Bioorganic & Medicinal Chemistry最新文献

{"title":"The journey of antibody-drug conjugates for revolutionizing cancer therapy: A review","authors":"Fatima Akram ,&nbsp;Amna Murrawat Ali ,&nbsp;Muhammad Tayyab Akhtar ,&nbsp;Taseer Fatima ,&nbsp;Ifrah Shabbir ,&nbsp;Ikram ul Haq","doi":"10.1016/j.bmc.2024.118010","DOIUrl":"10.1016/j.bmc.2024.118010","url":null,"abstract":"<div><div>Antibody-drug conjugates (ADCs) represent a powerful class of targeted cancer therapies that harness the specificity of monoclonal antibodies to deliver cytotoxic payloads directly to tumor cells, minimizing off-target effects. This review explores the advancements in ADC technologies, focusing on advancing next-generation ADCs with novel payloads, conjugation strategies, and enhanced pharmacokinetic profiles. In particular, we highlight innovative payloads, including microtubule inhibitors, spliceosome modulators, and RNA polymerase inhibitors, that offer new mechanisms of cytotoxicity beyond traditional apoptosis induction. Additionally, the introduction of sophisticated conjugation techniques, such as site-specific conjugation using engineered cysteines, enzymatic methods, and integration of non-natural amino acids, has greatly improved the homogeneity, efficacy, and safety of ADCs. Furthermore, the review delves into the mechanistic insights into ADC action, detailing the intracellular pathways that facilitate drug release and cell death, and discussing the significance of bioconjugation methods in optimizing drug-antibody ratios (DARs). The establishment of comprehensive databases like ADCdb, which catalog vital pharmacological and biological data for ADCs, is also explored as a critical resource for advancing ADC research and clinical application. Finally, the clinical landscape of ADCs is examined, with a focus on the evolution of FDA-approved ADCs, such as Gemtuzumab Ozogamicin and Trastuzumab Emtansine, as well as emerging candidates in ongoing trials. As ADCs continue to evolve, their potential to revolutionize cancer therapy remains immense, offering new hope for more effective and personalized treatment options. ADCs also offer a significant advancement in targeted cancer therapy by merging the specificity of monoclonal antibodies with cytotoxic potency of chemotherapeutic agents. Hence, this dual mechanism intensifies tumor selectivity while minimizing systemic toxicity, paving the way for more effective and safer cancer treatments.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118010"},"PeriodicalIF":3.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of protein post-translational modifications with site-specifically incorporated non-canonical amino acids","authors":"Jiayu Gu ,&nbsp;Lihui Lao ,&nbsp;Yulin Chen ,&nbsp;Shixian Lin","doi":"10.1016/j.bmc.2024.118013","DOIUrl":"10.1016/j.bmc.2024.118013","url":null,"abstract":"<div><div>Despite the important functions of protein post-translational modifications (PTMs) in numerous cellular processes, understanding the biological roles of PTMs remains quite challenging. Here, we summarize our efforts in recent years to incorporate a variety of non-canonical amino acids (ncAAs) to study the biological functions of protein PTMs in mammalian cells, with a focus on the use of ncAA tools to probe the biological functions of various protein PTMs. We design length-tunable lipidation mimics for studying lipidation function and designing protein drugs. We highlight the use of genetically encoded lysine aminoacylations as chemical baits to identify aminoacylated lysine ubiquitination. Finally, we discuss the use of genetically encoded electron-rich Trp derivatives to design binding affinity-enhancing histone methylations readers.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118013"},"PeriodicalIF":3.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAD18-catalysed formation of ubiquitination intermediate mimic of proliferating cell nuclear antigen PCNA","authors":"Liying Zhang ,&nbsp;Zhiheng Deng ,&nbsp;Yunxiang Du ,&nbsp;Ziyu Xu ,&nbsp;Tianyi Zhang ,&nbsp;Zebin Tong ,&nbsp;Huasong Ai ,&nbsp;Lu-Jun Liang ,&nbsp;Lei Liu","doi":"10.1016/j.bmc.2024.118016","DOIUrl":"10.1016/j.bmc.2024.118016","url":null,"abstract":"<div><div>The 2-((2-chloroethyl)amino)ethane-1-thiol (CAET)-based chemical trapping strategy is a practical tool for mechanistic studies of E3-catalysed ubiquitination. However, the construction of ubiquitination intermediate mimics (E2-Ub-substrate conjugates) via CAET has been limited to peptides, while its application to folded protein substrates remains unexplored. Here, we report that disulfide bond formation between E2-Ub (RAD6A-Ub) and the folded protein substrate PCNA (proliferating cell nuclear antigen) occurs upon the addition of the PCNA-associated E3 ligase RAD18. Leveraging this finding, we employed intein splicing technology to generate a stable, covalently linked RAD18-RAD6A-Ub-PCNA complex, enabling chemical crosslinking mass spectrometry (CX–MS) analysis to study the structure of this complex. This work showcases use of a substrate-associated E3 ligase to promote disulfide bond formation between an E2-Ub conjugate and a folded substrate for CAET-based trapping, thereby expanding the scope of this technique.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118016"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and biological evaluation of lappaconitine analogues as potential anti-neuroinflammatory agents by side chain modification and scaffold hopping strategy","authors":"Feng Xing ,&nbsp;Hong-Yi Su ,&nbsp;He-Yang Zhong ,&nbsp;Yu-Zhu Li ,&nbsp;Yin-Yong Zhang ,&nbsp;Lin Chen ,&nbsp;Xian-Li Zhou","doi":"10.1016/j.bmc.2024.118012","DOIUrl":"10.1016/j.bmc.2024.118012","url":null,"abstract":"<div><div>Neuroinflammation mediated by microglia is widely recognized as a key pathophysiological mechanism in neurodegenerative diseases. Lappaconitine (LA) is a natural C₁₈-diterpenoid alkaloid isolated from <em>Aconitum sinomontanum</em> Nakai, and previous study showed that LA and its derivatives inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. However, the anti-neuroinflammatory effects of LA and its derivatives on microglia are still not clear. Here, LA analogues were designed and synthesized, and the anti-neuroinflammatory activity of the synthesized compounds was screened using LPS-induced overexpression of NO in BV-2 microglia. The screening results showed that compound <strong>10</strong> displayed the highest ability to inhibit NO production (IC₅₀ = 9.98 ± 1.6 µM). Mechanistic investigations revealed that compound <strong>10</strong> attenuated LPS-activated neuroinflammation through suppression of TLR4/MyD88/NF-κB pathway in BV-2 microglia. Acute toxicity assays showed that compound <strong>10</strong> (LD₅₀ = 508.1 mg/kg) was safer relative to LA (LD₅₀ = 30.6 mg/kg). Collectively, our findings show that compound <strong>10</strong> could have potential as anti-neuroinflammatory agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118012"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142719920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of 3-(2-aminobenzo[d]thiazol-5-yl) benzamide derivatives as potent anticancer agents via ROR1 inhibition","authors":"Fang Luo ,&nbsp;Jie Liu ,&nbsp;Rongtao Wang,&nbsp;Huiyin Yang,&nbsp;Ting Zhong,&nbsp;Mingzhi Su,&nbsp;Yanhua Fan","doi":"10.1016/j.bmc.2024.118011","DOIUrl":"10.1016/j.bmc.2024.118011","url":null,"abstract":"<div><div>Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the receptor tyrosine kinase family, which was overexpressed in non-small cell lung cancer (NSCLC) and essential for cell proliferation, migration and invasion. Recently, accumulating evidences indicated that ROR1 played a critical role in maintaining the balance between the Src survival pathway and the p38 apoptotic pathway. Hence, ROR1 was considered as an attractive therapeutic target for the development of anticancer drugs. However, only a few small molecule ROR1 inhibitors were reported until now. Herein, a series of 3-(2-aminobenzo[<em>d</em>]thiazol-5-yl) benzamide derivatives were designed and synthesized via bioisosterism and simplification strategy guided by the lead compound <strong>9a</strong>. MTT assay showed that compound <strong>7h</strong> exhibited the best anti-cancer properties with IC₅₀ values of 18.16, 8.11 and 3.5 μM against A549, PC9 and H1975 cells, respectively. Meanwhile, the selectivity index (SI) of compound <strong>7h</strong> for H1975 cells was 22.86 compared to that of the lead compound <strong>9a</strong> of 1.83, which is at least 12 fold higher than that of lead compound <strong>9a</strong>, suggesting that <strong>7h</strong> had a favorable safety profile. In addition, the molecular docking, CETSA and DARTS assays suggested that compound <strong>7h</strong> might be a novel small molecule ROR1 inhibitor. More importantly, compound <strong>7h</strong> significantly suppressed the migration and invasion of H1975 cells <em>in vitro</em> by blocking Src survival pathway and reactivating the p38 apoptotic pathway, and induced H1975 cell cycle arrest in G1 phase. Collectively, our work suggested that the ROR1 inhibitor <strong>7h</strong> might be a novel drug candidate for NSCLC treatment.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118011"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142700370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thiazolidinedione-based structure modification of ergosterol peroxide provides thiazolidinedione-conjugated derivatives as potent agents against breast cancer cells through a PI3K/AKT/mTOR pathway","authors":"Siqi Deng ,&nbsp;Lu Wang ,&nbsp;Shuang Tian ,&nbsp;Jiale Wu ,&nbsp;Yu Lin ,&nbsp;Haijun Wang ,&nbsp;Xiaoshan Guo ,&nbsp;Cuicui Han ,&nbsp;Wenkang Ren ,&nbsp;Ying Long Han ,&nbsp;Jianwen Zhou ,&nbsp;Ming Bu","doi":"10.1016/j.bmc.2024.118007","DOIUrl":"10.1016/j.bmc.2024.118007","url":null,"abstract":"<div><div>Ergosterol peroxide (EP) is a steroidal compound isolated from the traditional Chinese medicine <em>Ganoderma lucidum</em>. However, EP is limited by its solubility and moderate potency in antitumor studies. In the present study, a series of novel ergosterol peroxide-3-thiazolidinedione derivatives were designed and synthesized, by changing the linker between ergosterol peroxide and thiazolidinedione, it is expected to obtain compounds with better antitumor activity. The cytotoxicity screening showed that compound <strong>13o</strong> is the most active derivative against the MCF-7 cell line with an IC₅₀ of 3.06 μM, and exhibited stronger antitumor activity compared to the parent EP. Further <em>in vitro</em> and <em>vivo</em> studies showed that compound <strong>13o</strong> may reduced the mitochondrial membrane potential, increased the reactive oxygen species level and blocked the cell cycle in G0/G1 phase, and induced apoptosis of tumor cells by inhibiting the PI3K/Akt/mTOR pathway. <em>In vivo</em> 4T1 mouse model of breast cancer showed that <strong>13o</strong> not only continued to inhibit tumor proliferation but also had a stronger effect than the marketed drug 5-fluorouracil, compound <strong>13o</strong> had a good safety profile <em>in vivo</em>. The results suggest that compound <strong>13o</strong> may represent a novel, highly potent and low-toxicity structural lead for the development of new breast cancer chemotherapies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118007"},"PeriodicalIF":3.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-penetrating anti-sense peptide nucleic acids targeting sulfatase 2 inhibit adipogenesis in human mesenchymal stem cells","authors":"Daram Jung ,&nbsp;Sungjin Ahn ,&nbsp;Yeasel Jeon ,&nbsp;Minhee Kim ,&nbsp;In Guk Park ,&nbsp;Areum Kim ,&nbsp;Minsoo Noh","doi":"10.1016/j.bmc.2024.118009","DOIUrl":"10.1016/j.bmc.2024.118009","url":null,"abstract":"<div><div>Targeting the genes regulate the lineage commitment of human mesenchymal stem cells (hMSCs) to adipocytes provides a promising strategy for addressing obesity. In this study, we investigated the therapeutic potential of cell-penetrating anti-sense peptide nucleic acids (PNAs) designed to enhance solubility and hybridization properties, specifically targeting sulfatase 2 (SULF2), a potential reciprocal regulator of adipocyte and osteoblast differentiation in hMSCs. Cell-penetrating modified PNA oligomers effectively inhibit SULF2 gene transcription, leading to significant reductions in adiponectin protein synthesis and intracellular lipid droplet accumulation during adipogenesis in human bone marrow-derived MSCs (hBM-MSCs). Notably, PNA oligomer compound <strong>5</strong> exhibited the most potent anti-adipogenic activity, with an IC₅₀ value of 0.28 μM. These findings show the potential of SULF2-targeting cell-penetrating PNA oligomers as novel therapeutic agents for obesity-related metabolic diseases.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118009"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esterase-responsive nanoparticles (ERN): A targeted approach for drug/gene delivery exploits","authors":"Ashok Kumar Madikonda ,&nbsp;Amritha Ajayakumar ,&nbsp;Sudeena Nadendla ,&nbsp;Janardhan Banothu ,&nbsp;Venkanna Muripiti","doi":"10.1016/j.bmc.2024.118001","DOIUrl":"10.1016/j.bmc.2024.118001","url":null,"abstract":"<div><div>Nanoparticles are being developed to enhance drug delivery to cancer tumors, leveraging advantages such as the enhanced permeability and retention (EPR) effect. However, traditional nanoparticles often face challenges with low specificity for cancer cells, leading to inefficient delivery and unwanted side effects. Esterase-responsive nanoparticles offer a maximum targeted approach to tumor cells because they release their therapeutic payload at the tumor site under the influence of esterase activity. This review explores the role of esterase-responsive nanoparticles in drug and gene delivery, examines esterase prodrug therapy, and discusses prostate-specific membrane antigen (PSMA) targets esterase-responsive nanoparticles in prostate cancer treatment. Additionally, we reviewed the current research progress and future potential of esterase-responsive nanoparticles in enhancing drug and gene delivery.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118001"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142651884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress on small molecule TLR4 antagonist against triple-negative breast cancer progression and complications","authors":"Darsshen Ramana A.L. Kathirasan ,&nbsp;Siti Nor ’Izzah Binti Normizan ,&nbsp;Nurul Athirah Binti Mohd Salleh ,&nbsp;Khor Poh-Yen","doi":"10.1016/j.bmc.2024.118000","DOIUrl":"10.1016/j.bmc.2024.118000","url":null,"abstract":"<div><div>Toll-like receptor 4 (TLR4) plays a vital role in the innate immune response, but its overactivation has been associated with several diseases, such as aggressive progression of triple-negative breast cancer (TNBC). As a result, inhibiting TLR4 has emerged as a potential therapeutic strategy for this challenging breast cancer subtype. This review summarizes recent advancements in the development of small-molecule TLR4 antagonists to suppress TNBC growth, metastasis, and chemotherapy resistance. We also examine their potential in managing cancer-related complications and propose future directions for their application in TNBC therapy.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"116 ","pages":"Article 118000"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of imidazo[1,5-a]quinoline scaffold as the pharmacophore in the design of bivalent ligands of central benzodiazepine receptors","authors":"Marco Paolino ,&nbsp;Mario Saletti ,&nbsp;Jacopo Venditti ,&nbsp;Federica Castriconi ,&nbsp;Germano Giuliani ,&nbsp;Samuele Maramai ,&nbsp;Alessandra Toti ,&nbsp;Carla Ghelardini ,&nbsp;Rosanna Matucci ,&nbsp;Narcy Alcazar Villalobos ,&nbsp;Maurizio Anzini ,&nbsp;Andrea Cappelli","doi":"10.1016/j.bmc.2024.118006","DOIUrl":"10.1016/j.bmc.2024.118006","url":null,"abstract":"<div><div>The imidazo[1,5-<em>a</em>]quinoline scaffold of central benzodiazepine receptor (CBR) ligands was used as the pharmacophore in the design of bivalent ligands bearing spacers showing variable length and different physicochemical features. The newly designed compounds were synthesized along with the corresponding reference monovalent compounds bearing the corresponding spacers terminated with a <em>tert</em>-butoxycarbonyl group. The novel compounds were tested in binding assays with different CBR preparations such as the cerebral cortex from male CD-1 albino mice or the human recombinant α1β3γ2 and α2β3γ2 γ-aminobutyric acid type A receptors (GABA_ARs) stably expressed in mouse L(tk-) cells. The tested compounds showed IC₅₀ values from the sub-micromolar up to the nanomolar range with very similar inhibition constants values for the two isoforms of GABA_ARs. The similarity in the affinity between the bivalent ligands and the corresponding monovalent ones appeared to rule out any bivalent interactions of these ligands with the two isoforms of GABA_ARs. Similarly, both series were able to inhibit the binding of radiolabeled flumazenil to GABA_ARs in cortical membranes of albino CD-1 mice, but most of the tested compounds showed biphasic inhibition curves, suggesting the existence of two well-distinct populations of binding sites. Finally, some CBR ligands selected from the bivalent ligands (i.e. <strong>6a</strong>,<strong>c</strong>) and from the reference monovalent ligands (i.e. <strong>7a</strong>) were then tested <em>in vivo</em> for their potential pharmacological effects, evaluating four classical benzodiazepine actions such as anticonvulsant, anxiolytic, locomotor, and anti-amnesic activities. All the tested compounds showed anticonvulsant and anxiolytic properties with neither muscle relaxant effect nor learning and memory impairments.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"117 ","pages":"Article 118006"},"PeriodicalIF":3.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}