MedChemComm最新文献

{"title":"Discovery of novel dehydroabietylamine–pyrimidine hybrids: design, synthesis and anti-tumor evaluation","authors":"Zhen-Wei Zhang, Ruo-Chen Huang, Kai Xiong and Yan-Qiu Deng","doi":"10.1039/D5MD00593K","DOIUrl":"10.1039/D5MD00593K","url":null,"abstract":"<p >Challenges in cancer treatment lie in the identification and development of novel agents with potent anti-tumor activity. A series of novel dehydroabietylamine–pyrimidine derivatives <strong>3a–3s</strong> were designed and synthesized based on the principles of molecular hybridization. The inhibitory activities of the target compounds against the proliferation of four different human cancer cell lines (HepG2, A549, HCT116 and MCF-7) were evaluated. Among them, compound <strong>3r</strong>, which contains a bicyclic quinuclidine ring, was identified as a potent apoptotic inducer, with a better IC<small>₅₀</small> value of 1.15 ± 0.31 μM on MCF-7 cells and a favorable selectivity index (SI = 27.7) on human normal mammary epithelial cells (MCF-10A). Cell clonogenic and migration assays further demonstrated that <strong>3r</strong> not only effectively inhibited colony formation but also suppressed the cell migratory capacity. Further mechanistic studies revealed that <strong>3r</strong> significantly elevates reactive oxygen species (ROS) levels and reduces mitochondrial membrane potential (MMP), thereby inducing cancer cell apoptosis and causing G2 phase cell cycle arrest.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4480-4491"},"PeriodicalIF":3.597,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016154","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":"New quinazoline-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines as inhibitors of EGFR: synthesis, anti-breast cancer evaluation and in silico studies†","authors":"Mahadev Dattatray Bandgar, Sampath Peddapelli, Ravikumar Kapavarapu, Joshodeep Boruwa, Sridhar Kavela and Sirassu Narsimha","doi":"10.1039/D5MD00103J","DOIUrl":"10.1039/D5MD00103J","url":null,"abstract":"<p >Breast cancer is the most frequently diagnosed malignancy in women. Invasive breast cancer will be diagnosed in approximately one in every eight women during their lifetime. Quinazoline-[1,2,4]triazolo[3,4-<em>b</em>][1,3,4]thiadiazines were designed and synthesized using a pharmacophore hybridization technique that combined biologically active scaffolds. <em>In vitro</em> assays of the synthesized compounds' cancer activity against three breast cancer cell lines: MCF-7, MDA-MB-231, and MDA-MB-468, compounds <strong>6i</strong>, <strong>6k</strong>, and <strong>6l</strong> exhibited significant activity. Compounds <strong>6j</strong> and <strong>6m</strong> exhibited equivalent efficacy relative to the standard drug against the MDA-MB-231 cell line, but compound <strong>6i</strong> showed significant activity against the MDA-MB-468 cell line. Moreover, compound <strong>6i</strong> (IC<small>₅₀</small> = 0.37 ± 0.03 μM) demonstrated superior efficacy compared to the standard erlotinib (IC<small>₅₀</small> = 0.42 ± 0.01 μM) <em>in vitro</em>, based on EGFR inhibitory assays and compound <strong>6k</strong> (IC<small>₅₀</small> = 0.51 ± 0.04 μM) showed good EGFR inhibitory activity. To validate the activity data and the drug-likeness of the compounds, six potent compounds were subjected to <em>in silico</em> molecular docking investigations using the Discovery Studio 2021 methodology.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4154-4169"},"PeriodicalIF":3.597,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675545","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 novel 1,8-naphthalimide-piperazine-amidobenzenesulfonamide derivative targets carbonic anhydrase IX to induce ferroptosis, apoptosis and autophagy in colorectal cancer cells†","authors":"Xiao-Qun Zhou, Yong-Xiao Huang, Qiao-Ling Liang, Ri-Zhen Huang, Ye Zhang, Hai-Rui Lu, Xian-Li Ma and Nur Syamimi Ariffin","doi":"10.1039/D5MD00348B","DOIUrl":"10.1039/D5MD00348B","url":null,"abstract":"<p >Carbonic anhydrases (CAs) are crucial for cancer cells to survive in hypoxia. Here we show that our newly synthesised 1,8-naphthalimide-piperazine-amidobenzenesulfonamide derivative, namely compound <strong>Q</strong>, specifically targets CA IX and causes cell death in colorectal cancer. Compound <strong>Q</strong> stably binds to the zinc atom in the active pocket of CA IX and selectively inhibits the activity of this enzyme. It kills SW480 cells under normoxic and hypoxic conditions, with an IC<small>₅₀</small> of 17.03 ± 1.09 μM and 10.90 ± 0.46 μM, respectively. The inhibitory effect of compound <strong>Q</strong> against CA IX activity is better under hypoxic conditions and it has low toxicity on normal colon with an IC<small>₅₀</small> of 38.83 ± 1.98 μM. Compound <strong>Q</strong> also inhibits tumour growth in the colorectal cancer SW480 xenograft model and it shows no adverse effects on nude mice body weight. Our analyses also demonstrate that compound <strong>Q</strong> induces ferroptosis, apoptosis and autophagy in colorectal cancer and we believe that these are the main mechanisms by which it promotes cell death in this cancer. Taken together, our data indicate that compound <strong>Q</strong> is a potent and selective CA IX inhibitor that is promising for the treatment of colorectal cancer.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4427-4439"},"PeriodicalIF":3.597,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733031","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":"Non-steroidal anti-inflammatory drugs conjugated to a synthetic peptide exhibit in vitro cytotoxic activity against cervical cancer and melanoma cells†","authors":"Daniel Alejandro Castellar-Almonacid, Andrea Carolina Barragán-Cárdenas, Karla Geraldine Rodríguez-Mejia, Laura Angélica Maldonado-Sanabria, Natalia Ardila-Chantré, Jose David Mendoza-Mendoza, Claudia Marcela Parra-Giraldo, Jhon Erick Rivera-Monroy, Zuly Jenny Rivera-Monroy, Javier Eduardo García-Castañeda and Ricardo Fierro-Medina","doi":"10.1039/D5MD00476D","DOIUrl":"10.1039/D5MD00476D","url":null,"abstract":"<p >Previous studies have shown that the palindromic peptide RWQWRWQWR derived from bovine lactoferricin (LfcinB) has exhibited selective <em>in vitro</em> cytotoxic effects against multiple cancer cells such as cervical, breast, and prostate cancer. We designed and synthesized peptides based on this palindromic sequence conjugated with non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ibuprofen to obtain novel hybrid peptides that could trigger inflammatory processes within cancer cells. Incorporating the non-natural amino acid ornithine as a spacer was done to improve the aqueous solubility of the NSAID–peptide conjugates. The antibacterial activity of the conjugated peptides was evaluated, and these peptides showed significant activity against <em>E. coli</em> strain ATCC 25922, with MIC values of 12 μM. Cytotoxicity was assessed in human cervical cancer cells (HeLa) and human melanoma cells (A375), showing that the NSAID-conjugated peptides retained and even exhibited better anticancer activity compared to the palindromic peptide from which they were derived. The NSAID-LfcinB conjugates showed good selectivity towards cancer cells in the concentration ranges evaluated, being non-hemolytic. The cytotoxic effect of the IBU-Orn<small>₃</small>-1 and NAP-Orn<small>₃</small>-1 peptides was rapid and selective, inducing severe morphological changes, including rounding, shrinkage, and vacuole formation, which are associated with apoptosis. Flow cytometry assays revealed that the ibuprofen-conjugated palindromic sequence induced apoptosis independently of peptide concentration and treatment duration. These results suggest that the palindromic peptide RWQWRWQWR could be used for new applications in cancer research, such as delivering small molecules with anti-inflammatory activity in tumoral environments. The conjugation of NSAIDs to anticancer peptide sequences is a novel, viable, and rapid strategy that facilitates the synthesis of hybrid peptides with enhanced anticancer activity, thereby expanding the pool of promising molecules for preclinical and clinical studies in cancer therapy development.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4170-4182"},"PeriodicalIF":3.597,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708603","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":"Discovery of semisynthetic derivatives of (R)- and (S)-usnic acids as potential antifungal agents against C. tropicalis and T. rubrum†","authors":"Anna Fontana, Alessio Colleoni, Roberta Listro, Giacomo Rossino, Pasquale Linciano, Barbara Vigani, Caterina Valentino, Valeria Cavalloro, Marta Elisabetta Eleonora Temporiti, Solveig Tosi, Emanuela Martino and Simona Collina","doi":"10.1039/D5MD00457H","DOIUrl":"10.1039/D5MD00457H","url":null,"abstract":"<p >The prevalence of human fungal infections (FIs) is rapidly increasing worldwide, posing substantial challenges to public health. The underestimation of FIs risk led to a limited knowledge of the fungal pathogenicity and a concomitant paucity of antimycotic drugs that are increasingly unable to effectively address resistance liabilities. The identification of innovative antifungal drugs is therefore an urgent need. Natural products have always been under scrutiny in the drug discovery process. Of these, usnic acid (<strong>UA</strong>) represents a compelling starting point for antifungal drug development due to its natural occurrence as a secondary metabolite in various lichen species, where it serves as a natural defence mechanism against fungal invasion. This dibenzofuran derivative possesses an intrinsically rigid three-dimensional architecture with stereogenic center, providing a pre-organized chiral scaffold with potential for selective interaction with fungal targets. Despite its high therapeutic potential as antimicrobial agent, <strong>UA</strong> suffers from poor solubility and hepatotoxicity issues. The proposed research explores the modification of <strong>UA</strong> scaffold to generate the series of semisynthetic compounds <strong>1–9</strong> by derivatizing the (<em>R</em>)- and (<em>S</em>)-<strong>UA</strong> as enamines. Considering the inherent chirality of <strong>UA</strong>, this work aims to identify structure–activity relationships that optimize antifungal efficacy while improving the pharmacokinetic properties of <strong>UA</strong>. The resulting compounds were evaluated for their antifungal activity against three strains, showing significant differences in potency concerning their absolute configuration. This research addresses the urgent need for novel antifungal agents in an era of increasing resistance to conventional treatments, identifying (9b<em>S</em>,15<em>S</em>)-<strong>1</strong>, <strong>3</strong>, <strong>4</strong>, and <strong>8</strong> compounds as promising compounds for developing antifungal therapeutics.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4390-4404"},"PeriodicalIF":3.597,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12272722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675609","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":"A momentous progress update: epidermal growth factor receptor inhibitors as viable agents for combating cancer","authors":"Neha Jangra, Bharti Sharma, Deepak Kumar and Archana Kapoor","doi":"10.1039/D4MD00799A","DOIUrl":"10.1039/D4MD00799A","url":null,"abstract":"<p >The epidermal growth factor receptor (EGFR) family comprises four distinct members with similar framework characteristics: EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). EGFR plays a pivotal role in cellular signaling pathways that regulate key pathological processes, including apoptosis, uncontrolled cell proliferation, metastasis, and angiogenesis. However, clinically used EGFRs such as apatinib, selumetinib, gefitinib, vandetanib, and erlotinib are not selective, thereby resulting in troublesome side effects. Drug obstruction, alteration, and specificity represent a few of the primary obstacles in the development of unique key compounds as EGFR inhibitors, stimulating medicinal chemists to discover innovative chemotypes. The development of drugs that block specific stages of cancerous cells, such as EGFR, is one of the main goals of many cancer treatments, including breast and lung tumors. Thus, the current study endeavored to summarize the numerous recent advancements (2016–2024) in the research and development of diverse epidermal growth factor receptor (EGFR) inhibitors, focusing on pyrrole, indole, pyrimidine, oxadiazole, isoxazole, and other structural classes. Preclinical, clinical, structure–activity relationships (SAR) with mechanism-based and <em>in silico</em> research, and other relevant data are compiled to offer directions for the scientific discovery of novel EGFR inhibitors with conceivable uses in therapy. The research trajectory of this entire field will provide incessant opportunities for the discovery of novel drug molecules with improved efficacy and selectivity.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 3893-3958"},"PeriodicalIF":3.597,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592134","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 and activity of conopressins: insights into in silico oxytocin/V2 receptor interactions, anti-inflammatory potential, and behavioural studies†","authors":"Pooja Dhurjad, Mohd Rabi Bazaz, Satyam Pati, Manoj P. Dandekar, Chandraiah Godugu and Rajesh Sonti","doi":"10.1039/D5MD00288E","DOIUrl":"10.1039/D5MD00288E","url":null,"abstract":"<p >Conopressins are single disulfide conopeptides with a close sequence similarity to vasopressin and oxytocin, exhibiting grooming and scratching effects in rodents. Here, we have investigated the impact of stereochemistry on the conserved arginine residue at position 4 and the truncation (Tr-Mo976 and Tr-Mo977) on the structure and activity of conopressins. 3D structures determined by solution NMR revealed distinct structural features for Mo1033 and <small>^D</small>R4-Mo1033. Molecular dynamics studies of the conopressins with oxytocin and V2 receptor complexes revealed that both Tr-Mo976 and Tr-Mo977 showed robust interactions with the OT receptor and reduced interactions with the V2 receptor. In addition, conopressins exhibited anti-inflammatory and antioxidant potential in LPS-stimulated macrophages. Behavioural studies in mice demonstrated high grooming and scratching behaviour for Tr-Mo976 and reduced locomotory activity with Tr-Mo977. To this end, results suggest that both the truncation of the tail region and the nature of residue 8 play an essential role in altering the activity of conopressins.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4106-4121"},"PeriodicalIF":3.597,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144733033","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":"Unveiling the therapeutic potential of prenyl motif-containing derivatives: a key structural fragment for designing antidepressant compounds","authors":"Md Jawaid Akhtar, Khalid Al Balushi, Bushara Al Sabahi, Shah Alam Khan and Afrah Al Tamimi","doi":"10.1039/D5MD00473J","DOIUrl":"10.1039/D5MD00473J","url":null,"abstract":"<p >Depression is a complex mental disorder, and consequently, the successful treatment of the depressive disorder remains challenging. The available medications often show limitations in terms of both safety and efficacy. In this case, the presence of the prenyl motif in pharmaceutical compounds has resulted in a broad spectrum of biological activities. Various studies have highlighted that the potent antidepressant activity of many natural compounds is associated with the presence of the prenyl motif. Thus, some studies have attempted to prepare prenyl fragment derivatives with the aim of enhancing their hydrophobicity and developing promising antidepressant compounds. Prenyl motif-containing compounds exhibit antidepressant action <em>via</em> multiple mechanisms, including selective serotonin/norepinephrine reuptake inhibition, blocking of NMDA receptors, 5-HT<small>₆</small> antagonism, TREK-1 inhibition, MAO-A inhibition, and anti-inflammatory and antioxidant properties. This review presents synthetic derivatives of xanthones, flavonoids, and chalcones bearing prenyl groups. It also covers polyprenylated benzoyl phloroglucinols/acylphloroglucinols, naphthoquinones, volatile oils, tricyclic products, and steroidal saponins containing prenyl motifs. This study aims to further guide and support medicinal chemists in directing the synthesis of more potent compounds possessing prenyl fragments as antidepressants, thus advancing treatment options for depression.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 3959-3981"},"PeriodicalIF":3.597,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660090","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":"New melatonin biphenyl-linked scaffold targeting colorectal cancer: design, synthesis, biological, and ADME-Tox modelling studies†","authors":"Mariluz Silva-García, Angie Herrera-Ramírez, Wilson Cardona-Galeano and Andrés F. Yepes","doi":"10.1039/D5MD00410A","DOIUrl":"10.1039/D5MD00410A","url":null,"abstract":"<p >A series of melatonin biphenyl-linked conjugates was designed and synthesized using a simple, cost-effective, and environmentally friendly method. All the new compounds were evaluated for their cytotoxic or cytostatic activity against SW480 human colorectal adenocarcinoma cells. Screening at 100 μM revealed that most compounds exhibited high activity (≥60% inhibition), with compounds <strong>3b</strong>, <strong>3h</strong>, <strong>4f</strong>, <strong>4g</strong>, and <strong>4i–l</strong> also demonstrating subtle lethality. Based on these initial results, a subset of the most active hybrids was selected for further in-depth evaluation to calculate three key parameters of cell viability: GI<small>₅₀</small>, TGI, and LC<small>₅₀</small> values. The results showed that most compounds, except <strong>3c</strong> and <strong>4d</strong>, significantly outperformed the parental compound (<strong>2</strong> and melatonin) in inhibiting cancer cell proliferation, highlighting the efficacy of hybridization in improving cytotoxic potential. Besides, it is noticeable that hybrids <strong>4f–l</strong> exhibited superior activity compared to 5-FU, as evidenced by lower GI<small>₅₀</small> values. Although hybrids <strong>4f</strong> and <strong>4g</strong> seemed to exert the greatest activity as demonstrated in the LC<small>₅₀</small> values (70.89 ± 11.72 μM and 68.03 ± 0.46 μM, respectively), we observed that only hybrids <strong>4j</strong> and <strong>4l</strong> showed significant selectivity, as revealed by higher GI<small>₅₀</small> concentrations over non-malignant cells (NCM460). The observed total growth inhibition and lack of LC<small>₅₀</small> values in <strong>4j</strong> and <strong>4l</strong> suggest their potential for a cytostatic effect. Lastly, theoretical evaluations of drug-likeness, pharmacokinetic behaviour, and toxicological parameters suggest that the most promising hybrids, compounds <strong>4j</strong> and <strong>4l</strong>, exhibit strong potential for advancement into preclinical studies. Our findings highlight the effectiveness of a novel melatonin biphenyl-linked scaffold, with <strong>4j</strong> and <strong>4l</strong> structures in particular serving as prototypes for future innovative adjuvant drugs.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 9","pages":" 4239-4256"},"PeriodicalIF":3.597,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560957","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":"Synthesis and biological evaluation of thiosemicarbazone-based antibody–drug conjugates†","authors":"Nandan Sheernaly, Irene Shajan, Axel Steinbrueck, Bauke Albada and Nils Metzler-Nolte","doi":"10.1039/D5MD00154D","DOIUrl":"10.1039/D5MD00154D","url":null,"abstract":"<p >Metal chelators belonging to the di-pyridyl-thiosemicarbazone (DpTs) class have shown great promise as adjuvant therapeutics for treating cancer, with DpC and Dp44mT emerging as the lead candidates. Despite their efficacy, these molecules also induce various undesirable side effects due to insufficient cancer cell targeting, highlighting the need to improve their selectivity. Here, we present a first generation of DpT–antibody conjugates. To this end, we developed a facile synthesis to functionalize DpTs strategically with click-able azido linkers. Moreover, selective side-chain modification of the clinical antibody trastuzumab (Tras) with a complementary bis-alkyne moiety is described. Using this new chemistry, we conjugated four different azido DpTs to trastuzumab <em>via</em> a combination of oxidation-controlled quinone (SPOCQ) and strain-promoted alkyne–azide click (SPAAC) chemistry. We evaluated the antiproliferative activity of the resulting novel antibody–drug conjugates (ADCs) against MCF-7 and SK-BR-3 cell lines. Linker positioning on the DpT scaffold significantly influences the cytotoxicity of the conjugates. For instance, conjugating Tras at the <em>ortho</em> position on the Dp44mT scaffold is more efficacious than conjugating at the <em>para</em> position with IC<small>₅₀</small> values of 25.7 ± 5.5 nM and 103.5 ± 2.0 nM, respectively, against MCF-7 cells. Furthermore, we observe intriguing cell line-dependent activity of the ADCs with increased selectivity towards MCF-7 cells, providing novel insights into the cytotoxic activity of DpTs and their antibody conjugates.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 8","pages":" 3512-3521"},"PeriodicalIF":3.597,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144529467","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}