RSC medicinal chemistry最新文献

Ruthenium(ii) polypyridyl complexes and the DNA damage response: mechanisms and therapeutic implications. 钌（ii）多吡啶复合物和DNA损伤反应：机制和治疗意义。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-05-06 DOI: 10.1039/d6md00154h

Martin R Gill

引用次数: 0

Structure-guided optimisation of fenofibrate-derived oxidative phosphorylation inhibitors to modify tumour hypoxia. 结构导向优化非诺贝特衍生的氧化磷酸化抑制剂，以改变肿瘤缺氧。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-28 DOI: 10.1039/d5md00742a

James P Holt-Martyn, Nicole Machado, James T T Coates, Rathi Puliyadi, Thomas Ashton, Elysia Traynor, Samina Aslam, Thomas K Wise, Gonzalo Rodriguez-Berriguete, Christopher J Schofield, Geoff S Higgins

{"title":"Structure-guided optimisation of fenofibrate-derived oxidative phosphorylation inhibitors to modify tumour hypoxia.","authors":"James P Holt-Martyn, Nicole Machado, James T T Coates, Rathi Puliyadi, Thomas Ashton, Elysia Traynor, Samina Aslam, Thomas K Wise, Gonzalo Rodriguez-Berriguete, Christopher J Schofield, Geoff S Higgins","doi":"10.1039/d5md00742a","DOIUrl":"https://doi.org/10.1039/d5md00742a","url":null,"abstract":"Solid tumours frequently manifest regions of abnormally low levels of oxygen (hypoxia), which negatively impacts cancer treatment outcomes. This is particularly detrimental to radiotherapy which requires oxygen to exert maximal therapeutic effects. Tumour hypoxia can be abolished by reducing oxygen consumption rates (OCR) through inhibition of oxidative phosphorylation (OXPHOS), though to date no hypoxia modifying OXPHOS inhibitors have successfully translated into routine clinical practise. Here, we demonstrate that the well-tolerated, pro-drug fenofibrate, which has moderate OXPHOS inhibitory activity, can serve as a scaffold for OXPHOS inhibitor development. Structural modification of the four different regions of fenofibrate, that is its isopropyl-, dimethyl-, chloro-, and ketone-groups, improves potency for OCR inhibition whilst eliminating ester hydrolysis. The derivatives improve hypoxia alleviation in 3D spheroid models, without inducing cytotoxicity. Substrate-dependent oxygen consumption assays support complex I-specific inhibition as the mechanism of action. Structure activity relationship studies led to development of a lead compound (IOX7), which demonstrates improved potency for OXPHOS inhibition, a superior solubility profile, and lack of in vitro cytotoxicity at effective doses compared to fenofibrate. IOX7 has the potential for development as a clinically useful hypoxia-modifying OXPHOS inhibitor.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779746","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}

引用次数: 0

Design, synthesis, and anticancer evaluation of novel pyrrole-pyrazoline/chalcone hybrids: in vitro and computational insights into EGFR inhibition. 新型吡咯-吡唑啉/查尔酮杂合体的设计、合成和抗癌评价：体外和对EGFR抑制的计算见解。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-27 DOI: 10.1039/d5md00800j

Mansour S Alturki, Marwa F Ahmed, Abdulaziz H Al Khzem, Mohamed S Gomaa, Mohammad Sarafroz, Nada Tawfeeq, Mashael M Alharbi, Abdulaziz K Al Mouslem, Mohammed F Aldawsari, Wajin R Alruwili, Shah Alam Khan, Radwan El-Haggar, Atiah H Almalki

{"title":"Design, synthesis, and anticancer evaluation of novel pyrrole-pyrazoline/chalcone hybrids: in vitro and computational insights into EGFR inhibition.","authors":"Mansour S Alturki, Marwa F Ahmed, Abdulaziz H Al Khzem, Mohamed S Gomaa, Mohammad Sarafroz, Nada Tawfeeq, Mashael M Alharbi, Abdulaziz K Al Mouslem, Mohammed F Aldawsari, Wajin R Alruwili, Shah Alam Khan, Radwan El-Haggar, Atiah H Almalki","doi":"10.1039/d5md00800j","DOIUrl":"https://doi.org/10.1039/d5md00800j","url":null,"abstract":"A novel series of pyrrole-pyrazoline/chalcone hybrids were designed, synthesized and evaluated for antiproliferative activity to target epidermal growth factor receptor (EGFR) inhibition. All the synthesized compounds were evaluated in the NCI panel of 59 human cancer cell lines, where compound 6b emerged as the most active analogue. Enzyme-binding assays confirmed its potent EGFR inhibitory activity (IC50 = 0.225 μM), comparable to the reference inhibitor erlotinib (IC50 = 0.198 μM). Flow cytometry analysis of human breast cancer cells (MCF-7) showed that 6b induces significant cell arrest in the G2/M phase. Real-time polymerase chain reaction (RT-PCR) experiments further confirmed the molecular mechanisms, revealing that 6b modulated key apoptotic regulators, significantly increasing the Bax/Bcl-2 ratio and upregulating p53, BAX, and caspase-7, while concurrently suppressing Bcl-2 expression. Molecular simulation studies provide evidence for the preferential binding of 6b to the active state of EGFR, consistent with the experimental results. The synthetic strategy used to prepare the pyrrole-pyrazoline/chalcone scaffold is simple, hence providing efficient access to the title compounds whose potential can be further explored as an EGFR-targeted anticancer chemotype.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779499","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}

引用次数: 0

Lead optimization of 5jc21 (CG13250), a quinolin-2(1H)-one-based inhibitor of the BRD4 member of the bromodomain and extraterminal (BET) family of proteins. 5jc21 （CG13250）是一种基于喹啉-2(1H)- 1的溴域和外域（BET）蛋白家族BRD4成员抑制剂。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-24 DOI: 10.1039/d5md01082a

Jay Chauhan, Sarah Pogash, Makoto Yoshioka, Mithun Raje, Daniel Van Eker, Jeffrey W Strovel, Steven Fletcher

引用次数: 0

New terpenyl-cinnamoyl-hydrazone analogues of cannabidiol with potent antinociceptive effect. 新的大麻二酚萜基肉桂酰腙类似物具有有效的抗伤性作用。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-24 DOI: 10.1039/d6md00185h

João Pedro Barros de Paiva, Anna Carolina Pereira Lontra, Rachel Marins Campos, Eduardo Araújo, Thais Biondino Sardella Giorno, Mikaela Lucinda de Souza, Graziella Dos Reis Rosa Franco, Claudio Viegas, Patrícia Dias Fernandes

{"title":"New terpenyl-cinnamoyl-hydrazone analogues of cannabidiol with potent antinociceptive effect.","authors":"João Pedro Barros de Paiva, Anna Carolina Pereira Lontra, Rachel Marins Campos, Eduardo Araújo, Thais Biondino Sardella Giorno, Mikaela Lucinda de Souza, Graziella Dos Reis Rosa Franco, Claudio Viegas, Patrícia Dias Fernandes","doi":"10.1039/d6md00185h","DOIUrl":"https://doi.org/10.1039/d6md00185h","url":null,"abstract":"In this study, novel terpenyl-cinnamoyl-hydrazone analogs were synthesized and evaluated for antinociceptive potential in preclinical nociception models. The compounds were tested in chemical (formalin-induced licking) and thermal (hot plate) assays in mice. Mechanistic studies employed naloxone (opioid receptor antagonist), atropine (muscarinic receptor antagonist), AM251 (CB1 receptor antagonist), yohimbine (α2-adrenergic receptor antagonist), and ondansetron (5-HT3 receptor antagonist). Most compounds displayed antinociceptive activity, with PQM-274, PQM-291, and PQM-294 showing greater effects than cannabidiol (CBD). Naloxone and AM251 reversed the effects of these three compounds. Atropine abolished PQM-291's effect, and ondansetron inhibited PQM-290's activity, whereas yohimbine produced no change. This study reports, for the first time, the antinociceptive properties of terpenyl-cinnamyl-N-acyl-hydrazones with structural features inspired by CBD, suggesting their potential as novel multitarget analgesic candidates.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842198","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}

引用次数: 0

Design, synthesis and pharmacological evaluation of 3H-spiro[benzofuran-2,4'-piperidine] IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma. 3h -螺[苯并呋喃-2,4'-哌啶]IRAK4抑制剂治疗弥漫性大b细胞淋巴瘤的设计、合成及药理评价

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-24 DOI: 10.1039/d6md00025h

Zhiwei Chen, Qi Zhang, Yun Chen, Yi Ning, Q-I Zhang, Mengxiao Zhang, Qiupei Liu, Yi Xue, Linjiang Tong, Jian Ding, Hua Xie, Wenhu Duan

引用次数: 0

Emerging cellular uptake mechanisms of bRo5 PROTACs. 新兴的bRo5 protac细胞摄取机制。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-23 DOI: 10.1039/d6md00243a

Toshihiko Tashima

{"title":"Emerging cellular uptake mechanisms of bRo5 PROTACs.","authors":"Toshihiko Tashima","doi":"10.1039/d6md00243a","DOIUrl":"https://doi.org/10.1039/d6md00243a","url":null,"abstract":"Proteolysis-targeting chimeras (PROTACs) predominantly occupy beyond-rule-of-5 (bRo5) chemical space, where the mechanisms governing their cellular uptake remain incompletely understood and are not captured by classical models of passive membrane diffusion. Considerable progress has been made in rationalizing the permeability of bRo5 compounds, including the contributions of chameleonic conformational behavior, intramolecular hydrogen bonding, and lipophilicity-driven membrane partitioning. However, these factors do not fully explain the intracellular activity observed for certain large and polar PROTACs, suggesting that additional uptake mechanisms may be involved. Recent studies have proposed that receptor-mediated processes may contribute to the cellular uptake of selected PROTACs. Among these, CD36-mediated endocytosis has emerged as one potential pathway for certain bRo5 PROTACs, including SIM1-Me and MZ1, although the current evidence remains limited and its broader applicability across PROTAC chemical space is unclear and likely context-dependent. In this review, I critically examine emerging uptake mechanisms for bRo5 PROTACs within the broader framework of established permeability models. Experimentally supported observations are clearly distinguished from mechanistic hypotheses, and I evaluate the biological plausibility of receptor-mediated contributions, with particular focus on CD36 in the context of its established roles in lipid and lipoprotein uptake. Within this framework, CD36-mediated endocytosis is considered as a complementary, context-dependent pathway that may operate alongside passive diffusion and other permeability mechanisms, particularly for subsets of PROTACs with structural features that enable receptor engagement. Finally, I outline key structural and biological determinants that may influence uptake pathway selection and highlight critical experimental questions required to assess the generality and design relevance of these mechanisms for PROTAC development.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13147475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147842208","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}

引用次数: 0

Pyrazole-triazole hybrids as kinase-triad inhibitors: a triple-target strategy for synergistic anticancer therapy. 吡唑-三唑复合物作为激酶三联体抑制剂：协同抗癌治疗的三靶点策略。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-22 DOI: 10.1039/d6md00022c

Mahmoud S Elkotamy, Mohamed K Elgohary, Mariam M Fakhry, Mohamed E Albakri, Abdelrahman A Naglah, Abdulrahman A Almehizia, Ahmed M Naglah, Mohamed Fares, Haytham O Tawfik, Wagdy M Eldehna, Hatem A Abdel-Aziz

{"title":"Pyrazole-triazole hybrids as kinase-triad inhibitors: a triple-target strategy for synergistic anticancer therapy.","authors":"Mahmoud S Elkotamy, Mohamed K Elgohary, Mariam M Fakhry, Mohamed E Albakri, Abdelrahman A Naglah, Abdulrahman A Almehizia, Ahmed M Naglah, Mohamed Fares, Haytham O Tawfik, Wagdy M Eldehna, Hatem A Abdel-Aziz","doi":"10.1039/d6md00022c","DOIUrl":"https://doi.org/10.1039/d6md00022c","url":null,"abstract":"The ongoing issue of drug resistance and the lack of specificity in existing cancer treatments highlight the necessity for innovative multi-target agents. This study presents the design and synthesis of two series of pyrazolyl-1,2,3-triazole hybrids: pyrazole-1,2,3-triazole series (7a-i) and pyrazole-di(1,2,3-triazole) series (10a-i). These hybrids incorporate strategic substitutions aimed at targeting the ATP-binding sites of EGFR, VEGFR-2, and AURKA. Antiproliferative screening against MCF-7 (breast) and A549 (lung) cancer cell lines demonstrated that di(1,2,3-triazole) derivatives exhibited increased activity in MCF-7 (IC50: 18.7-21.9 μM), while mono-derivatives, particularly 7i, displayed greater potency in A549 (IC50: 3.56 μM). Flow cytometry revealed S-phase arrest in A549 cells induced by 7i and 10a, while the clonogenic assay validated reduced colony formation and elevated cell mortality. The combination treatment involving doxorubicin demonstrated synergistic effects, with 7i/Dox IC50 at 0.29 μM and 10a/Dox IC50 at 0.95 μM. Biochemical markers such as Ki-67, PCNA, p21, Bax, Bcl-2, caspase-3, VEGF, P-gp, and E-cadherin exhibited improved antiproliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic effects when subjected to combination therapy. Enzyme assays demonstrated low-nanomolar inhibition by 7i (EGFR = 73 nM; VEGFR-2 = 176 nM; AURKA = 89 nM) and moderate potency for 10a. Molecular docking confirmed essential interactions in the active site of each kinase, while in silico ADME profiling indicated favorable drug-likeness, especially for series 7. These findings identify compounds 7i and 10a as potential dual-scaffold leads for subsequent preclinical development as multi-target anticancer agents.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779688","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}

引用次数: 0

Diverse ring architectures of cyclic peptidomimetics targeting melanocortin receptors. 针对黑素皮质素受体的环状肽模拟物的不同环结构。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-21 DOI: 10.1039/d6md00115g

Wenxiao K Yue, Nicholas Barlow, Philip E Thompson

引用次数: 0

Discovery of novel BCAT2 inhibitors: design, synthesis, in vitro evaluation, and molecular modeling studies. 新型BCAT2抑制剂的发现：设计、合成、体外评价和分子模型研究。

IF 3.6 4区医学

RSC medicinal chemistry Pub Date : 2026-04-20 DOI: 10.1039/d6md00019c

Dong Xu, Wenxiu Weng, Huining Cao, Chao Zhang, Yudi Zhang, Yan Li, Junhai Xiao, Hua Xie, Jialin Guo, Guoliang Chen

{"title":"Discovery of novel BCAT2 inhibitors: design, synthesis, in vitro evaluation, and molecular modeling studies.","authors":"Dong Xu, Wenxiu Weng, Huining Cao, Chao Zhang, Yudi Zhang, Yan Li, Junhai Xiao, Hua Xie, Jialin Guo, Guoliang Chen","doi":"10.1039/d6md00019c","DOIUrl":"https://doi.org/10.1039/d6md00019c","url":null,"abstract":"Branched-chain amino acid transaminase 2 (BCAT2) is a promising therapeutic target for metabolic diseases and cancers such as pancreatic ductal adenocarcinoma. In this study, we report the discovery of novel and potent inhibitors against this enzyme. Through a structure-based strategy integrating scaffold hopping, core simplification, and hydrophobic cavity filling, three series of compounds (A, B, and C) were designed and synthesized. Several compounds in series C exhibited nanomolar inhibitory potency (C10, IC50 = 44 nM; C11, IC50 = 54 nM). Key structure-activity relationships were elucidated, highlighting the critical roles of the aromatic core, the polar substituent at the 2-position, and occupation of the upper hydrophobic pocket in enhanced activity. Molecular docking and dynamics simulations predict that the compounds bind stably to the BCAT2 active site, engaging in persistent π-π stacking and hydrogen-bonding networks with key residues such as Phe-30 and Tyr-173. This work provides valuable lead compounds and structural insights into the development of highly potent and selective BCAT2 inhibitors.","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147779597","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}

引用次数: 0