may warrant further investigation as a promising anti-obesity agent for the treatment of human obesity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4278-4296"},"PeriodicalIF":3.597,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592135","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":"A review on small molecular mimics of antimicrobial peptides with an emphasis on the structure–activity relationship perspective","authors":"Sanghamitra Das, Raghav Poudel, Kalyan Dutta and Mohini Mohan Konai","doi":"10.1039/D5MD00407A","DOIUrl":"10.1039/D5MD00407A","url":null,"abstract":"<p >The rapid emergence of antibiotic resistance in bacteria has created an alarming situation in public health, which remains a major concern worldwide. In addition, the biofilm-forming ability of bacteria has further complicated the situation in the current scenario. To address these global clinical threats, small molecular mimics of antimicrobial peptides (AMPs) have emerged as a promising class of antibacterial agents. These molecules primarily kill bacteria by targeting their membranes, making it difficult for bacteria to develop resistance against them. Some of these classes of molecules have already been reported as potent antibiofilm agents and have demonstrated promising <em>in vivo</em> efficacy. In this review, we aim to provide an overview of this class of molecules with a focus on recent developments in the field. Different classes of small molecular AMP mimics are discussed with an emphasis on design rationale and the structure–activity-relationship (SAR) facet. The role of different parameters (such as hydrophobicity, charge, structural flexibility/rigidity, and spatial distribution of hydrophobicity) that control their physico-chemical property and thereby the antibacterial activity and toxicity is illustrated. Moreover, the antibiofilm ability and <em>in vivo</em> efficacy of this class of molecules are described to elucidate the possibility of being developed as future antibacterial drugs. Finally, the challenges associated with this class of molecules for their clinical translation as antibacterial therapy are discussed along with future perspectives for advancing the field.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 3982-4002"},"PeriodicalIF":3.597,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144627028","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":"Syntheses and preclinical evaluations of 11C-labeled radioligands for imaging brain orexin-1 and orexin-2 receptors with positron emission tomography†","authors":"Susovan Jana, Pooyeh Ahmadi, Xuefeng Yan, Ping Bai, Jeih-San Liow, Adrian E. Jenson, Matilah T. Pamie-George, Sami S. Zoghbi, Shawn Wu, Changning Wang, Robert B. Innis, Victor W. Pike and Sanjay Telu","doi":"10.1039/D5MD00382B","DOIUrl":"10.1039/D5MD00382B","url":null,"abstract":"<p >Despite their importance in regulating several functions in the brain, there is no effective radioligand for <em>in vivo</em> imaging of brain orexin-1 (OX<small>₁</small>R) or orexin-2 receptors (OX<small>₂</small>R) with positron emission tomography (PET). In a search for radioligand candidates, we identified GSK1059865 (<strong>1</strong>) as a highly potent and selective inhibitor for OX<small>₁</small>R (<em>K</em><small>_i</small> = 5.0 nM for OX<small>₁</small>R, ∼80-fold selective over OX<small>₂</small>R) and similarly ET1 (<strong>2</strong>) for OX<small>₂</small>R (IC<small>₅₀</small> = 0.8 nM for OX<small>₂</small>R, ∼3000-fold selective over OX<small>₁</small>R) with each possessing many physicochemical properties conducive for good brain permeability. We labeled compound <strong>1</strong> and compound <strong>2</strong> with carbon-11 (<em>t</em><small>_1/2</small> = 20.4 min) in high isolated yields (∼10–20%), radiochemical purities (≥99.5%), and molar activities (100–340 GBq μmol<small>⁻¹</small>) and assessed their potential as PET radioligands for <em>in vivo</em> imaging of brain OX<small>₁</small>R and OX<small>₂</small>R in healthy rodents and non-human primates. [<small>¹¹</small>C]<strong>1</strong> and [<small>¹¹</small>C]<strong>2</strong> showed excellent <em>in vitro</em> stability and also lipophilicity in a desirable range with measured log<em>D</em><small>_7.4</small> values of 3.69 and 2.90, respectively. After intravenous administration to mouse or monkey, both [<small>¹¹</small>C]<strong>1</strong> and [<small>¹¹</small>C]<strong>2</strong> gave moderately high peak radioactivity in brain (∼1.0–1.6 SUV). Unexpectedly, both [<small>¹¹</small>C]<strong>1</strong> and [<small>¹¹</small>C]<strong>2</strong> showed slightly lower monkey brain uptakes and distribution volumes at baseline than under blocking with suvorexant (a dual OX<small>₁</small>R/OX<small>₂</small>R antagonist), indicating a lack of specific binding to the target receptors in healthy animals. We infer that both OXRs exist in healthy mouse and monkey brain at very low density. Animal models, where OX<small>₁</small>R and OX<small>₂</small>R levels might be elevated, are desirable for candidate PET radioligand development, as are candidates with higher affinity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3787-3798"},"PeriodicalIF":3.597,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476595","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":"Current progress in targeting mitotic kinases in PDAC","authors":"Thomas M. A. Barlow, Ilse Rooman and Steven Ballet","doi":"10.1039/D5MD00162E","DOIUrl":"10.1039/D5MD00162E","url":null,"abstract":"<p >For a number of reasons, and unlike most other cancers, the mortality rate of PDAC is set to increase and, as such, it is predicted to become the second most common cause of cancer related mortality in the western world by the end of the current decade. One of the main reasons for this is the dire lack of robust therapeutic options. The clinical landscape of PDAC therapeutics is changing at an encouraging pace, exemplified by the breakthroughs in targeting not only KRAS but developing mutant-specific drugs against it. Nevertheless, the clinical community is still faced with a dire lack of effective therapeutics. The targeting of mitotic kinases – here limited to CDKs, Wee1, Chk1, Plk1 and the Aurora kinases – offers one potential avenue for exploitation. Here, we discuss ongoing efforts to target the mitotic kinases and present the advances that have been made for each, whilst also presenting the clinical and therapeutic perspectives for each category.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3362-3385"},"PeriodicalIF":3.597,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144497986","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-guided design of a methyltransferase-like 3 (METTL3) proteolysis targeting chimera (PROTAC) incorporating an indole–nicotinamide chemotype†","authors":"Annabelle C. Weldert, Ariane F. Frey, Mackenzie W. Krone, Franziska Krähe, Hannah Kuhn, Christian Kersten and Fabian Barthels","doi":"10.1039/D5MD00359H","DOIUrl":"10.1039/D5MD00359H","url":null,"abstract":"<p >Methyltransferase-like 3 (METTL3) is the main catalytic subunit of the m<small>⁶</small>A methyltransferase complex (MTC) and plays an essential role in various disease indications, including acute myeloid leukemia (AML). Here, we describe the structure-guided design and evaluation of METTL3 proteolysis-targeting chimeras (PROTACs), starting from the potent small-molecule inhibitor STM2457. Across four design generations, we highlight key considerations, particularly regarding the exit vector, linker mechanics, and METTL3-binding chemotype composition. Our most effective PROTAC, AF151, forms a stable complex between the E3 ligase von Hippel–Lindau (VHL) and the target-of-interest METTL3, demonstrating efficient METTL3 degradation (DC<small>₅₀</small> = 430 nM) in the AML cell line MOLM-13. This molecule candidate exhibits more pronounced effects on viability inhibition (IC<small>₅₀</small> = 0.45 μM) and more significant m<small>⁶</small>A level reduction in cancer cells than its non-PRTOAC parent compounds. By incorporating the indole-nicotinamide chemotype as the METTL3-binding recruiter, this PROTAC is structurally distinct from recently published METTL3 PROTACs, expanding the design options for future METTL3 degrader development.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4194-4207"},"PeriodicalIF":3.597,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144542104","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":"Rational design of gold(i)-NHC complexes as anticancer agents: induction of necroptosis and paraptosis in lung adenocarcinoma†","authors":"Sayari Dewan, Himanshu Sonker, Kajal Chaudhary and Ritika Gautam Singh","doi":"10.1039/D5MD00290G","DOIUrl":"10.1039/D5MD00290G","url":null,"abstract":"<p >Gold(<small>I</small>)-NHC complexes bearing sterically demanding ligands remain largely underexplored as anticancer agents. In this study, we rationally designed and synthesized a series of gold(<small>I</small>)-NHC complexes derived from cytotoxic 1,10-phenanthroline-based NHC ligands. Comprehensive structural characterization was performed using <small>¹</small>H and <small>¹³</small>C NMR spectroscopy, ESI-MS, IR spectroscopy, and single-crystal X-ray diffraction. Among the synthesized complexes <strong>AuL1–AuL7</strong>, <strong>AuL4</strong> emerged as the most active compound, exhibited potent anticancer activity, triggering mitochondrial membrane depolarization and inducing necroptosis and paraptosis in human lung adenocarcinoma (A549) cells—a mechanism distinct from conventional apoptosis-inducing gold complexes. Notably, <strong>AuL4</strong> effectively suppressed both metastasis and clonal expansion of malignant cells, reinforcing the therapeutic potential of gold-based chemotherapeutics. These findings establish <strong>AuL4</strong> and its analogues as promising candidates for the development of next-generation gold(<small>I</small>)-NHC anticancer agents, particularly for treating apoptosis-resistant lung cancers.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4208-4219"},"PeriodicalIF":3.597,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144554377","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":"Identifying and evaluating understudied protein kinases using biological and chemical criteria","authors":"Selina Koch and Jürgen Bajorath","doi":"10.1039/D5MD00306G","DOIUrl":"10.1039/D5MD00306G","url":null,"abstract":"<p >Protein kinases (PKs) play a central role in cellular signaling. Uncontrolled signaling by deregulated PKs is implicated in a variety of diseases. As a consequence, PKs are among the most popular pharmaceutical targets. The preferred strategy for therapeutic intervention of medical conditions caused by deregulated PKs is the inhibition of their catalytic phosphorylation activity. Accordingly, small-molecular PK inhibitors (PKIs) have become a major drug class in oncology and prime candidates in other therapeutic areas. While cellular functions of many PKs and potential involvement in disease biology have been intensely investigated, others have received comparably little attention, leading to the identification of understudied 162 kinases representing the dark “dark kinome”. Dark PKs have for the most part been categorized based on the absence of functional information and lack of reagents. Large-magnitude projects have been initiated to further explore and functionally characterize the dark kinome. In addition, different categories of PKs have also been defined based on their degree of chemical exploration in medicinal chemistry, representing complementary assessments of understudied PKs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3386-3392"},"PeriodicalIF":3.597,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286464","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":"Synergistic effect of the hybrid compounds of cationic pillararene and an efflux pump inhibitor against Gram-negative bacteria†","authors":"Yisu Liu, Guangpu Wu, Jiang Zhu, Yao Jiang and Hui Liu","doi":"10.1039/D5MD00262A","DOIUrl":"10.1039/D5MD00262A","url":null,"abstract":"<p >Novel antibiofilm agents were designed by integrating cationic pillararene with an efflux pump inhibitor. The hybrid compounds were prepared and characterized using NMR and HRMS. These compounds exhibited potent activity to inhibit biofilm formation and disrupt the outer membrane in Gram-negative bacteria. In addition, the synergistic effect of the hybrid compounds was observed in combination with antibiotics, especially against <em>P. aeruginosa</em>. The hybridization strategy not only reduced the dosages required for the efflux pump inhibitor but also enhanced the antibacterial efficacy of antibiotics, making this a promising approach for developing antibacterial drugs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3778-3786"},"PeriodicalIF":3.597,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144476594","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":"Introduction to the themed collection on ‘Induced-Proximity Pharmacology’","authors":"Ingo V. Hartung, Lindsey I. James and Lyn H. Jones","doi":"10.1039/D5MD90023A","DOIUrl":"10.1039/D5MD90023A","url":null,"abstract":"<p >A graphical abstract is available for this content</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 6","pages":" 2311-2313"},"PeriodicalIF":3.597,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226469","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}