RSC medicinal chemistry最新文献

{"title":"Site-selective acylation of human insulin to engineer a long-acting monovalent insulin-Fc conjugate.","authors":"Wanrong Yang, Ruolin Xu, Wanyi Tai","doi":"10.1039/d6md00313c","DOIUrl":"https://doi.org/10.1039/d6md00313c","url":null,"abstract":"<p><p>Basal insulin therapy requires sustained and low-variability of insulin exposure; however, natural human insulin is rapidly cleared, thus necessitating frequent subcutaneous injections. Here we report a modular chemical platform for constructing monovalent insulin-Fc conjugates with structural homogeneity and long-term action. Site-selective acylation on three accessible amines of insulin (Gly^A1, Phe^B1, or Lys^B29) yields a panel of alkynyl insulin analogs (3a-3c), which could couple with an azido Fc protein by CuAAC to produce monovalent insulin-Fc conjugates. Among these conjugates, Fc conjugation at Lys^B29 of insulin, namely 3c-Fc, retains the bioactivity, while insulin at Gly^A1 (3a-Fc) and Phe^B1 (3b-Fc) were markedly deactivated, as assessed by the downstream Akt phosphorylation test. <i>In vivo</i>, the 3c-Fc conjugate exhibits a long pharmacokinetic and pharmacodynamic profile, which may result from the increase in the molecular size, the recycling by the neonatal Fc receptor, and the monovalence for slow insulin receptor-mediated clearance. Overall, we describe here the method of site-selective acylation and Fc conjugation to tune the basal-leaning pharmacology of insulin.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13636236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114418","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}

{"title":"Synthesis and evaluation of novel 3,5-dinitrobenzoyl substituted amino acid hydrazides against <i>Mycobacterium tuberculosis</i>.","authors":"Fatimah M Alsalem, Alistair K Brown, Andrew K Crowhurst, Charlotte A Taylor, Luka G Larkin, Jason H Gill, Jonathan D Sellars","doi":"10.1039/d6md00338a","DOIUrl":"10.1039/d6md00338a","url":null,"abstract":"<p><p>Multidrug-resistant tuberculosis (MDR-TB) represents an urgent unmet clinical need, with current regimens limited by prolonged duration, toxicity, and escalating resistance. We report the design, synthesis, and biological evaluation of 43 novel 3,5-dinitrobenzoyl amino acid hydrazide analogues against wild-type and multidrug-resistant strains of <i>Mycobacterium tuberculosis</i>. Systematic variation of both the amino acid side chain and the aryl hydrazide substituent revealed that hydrophobic, extended side chains confer superior antimycobacterial potency, whilst the influence of the hydrazide substituent appears context-dependent, modulated by the steric demands of the amino acid side chain. Cytotoxicity against mammalian cells was observed for several potent analogues, representing an early-stage optimisation challenge with clearly identified structure-dependent separability. Molecular docking against decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) is presented as a hypothesis-generating framework to rationalise key SAR trends. These findings establish a refined SAR landscape that will guide future structural optimisation of this promising antitubercular scaffold.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":"4913-4922"},"PeriodicalIF":4.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13587841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149008859","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}

{"title":"Flavonoids and chalcones as selective α-glucosidase inhibitors: from enzymatic screening to validation using the human enzyme.","authors":"Beatriz Vicente, Filipa Amaro, Paula Guedes de Pinho, Carina Proença, M Luísa Corvo, Eduarda Fernandes, Marisa Freitas","doi":"10.1039/d6md00685j","DOIUrl":"10.1039/d6md00685j","url":null,"abstract":"<p><p>α-Glucosidase is a key therapeutic target for postprandial glucose control, but most clinically available inhibitors also inhibit α-amylase, leading to gastrointestinal side effects. Natural polyphenols have been widely reported as potent and selective α-glucosidase inhibitors, primarily based on screening assays using yeast enzyme and synthetic substrates. In this study, thirteen flavonoids and five chalcones were initially evaluated using this conventional approach to elucidate the structural determinants of selective α-glucosidase inhibition. Among them, genistein and myricetin emerged as the most potent inhibitors of yeast α-glucosidase, with IC₅₀ values significantly lower than that of acarbose, the most widely used α-glucosidase inhibitor. Both flavonoids showed high selectivity, with minimal or no inhibition of α-amylase. To assess the translational relevance of these findings, these compounds were subsequently tested against human α-glucosidase from C2BBe1 cell extracts using the physiological substrate maltose. Under these conditions, only myricetin retained measurable inhibitory activity at low concentrations, which was further validated through chromatographic analysis. These findings demonstrate that current screening strategies relying solely on yeast α-glucosidase can substantially overestimate the inhibitory activity of natural polyphenols. This work highlights the importance of incorporating physiologically relevant enzyme sources, natural substrates, and controls for spectrophotometric assay interference into the discovery of novel α-glucosidase inhibitors, providing a more reliable workflow for the assessment of natural products.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":"4838-4850"},"PeriodicalIF":4.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13559892/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930711","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}

{"title":"Novel triazole-adenosine conjugates as mammalian seryl-tRNA synthetase inhibitors to protect cells from ischemia-reperfusion injury.","authors":"Lauriane Simon, Audrey Di Giorgio, Marc Cougnon, Michel Tauc, Didier F Pisani, Maria Duca","doi":"10.1039/d6md00593d","DOIUrl":"https://doi.org/10.1039/d6md00593d","url":null,"abstract":"<p><p>Aminoacyl-tRNA synthetases (aaRSs) have emerged as multifunctional therapeutic targets beyond their canonical role in protein synthesis. Among them, seryl-tRNA synthetase (SerRS) has been identified as a key regulator of translational stress responses and a promising target for ischemic protection. Building on prior evidence demonstrating that SerRS inhibition confers cytoprotection against anoxia in renal and neuronal cells, we report here the rational design, synthesis, and biological evaluation of a novel series of SerRS inhibitors based on the 5'-adenosine scaffold. First, we showed that the validated seryl-sulfamoyl adenosine (Ser-SA), a stable mimic of the natural l-seryl adenylate intermediate, represented a potent inhibitor of protein translation, likely thanks to inhibition of SerRS, with a very promising protecting effect against ischemia reperfusion injury. To overcome the synthetic limitations of Ser-SA, a new series of nine analogs was designed by replacing the sulfamoyl linker with a 1,2,3-triazole moiety and we demonstrated that this chemical modification preserved the desired biological activity. These results establish triazole-adenosine conjugates as a new chemotype of translation inhibitors with broad cytoprotective activity against I/R injury and support the further development of this scaffold toward optimized anti-ischemic agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149171622","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}

{"title":"Pyrimidine- and furo[2,3-<i>d</i>]pyrimidine-isoxazole hybrids and their Re(i) tricarbonyl complexes with antiproliferative activity against hematological malignancies.","authors":"Martina Piškor Benković, Ivan Ćorić, Leon Sačer, Lorena Damjanović, Katarina Mišković Špoljarić, Berislav Perić, Srećko I Kirin, Ljubica Glavaš-Obrovac, Silvana Raić-Malić","doi":"10.1039/d6md00379f","DOIUrl":"10.1039/d6md00379f","url":null,"abstract":"<p><p>Pyrimidine and furo[2,3-<i>d</i>]pyrimidine derivatives have emerged as promising anticancer agents that act through multiple mechanisms, including modulation of downstream signaling pathways such as a JAK2/STAT3 cascade. Herein, we report the synthesis of novel pyrimidine- and furo[2,3-<i>d</i>]pyrimidine-isoxazole hybrids <i>via</i> base-promoted 1,3-dipolar cycloaddition and their evaluation for antiproliferative activity. The compounds were assessed <i>in vitro</i> against five cancer cell lines (CaCo-2, HeLa, HuT-78, THP-1, and CCRF-CEM) and two non-tumor cell lines (MRC-5 and BJ). Within the 5-alkynyl-substituted pyrimidine series, compound 7g', bearing a 5-chloropentynyl substituent, showed the highest activity against the cutaneous T-cell lymphoma HuT-78 (IC₅₀ = 20.8 μM). Enhanced antiproliferative activity against HuT-78 cells was observed for the furo[2,3-<i>d</i>]pyrimidine isoxazole derivatives 8f', 9d', and 9f', with IC₅₀ values of 20.6, 15.5, 16.9 μM, respectively. Coordination to Re(i) improved activity in selected cases: complex showed strong and selective antiproliferative effects against hematological cancer cell lines (IC₅₀ = 1.5-2.1 μM, SI > 20), whereas demonstrated notable activity against THP-1 cells (IC₅₀ = 2.2 μM, SI > 14). Mechanistic studies in HuT-78 cells revealed that selected derivatives, 8f', 9f', and 9g', induced G0/G1 cell cycle arrest, increasing the G0/G1 population to approximately 57% with a concomitant decrease in the G2/M phase. Collectively, 7g', 8f', 9d', 9f', and 9g' were identify as promising lead compounds with potent antiproliferative activity in HuT-78 cells, mediated through G0/G1 cell-cycle arrest, mitochondrial dysfunction, and modulation of the PI3K/AKT and JAK/STAT signaling pathways. In contrast, the complex 7d_Re appears to exert its antiproliferative effects through a cell-cycle-independent mechanism that may involve modulation of the autophagic pathway in HuT-78 cells, without triggering classical apoptosis. These results support the potential of these pyrimidine- and furo[2,3-<i>d</i>]pyrimidine-based scaffolds for the development of therapeutic agents targeting T-cell lymphoma and other hematological malignancies.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":"4543-4563"},"PeriodicalIF":4.6,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148971003","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}

{"title":"Relationship between nanoscale assembly and cytotoxicity in the piperazine amides of betulinic acid: an <i>in vitro</i> study.","authors":"Martina Wimmerová, Miroslav Šlouf, Lucie Rárová, Marie Kvasnicová, David Šaman, Zdeněk Wimmer","doi":"10.1039/d6md00638h","DOIUrl":"10.1039/d6md00638h","url":null,"abstract":"<p><p>Six new piperazine amides of betulinic acid, partly decorated with a glycine unit, were synthesized and purified and their structures were elucidated. This study explored whether relationships could be identified among the molecular structures, nanoscale self-assembly, and cytotoxicity of the synthesized compounds. Because of the limited quantities of the target compounds finally available for the analytical methods, their selection had to be very careful. NMR spectroscopy and mass spectrometry were used to elucidate the molecular structures, while transmission electron microscopy (TEM) was employed to characterize the supramolecular structures formed after dissolution in methanol and water. The target compounds reproducibly displayed several basic morphologies depending on the solvent type (methanol <i>vs.</i> water) and the time in solution (1 h <i>vs.</i> 48 h). Several characteristic morphologies were observed, including cloud-like assemblies, isometric nanoparticles of various sizes, fibrous nanostructures with thicknesses below 10 nm, and combinations of these structures, depending on the compound, solvent, and time in solution. The target compounds (6 and 8), the parent compound (1) and the intermediates (2 and 4) were subjected to cytotoxicity assays in the HeLa and MCF7 cancer cell lines while using normal human fibroblasts (BJ) as the reference cells. Cisplatin (<i>cis</i>-diaminedichloroplatinum(ii), <b>CDDP</b>), a pharmacologically used anticancer agent, was used for comparing the cytotoxicity levels and cytotoxicity profiles of the studied compounds. Compounds 6 and 8 were specifically examined for possible associations between nanoscale self-assembly and cytotoxicity studied <i>in vitro</i>. The results provided initial insights into the complex relationship among the molecular structures, self-assembly, and cytotoxicity of the studied compounds.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":"5050-5057"},"PeriodicalIF":4.6,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114475","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}

{"title":"A multi-evidence computational and experimental strategy for <i>Silene nerimaniae</i>: combining phytochemical characterization, bioactivity assessment, and ADEFRank-HCT-116-based metabolite prioritization.","authors":"Ahmet Erharman, Sakina Yagi, Abdullahi Ibrahim Uba, Filip Nikolić, Uroš Gašić, Mikail Acar, Nurettin Dogan, Ismail Koyuncu, Ismail Yapıcı, Ilhami Gulcin, Meng-Yao Li, Gunes Ak, Bengusu H Akgul, Gokhan Zengin","doi":"10.1039/d6md00624h","DOIUrl":"https://doi.org/10.1039/d6md00624h","url":null,"abstract":"<p><p>This study presents the first comprehensive evaluation of the phytochemical composition, antioxidant properties, enzyme inhibitory effects, and cytotoxic potential of <i>Silene nerimaniae</i> G.E.Genç, Kandemir & İ.Genç (family Caryophyllaceae). Ethyl acetate, acetone, 70% acetone, and aqueous extracts were obtained from the aerial parts of the plant through maceration. Among the tested extracts, the acetone extract contained the highest total phenolic (24.37 mg GAE per g) and flavonoid (24.64 mg RE per g) contents. LC-MS analysis identified 52 bioactive constituents, including sugars, organic acids, phenolic acids, flavonoids, and fatty acids. The aqueous extract demonstrated the strongest radical scavenging activity against DPPH (23.02 mg TE per g) and ABTS (55.76 mg TE per g), as well as the highest Fe³⁺ reducing power (37.53 mg TE per g). In combination with the acetone extract, it also exhibited notable Cu²⁺ reducing activity (47.78 mg TE per g). Regarding enzyme inhibition, the ethyl acetate, acetone, and hydroacetone extracts displayed the strongest inhibitory activities against acetylcholinesterase (1.87 mg GALA per g), butyrylcholinesterase (2.92 mg GALA per g), and tyrosinase (60.44 mg KAE per g), respectively. All three extracts also inhibited α-amylase activity within the range of 0.73-0.77 mmol ACAE per g (<i>p</i> ≥ 0.05). In addition, the hydroacetone extract showed considerable inhibition of human carbonic anhydrase isoenzymes I (IC₅₀ = 38.78 μg mL^-1) and II (IC₅₀ = 19.59 μg mL^-1). The ethyl acetate extract exhibited the strongest cytotoxic effect against the colorectal cancer cell line HCT-116, with an IC₅₀ value of 0.639 μg mL^-1 and a selectivity index of 1.7. To contextualize this HCT-116-associated activity at the metabolite level, an ADEFRank-HCT116 (abundance-domain-evidence fusion ranking) workflow was applied by integrating EtOAc abundance, HCT-116-oriented QSAR evidence, applicability-domain confidence, and structure-assignment reliability. This analysis prioritized diosmetin, luteolin, eriodyctiol, acacetin, and isorhamnetin as core candidates for structure-based follow-up. Molecular docking screening predicted favorable docking profiles for the prioritized candidates, while 100 ns molecular dynamics simulations were used to assess the dynamic stability of the representative luteolin-PI3Kα, diosmetin-AKT1, and isorhamnetin-GSK-3β complexes. Taken together, these results indicate that <i>S. nerimaniae</i> may represent a valuable source of active compounds for various functional nutraceutical, cosmetic and pharmaceutical uses.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149184196","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}

{"title":"Strategic synthesis, antibacterial evaluation and SAR analysis of bisindole-chromone hybrids as an anti-staphylococcal agent.","authors":"Arti Rathore, Rohit Singh, Biplab Sarkar, Chirag Kumar Chourasia, Shifa Firdous, Ravindra S Phatake, Avisek Mahapa","doi":"10.1039/d6md00569a","DOIUrl":"https://doi.org/10.1039/d6md00569a","url":null,"abstract":"<p><p>Antimicrobial resistance has diminished the effectiveness of existing antibiotics, necessitating the development of novel antibacterial agents. Herein, a focused library of twenty halogenated bisindole-chromone hybrids was designed through scaffold-hopping approaches and synthesized by a molecular hybridization technique <i>via</i> an efficient iodine-mediated coupling protocol. Antibacterial evaluation identified thirteen hybrids with potent anti-staphylococcal behaviour and favorable safety profiles toward mammalian cells and RBCs. Structure-activity relationship studies revealed that fluorine substitution on both chromone and bisindole fragments enhanced antibacterial potency, and identified <b>BIC-12</b> as the optimal lead compound. <b>BIC-12</b> exhibited MIC values of (1.5 μM/0.4 μg mL^-1) and (6.2 μM/2.0 μg mL^-1) against MSSA and MRSA, respectively, with rapid bactericidal activity and excellent antibiofilm efficacy. Mechanistic investigations revealed mild membrane perturbation together with pronounced cellular deformation and morphological alterations. These findings suggest that <b>BIC-12</b> acts through a mechanism distinct from direct membrane disruption, although the precise molecular target remains to be elucidated. These findings identify fluorinated analogue <b>BIC-12</b> as a promising <i>in vitro</i> anti-staphylococcal hit for further lead optimization and mechanistic investigation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149114415","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}

{"title":"Oridonin derivatives suppress inflammation by modulating a novel NLRP3/<i>Stfa2</i> axis in RAW 264.7 cells and a mouse model of acute lung injury.","authors":"Peng Li, Qiqi Wang, Zhanpan Wu, Huiping Ou, Qiufeng Huang, Wancun Wang, Jinhua Ning, Guochun Yang, Wen Bin Jin, Ran Liu","doi":"10.1039/d6md00274a","DOIUrl":"https://doi.org/10.1039/d6md00274a","url":null,"abstract":"<p><p>Oridonin, a major bioactive constituent of the traditional Chinese herb <i>Isodon rubescens</i>, was structurally modified in our previous study to obtain significantly improved anti-inflammatory properties. Here, we designed and synthesized 16 novel 1-<i>O</i>- and 14-<i>O</i>-derivatives of oridonin to investigate their anti-inflammatory activity and mechanisms. Compound 4d, bearing an α,β-unsaturated carbonyl moiety at C-14, markedly suppressed the expression and secretion of the inflammatory cytokines IL-6 and IL-1β in RAW 264.7 macrophage-like cells. Mechanistic studies indicated that 4d attenuated inflammation both <i>in vitro</i> and in <i>vivo</i> through modulation of the NLRP3 inflammasome and its downstream effector <i>Stfa2</i>. Functional validation <i>via</i> knockdown and overexpression experiments for the first time established that <i>Stfa2</i> acts downstream of NLRP3 and represses the expression of IL-6, IL-1β, and COX-2. Complementary computational analyses suggested that 4d can adopt a plausible and stable binding mode within NLRP3, supported by specific hydrogen bonds, hydrophobic interactions, and favorable binding energy profiles, along with minimal structural fluctuation and high thermodynamic stability. This study clarifies the structure-activity relationships of oridonin derivatives with respect to their anti-inflammatory activity and identifies <i>Stfa2</i> as a novel anti-inflammatory mediator downstream of NLRP3 and highlights the potential of <i>Stfa2</i> as a novel therapeutic target for the treatment of inflammatory disorders.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":"17 10","pages":"4982-5001"},"PeriodicalIF":4.6,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149272927","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}

{"title":"Purine nucleoside phosphorylase in breast cancer from metabolic regulation to targeted therapy: challenges and opportunities.","authors":"Sahar Salem, Rania Hamdy, Sarra B Shakartalla, Dana Halawy, Sarina Hashim, Nabiha B Remmani, Ahmed M Almehdi, Sameh S M Soliman","doi":"10.1039/d6md00400h","DOIUrl":"10.1039/d6md00400h","url":null,"abstract":"<p><p>Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway that has recently emerged as a potential therapeutic target in cancer. While its role in hematological malignancies is relatively well established, its contribution to solid tumors, particularly breast cancer, remains insufficiently defined. This review aims to critically evaluate the role of PNP in breast cancer progression, with a focus on its involvement in metabolic reprogramming, tumor aggressiveness, and immune modulation, in addition to therapeutic targeting potential. Current evidence indicates that PNP overexpression supports nucleotide homeostasis, promotes proliferation, and contributes to metastatic phenotypes through metabolites such as hypoxanthine. Structural and computational studies have facilitated the development of diverse PNP inhibitors; however, their clinical translation into breast cancer therapy remains limited. A major research gap lies in the lack of mechanistic integration between PNP-driven metabolism, tumor-immune interactions, and subtype-specific breast cancer biology, as well as insufficient <i>in vivo</i> and clinical validation of candidate inhibitors in solid tumors. To address these limitations, future research should focus on integrating multi-omics approaches, advanced computational modeling, and patient-derived models to elucidate PNP-centered metabolic-immune networks. In parallel, the rational design of selective inhibitors with improved pharmacokinetic profiles, combined with biomarker-driven patient stratification and combination therapy strategies, establishes a strong rationale for the development of clinically effective PNP-targeted therapies for breast cancer.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13537612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881541","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}