Bioorganic Chemistry最新文献_第7页

Combretastatin A-4 based compounds as potential anticancer agents: A review. 以联合他汀 A-4 为基础的化合物作为潜在的抗癌剂：综述。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI: 10.1016/j.bioorg.2024.107930

Mai H Omar, Soha H Emam, Demiana S Mikhail, Salwa Elmeligie

引用次数: 0

Rational design of new quinoline-benzimidazole scaffold bearing piperazine acetamide derivatives as antidiabetic agents. 作为抗糖尿病药物的新型喹啉-苯并咪唑支架哌嗪乙酰胺衍生物的合理设计。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI: 10.1016/j.bioorg.2024.107908

Mehran Ghasemi, Aida Iraji, Maryam Dehghan, Yazdanbakhsh Lotfi Nosood, Cambyz Irajie, Nafiseh Bagherian Khouzani, Somayeh Mojtabavi, Mohammad Ali Faramarzi, Mohammad Mahdavi, Ahmed Al-Harrasi

{"title":"Rational design of new quinoline-benzimidazole scaffold bearing piperazine acetamide derivatives as antidiabetic agents.","authors":"Mehran Ghasemi, Aida Iraji, Maryam Dehghan, Yazdanbakhsh Lotfi Nosood, Cambyz Irajie, Nafiseh Bagherian Khouzani, Somayeh Mojtabavi, Mohammad Ali Faramarzi, Mohammad Mahdavi, Ahmed Al-Harrasi","doi":"10.1016/j.bioorg.2024.107908","DOIUrl":"10.1016/j.bioorg.2024.107908","url":null,"abstract":"In this study, a series of fifteen compounds (7a-o) based on a quinoline-benzimidazole scaffold bearing piperazine acetamide derivatives were synthesized and evaluated for their potential as α-glucosidase inhibitors, which are important therapeutic agents in the management of type 2 diabetes mellitus. Among the synthesized compounds, 7m exhibited the most potent inhibitory activity, demonstrating a 28-fold greater efficacy than the standard clinical inhibitor, acarbose. Molecular docking studies indicated strong binding interactions between 7m and the α-glucosidase active site, including hydrogen bonding, π-π stacking, and π-cation interactions. Furthermore, molecular dynamics simulations revealed that compound 7m formed a highly stable complex with the enzyme. These findings suggest that compound 7m is a promising candidate for further development as an effective antidiabetic agent, offering valuable insights into the design of potent α-glucosidase inhibitors based on the quinoline-benzimidazole framework.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107908"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Research progress and development strategy of PI3K inhibitors for breast cancer treatment: A review (2016-present). 用于乳腺癌治疗的 PI3K 抑制剂的研究进展和开发策略：综述（2016 年至今）。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-28 DOI: 10.1016/j.bioorg.2024.107934

Rujue Peng, Yujie Zhan, Anqi Li, Qiaoli Lv, Shan Xu

{"title":"Research progress and development strategy of PI3K inhibitors for breast cancer treatment: A review (2016-present).","authors":"Rujue Peng, Yujie Zhan, Anqi Li, Qiaoli Lv, Shan Xu","doi":"10.1016/j.bioorg.2024.107934","DOIUrl":"10.1016/j.bioorg.2024.107934","url":null,"abstract":"Phosphatidylinositol 3-kinases (PI3Ks) are widely expressed in tissues and cells throughout the body and are involved in a variety of physiological processes including cell growth and metabolism. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR, PAM) is a promising target for the treatment of many cancer types because it is significantly linked to tumorigenesis and development. Aberrant activation of this pathway is observed in the majority of tumors, particularly in breast cancer. The development of PI3K inhibitors has received much attention in recent years. PI3K inhibitors are effective drugs for the treatment of various types of malignant tumors. The FDA has approved a few PI3K inhibitors for commercialization, and the majority of PI3K inhibitors under clinical trials are expected to conquer cancers, including breast cancer. This article discusses the link between the PAM signaling system and breast cancer, as well as the current clinical applications of PAM pathway inhibitors in the treatment of breast cancer. This work summarizes and describes the development tactics of seven types of PI3K inhibitors targeting breast cancer, including morpholine-substituted thienopyrimidines, with the goal of informing future PI3K inhibitor research.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107934"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability. 喹唑啉衍生物通过调节 DNA 损伤修复和微卫星不稳定性，以依赖 WRN 螺旋酶的方式抑制前列腺癌细胞的生长。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-14 DOI: 10.1016/j.bioorg.2024.107963

Jia Yu, Yunyun Zhou, Guangyan Liang, Sha Cheng, Jiaomei Wei, Huimin Li, Xinyu Liu, Chang You, Mengsha Mao, Mashaal Ahmad, Gang Yu, Bixue Xu, Heng Luo

{"title":"Quinazoline derivatives inhibit cell growth of prostate cancer as a WRN helicase dependent manner by regulating DNA damage repair and microsatellite instability.","authors":"Jia Yu, Yunyun Zhou, Guangyan Liang, Sha Cheng, Jiaomei Wei, Huimin Li, Xinyu Liu, Chang You, Mengsha Mao, Mashaal Ahmad, Gang Yu, Bixue Xu, Heng Luo","doi":"10.1016/j.bioorg.2024.107963","DOIUrl":"10.1016/j.bioorg.2024.107963","url":null,"abstract":"WRN helicase is a crucial target of synthetic death in cancer and has a unique advantage in the treatment of microsatellite unstable cancers. Our previous studies have found that quinazoline derivatives showed the WRN-dependent antiproliferative activity. In this study, a series of new quinazoline derivatives were designed and synthesized by optimizing the structure, and evaluating the targeting and sensitivity to WRN helicase. Cell growth inhibition experiments on WRN overexpressing PC3 cells (PC3-WRN) showed that the antiproliferative activity of some compounds was significantly dependent on WRN helicase. Moreover, the antitumor activity of 9in vivo was significantly decreased in the nude mouse model constructed with WRN knockdown PC3 cells (PC3-shWRN) compare (P < 0.01) to the control group. The molecular docking and CETSA results showed that 9 directly binds to WRN protein. Mechanism studies have confirmed that 9 targeted WRN, and may affect the binding between WRN and other key regulators, to destroy the repair function and regulate genomic stability. In addition, 9 also has suitable pharmacokinetic parameters and low toxicity in vivo. This result indicates that the quinazoline derivative 9 could be a novel WRN function inhibitor for the treatment of prostate cancer.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107963"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis, and structure-activity relationships of xanthine derivatives as broad-spectrum inhibitors of coronavirus replication. 作为冠状病毒复制广谱抑制剂的黄嘌呤衍生物的设计、合成和结构-活性关系。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-28 DOI: 10.1016/j.bioorg.2024.107925

Xiaofang Chen, Xiaotian Ding, Cong Bian, Kun Wang, Xiao Zheng, Haiyan Yan, Mengqian Qiao, Shuo Wu, Yihua Li, Li Wang, Lifei Wang, Yu Du, Yuhuan Li, Bin Hong

{"title":"Design, synthesis, and structure-activity relationships of xanthine derivatives as broad-spectrum inhibitors of coronavirus replication.","authors":"Xiaofang Chen, Xiaotian Ding, Cong Bian, Kun Wang, Xiao Zheng, Haiyan Yan, Mengqian Qiao, Shuo Wu, Yihua Li, Li Wang, Lifei Wang, Yu Du, Yuhuan Li, Bin Hong","doi":"10.1016/j.bioorg.2024.107925","DOIUrl":"10.1016/j.bioorg.2024.107925","url":null,"abstract":"Illuminated by insights into the hijacking of host cellular metabolism by coronaviruses, we identified an initial hit compound 7030B-C5, characterized by a xanthine scaffold, via a cellular-level phenotypic screening from a domestic repertoire of lipid-modulating agents. A series of derivatives were synthesized and optimized through comprehensive structure-activity relationship (SAR) studies focusing on the N-1, C-8, and N-7 positions of xanthine and preliminary exploration on the N-3 position and parent nucleus. Compounds 10e, 10f and 10o, featuring modifications at the N-7 position, showed inhibitory activity with half maximal effective concentration (EC50) values in the three-digit nanomolar range against human coronavirus-229E (HCoV-229E). In particular, compound 10o exerted superior potency across various coronavirus strains, including HCoV-229E, HCoV-OC43, and the Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Further investigations revealed that 10o acted on the post-entry stages of virus replication and exhibited a distinctive antiviral mechanism from that of clinically approved nirmatrelvir and molnupiravir. Moreover, drug combination study indicates that 10o operates additively with nirmatrelvir, molnupiravir or omicsynin B4, a dual inhibitor of host proteases for S protein priming. Additionally, in vivo assessments show that 10o has favorable pharmacokinetic and safety profiles compared to its parent compound 7030B-C5. These findings underscore the potential of 10o as a promising antiviral candidate for the treatment of current and potential future coronavirus infections.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107925"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Disclosing novel melanogenesis pathways: Formation of unexpected biphenyl-type dimers through radical-radical coupling by solid-state oxidation of the melanin biosynthetic precursor 5,6-dihydroxyindole. 揭示新型黑色素生成途径：通过固态氧化黑色素生物合成前体 5,6-二羟基吲哚，通过自由基-自由基耦合形成意想不到的联苯型二聚体。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-29 DOI: 10.1016/j.bioorg.2024.107928

Sara Viggiano, Maria Laura Alfieri, Lucia Panzella, Orlando Crescenzi, Alessandra Napolitano

{"title":"Disclosing novel melanogenesis pathways: Formation of unexpected biphenyl-type dimers through radical-radical coupling by solid-state oxidation of the melanin biosynthetic precursor 5,6-dihydroxyindole.","authors":"Sara Viggiano, Maria Laura Alfieri, Lucia Panzella, Orlando Crescenzi, Alessandra Napolitano","doi":"10.1016/j.bioorg.2024.107928","DOIUrl":"10.1016/j.bioorg.2024.107928","url":null,"abstract":"Investigation of the oxidation pathway of 5,6-dihydroxyindole (DHI), one of the main biosynthetic precursors of the brown-to-black skin and hair melanin pigments, represents a promising approach for the elucidation of the structure of these pigments in biological systems. We report herein the exploration of DHI oxidation chemistry under conditions so far poorly investigated, i.e. solid-state mechanochemical conditions, mimicking those that could be found in vivo in melanosomes, where melanin growth takes place in a confined space on a solid proteinaceous matrix, that allowed for the isolation and characterization of new dimers. Mechanistic experiments allowed to propose radical-radical coupling as the main dimerization pathway under solid-state conditions preventing ionic polymerization of the 5,6-dihydroxyindole system, indicating that the oxidation chemistry of this melanogenic precursor strongly depends on the reaction environment. The relevance for melanogenesis of the DHI oxidation pathway, disclosed herein, was also demonstrated by ad hoc experiments in which the solid-state reaction was carried out in the presence of proteins. Finally, the chromophores of the species generated by oxidation of the new dimers were investigated with a view to expanding the knowledge on the functional properties of melanin pigments, including mainly photoprotection.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107928"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Steroid and bioactive molecule conjugates: Improving therapeutic approaches in disease management. 类固醇和生物活性分子共轭物：改进疾病治疗方法。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-05 DOI: 10.1016/j.bioorg.2024.107933

Anna Kawka, Hanna Koenig, Tomasz Pospieszny

引用次数: 0

Discovery of epigenetic modulators targeting HDACs and EZH2 simultaneously for the treatment of hematological malignancies. 发现同时针对 HDAC 和 EZH2 的表观遗传调节剂，用于治疗血液恶性肿瘤。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-19 DOI: 10.1016/j.bioorg.2024.107964

Jinwei Zhang, Maoshuo Yang, Qian Liu, Xintong Xue, Sijia Tian, Xi Hu, Mengzhe Li, Jintao Li, Qipeng Chai, Fabao Liu, Xiaona You, Yingjie Zhang

{"title":"Discovery of epigenetic modulators targeting HDACs and EZH2 simultaneously for the treatment of hematological malignancies.","authors":"Jinwei Zhang, Maoshuo Yang, Qian Liu, Xintong Xue, Sijia Tian, Xi Hu, Mengzhe Li, Jintao Li, Qipeng Chai, Fabao Liu, Xiaona You, Yingjie Zhang","doi":"10.1016/j.bioorg.2024.107964","DOIUrl":"10.1016/j.bioorg.2024.107964","url":null,"abstract":"Epigenetic-targeted therapy has been applied in the treatment of several types of cancer. Herein, based on the synergistic antitumor effects of co-targeting HDACs and EZH2 in some hematological malignancies, a novel series of tazemetostat-based HDACs/EZH2 dual inhibitors were rationally designed, synthesized, and biologically evaluated. Satisfyingly, compounds 22a and 22b were identified as potent HDACs/EZH2 dual inhibitors with robust antiproliferative activities against one diffuse large-cell B cell lymphomas (DLBCL) cell line harboring EZH2 mutation and multiple acute myeloid leukemia (AML) cell lines. Notably, after a short-term treatment in the EZH2 mutant DLBCL cell line (SU-DHL-6), 22a and 22b displayed much stronger antiproliferative activities than the approved EZH2 inhibitor tazemetostat, while after a long-term treatment in SU-DHL-6 cells, 22a and 22b displayed comparable or even superior antiproliferative activities to the approved HDACs inhibitor SAHA. In AML cells, compounds 22a and 22b displayed much more potent antiproliferative activities than tazemetostat, as well as distinctive differentiation-inducing abilities and superior apoptosis-inducing abilities relative to tazemetostat and SAHA. Moreover, the synergistic anti-AML effects of HDACs/EZH2 dual inhibitors combined with various anti-AML drugs were demonstrated.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107964"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142685676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to "Discovery of neuroprotective agents: Potent, brain penetrating, lipoic acid derivatives for the potential treatment of ischemic stroke by regulating oxidative stress and inflammation - A preliminary study" [Bioorg. Chem. 147 (2024) 107339]. 发现神经保护剂：通过调节氧化应激和炎症潜在治疗缺血性中风的强效、脑穿透性硫辛酸衍生物--初步研究" [Bioorg.

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-12 DOI: 10.1016/j.bioorg.2024.107927

Chenchen Zhu, Yun Wang, Yi Li, Tingfang Wang, Fei Ye, Wei Su, Ting Chen, Chuan Zhang, Liyan Xiong

引用次数: 0

Structure-Based identification of a potent KDM7A inhibitor exerts anticancer activity through transcriptionally reducing MKRN1 in taxol- resistant and -sensitive triple-negative breast cancer cells. 基于结构鉴定的强效 KDM7A 抑制剂通过转录减少 MKRN1 在对紫杉醇耐药和敏感的三阴性乳腺癌细胞中发挥抗癌活性。

IF 4.5 2区医学

Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-11-05 DOI: 10.1016/j.bioorg.2024.107945

Jin-Jin Shi, Yan-Jun Liu, Zhi-Guo Liu, Ru-Yi Chen, Ran Wang, Jing Yu, Chang-Yun Li, Guan-Jun Yang, Jiong Chen

{"title":"Structure-Based identification of a potent KDM7A inhibitor exerts anticancer activity through transcriptionally reducing MKRN1 in taxol- resistant and -sensitive triple-negative breast cancer cells.","authors":"Jin-Jin Shi, Yan-Jun Liu, Zhi-Guo Liu, Ru-Yi Chen, Ran Wang, Jing Yu, Chang-Yun Li, Guan-Jun Yang, Jiong Chen","doi":"10.1016/j.bioorg.2024.107945","DOIUrl":"10.1016/j.bioorg.2024.107945","url":null,"abstract":"KDM7A, a histone demethylase implicated in cancer proliferation, metastasis, and drug resistance, represents a crucial therapeutic target. Utilizing \"mcule.com\" for virtual screening of 100,000 compounds from the ZINC database, we identified 12 compounds with high affinity for KDM7A, with compound 4 emerging as the leading candidate for effectively inhibiting KDM7A's demethylase activity. Analysis of the GTRD database, the Breast Cancer Gene Expression Miner website, and recent studies highlighted MKRN1, a gene associated with cell proliferation and drug resistance, as a key intersecting factor. Compared to 2,4-pyridine dicarboxylic acid, compound 4 significantly reduced breast cancer stem cells and induced G1 phase cell cycle arrest. Mechanistically, compound 4 inhibited KDM7A's binding to H3K27me3, decreased MKRN1 transcription, and increased the levels of cell cycle regulators p16, p21, and p27, while reducing stem cell markers ALDH1A1, CD44, and CD133. These findings suggest that compound 4 could serve as a promising lead for selective KDM7A-targeting drugs. Additionally, this study is the first to demonstrate MKRN1 as a downstream gene of KDM7A, showing significant inhibitory effects in both taxol-resistant and drug-sensitive triple-negative breast cancer (TNBC) cells. This research offers new insights into the anticancer mechanisms of KDM7A inhibitors and underscores KDM7A's potential as a therapeutic target against TNBC.","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"153 ","pages":"107945"},"PeriodicalIF":4.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0