Bioorganic & Medicinal Chemistry最新文献_第9页

The unique activity of saponin: Induction of cytotoxicity in HTLV-1 infected cells 皂苷的独特活性:诱导HTLV-1感染细胞的细胞毒性

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117408

Wataru Shida , Yurika Tahara , Saki Morikawa , Kazuaki Monde , Ryoko Koga , Takeo Ohsugi , Masami Otsuka , Atsushi Ikemoto , Hiroshi Tateishi , Tsuyoshi Ikeda , Mikako Fujita

{"title":"The unique activity of saponin: Induction of cytotoxicity in HTLV-1 infected cells","authors":"Wataru Shida , Yurika Tahara , Saki Morikawa , Kazuaki Monde , Ryoko Koga , Takeo Ohsugi , Masami Otsuka , Atsushi Ikemoto , Hiroshi Tateishi , Tsuyoshi Ikeda , Mikako Fujita","doi":"10.1016/j.bmc.2023.117408","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117408","url":null,"abstract":"<div>Infection with the retrovirus human T-cell leukemia virus type 1 (HTLV-1) sometimes causes diseases that are difficult to cure. To find anti-HTLV-1 natural compounds, we opted to screen using the HTLV-1-infected T-cell line, MT-2. Based on our results, an extract of the pulp/seeds of Akebia quinata Decaisne fruit killed MT-2 cells but did not affect the Jurkat cell line that was not infected with virus. To determine the active ingredients, seven saponins with one-six sugar moieties were isolated from A. quinata seeds, and their activities against the two cell lines were examined. Both cell lines were killed in a similar manner by Akebia saponins A and B. Further, Akebia saponins D, E, PK and G did not exhibit cytotoxicity. Akebia saponin C had a similar activity to the extract found in the screening. This compound was found to enhance Gag aggregation, induce the abnormal cleavage of Gag, suppress virion release, and preferentially kill HTLV-1 infected cells; however, their relationship remains elusive. Our findings may lead to the development of new therapies for infectious diseases based on the removal of whole-virus-infected cells.</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117408"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"2614627","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}

引用次数: 0

Scaffold hopping derived novel benzoxazepinone RIPK1 inhibitors as anti-necroptosis agents 支架跳跃衍生的新型苯并恶西平酮RIPK1抑制剂作为抗坏死性下垂剂

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117385

Jiaqin Tang , Yanran Wu , Wenli Zhao, Zhuo Qu, Jianqiang Yu, Zhizhong Wang, Ying Shi

{"title":"Scaffold hopping derived novel benzoxazepinone RIPK1 inhibitors as anti-necroptosis agents","authors":"Jiaqin Tang , Yanran Wu , Wenli Zhao, Zhuo Qu, Jianqiang Yu, Zhizhong Wang, Ying Shi","doi":"10.1016/j.bmc.2023.117385","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117385","url":null,"abstract":"<div>Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis is believed to have a significant role in contributing to inflammatory diseases. Inhibiting RIPK1 has shown promise in effectively alleviating the inflammation process. In our current study, we employed scaffold hopping to develop a series of novel benzoxazepinone derivatives. Among these derivatives, compound o1 displayed the most potent antinecroptosis activity (EC50     nM) in cellular assays and exhibited the strongest binding affinity to the target site. Molecular docking analyses further elucidated the mechanism of action of o1, revealing its ability to fully occupy the protein pocket and form hydrogen bonds with the amino acid residue Asp156. Our findings highlight that o1 specifically inhibits necroptosis, rather than apoptosis, by impeding the RIPK1/Receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like (MLKL) pathway's phosphorylation, triggered by TNFα, Smac mimetic, and z-VAD (TSZ). Additionally, o1 demonstrated dose-dependent improvements in the survival rate of mice with Systemic Inflammatory Response Syndrome (SIRS), surpassing the protective effect observed with GSKʹ772.</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117385"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1828277","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}

引用次数: 0

Di-indenopyridines as topoisomerase II-selective anticancer agents: Design, synthesis, and structure–activity relationships 二独立吡啶作为拓扑异构酶ii选择性抗癌药物:设计、合成和构效关系

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117403

Aarajana Shrestha , Soo-Yeon Hwang , Surendra Kunwar , Tara Man Kadayat , Seojeong Park , Yi Liu , Hyunji Jo , Naeun Sheen , Minjung Seo , Eung-Seok Lee , Youngjoo Kwon

{"title":"Di-indenopyridines as topoisomerase II-selective anticancer agents: Design, synthesis, and structure–activity relationships","authors":"Aarajana Shrestha , Soo-Yeon Hwang , Surendra Kunwar , Tara Man Kadayat , Seojeong Park , Yi Liu , Hyunji Jo , Naeun Sheen , Minjung Seo , Eung-Seok Lee , Youngjoo Kwon","doi":"10.1016/j.bmc.2023.117403","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117403","url":null,"abstract":"<div>Topoisomerases are key molecular enzymes responsible for altering DNA topology, thus they have long been considered as attractive targets for novel chemotherapeutic agents. Topoisomerase type II (Topo II) catalytic inhibitors embrace a fresh perspective meant to get beyond drawbacks caused by topo II poisons, such as cardiotoxicity and secondary malignancies. Based on previously reported 5H-indeno[1,2-b]pyridines, here we presented new twenty-three hybrid di-indenopyridines along with their topo I/IIα inhibitory and antiproliferative activity. Most of the prepared 11-phenyl-diindenopyridines showed negligible topo I inhibitory activity, showing selectivity over topo II. Among the series, we finally selected compound 17, which displayed 100 % topo IIα inhibition at 20 μM concentration and comparable antiproliferative activity against the tested cell lines. Through competitive EtBr displacement assay, cleavable complex assay, and comet assay, compound 17 was finally determined as a non-intercalative catalytic topo IIα inhibitor. The findings in this study highlight the significance of phenolic, halophenyl, thienyl, and furyl groups at the 4-position of the indane ring in the design and synthesis of di-indenopyridines as potent catalytic topo IIα inhibitors with remarkable anticancer effects.</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117403"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"3202823","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}

引用次数: 0

Effect of helicity and hydrophobicity on cell-penetrating ability of arginine-rich peptides 螺旋度和疏水性对富含精氨酸肽穿透细胞能力的影响

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117409

Makoto Oba , Shun Nakajima , Kurumi Misao , Hidetomo Yokoo , Masakazu Tanaka

引用次数: 1

Identification of new modulator of DNA repairing pathways based on natural product (±)-peharmaline A 基于天然产物(±)-peharmaline A的DNA修复途径新调节剂的鉴定

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117365

Akshay S. Kulkarni , Anshurekha Dash , Rahul D. Shingare , Jagdish Chand , Diksha Manhas , Aman Singh , Utpal Nandi , Anindya Goswami , D. Srinivasa Reddy

{"title":"Identification of new modulator of DNA repairing pathways based on natural product (±)-peharmaline A","authors":"Akshay S. Kulkarni , Anshurekha Dash , Rahul D. Shingare , Jagdish Chand , Diksha Manhas , Aman Singh , Utpal Nandi , Anindya Goswami , D. Srinivasa Reddy","doi":"10.1016/j.bmc.2023.117365","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117365","url":null,"abstract":"<div>The complex heterogenic environment of tumour mass often leads to drug resistance and facilitate chemo insensitivity triggering more malignant phenotypes among cancer patients. Major DNA-damaging cancer drugs have been consistently proven unsuccessful in terms of elevating chemo-resistance. (±)-peharmaline A, a hybrid natural product isolated from seeds of Peganum harmala L. possesses significant cytotoxic activities. Herein, we have described the design, and synthesis of a novel library of close and simplified analogues around the anticancer natural product (±)-peharmaline A and investigated their cytotoxic activities, which led to the identification of three structurally simplified lead compounds exhibiting better potency than parent natural product. Among them, demethoxy analogue of peharmaline A was further investigated for its anticancer potential eliciting demethoxy analogue as potent DNA-damage inducing agent attenuating the expression of the proteins responsible for the DNA damage repair. Therefore, this demethoxy analogue warrants detailed investigations for the confirmations of the molecular mechanism-based studies responsible for its anticancer activity.______________________________________________________________________________</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117365"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1812598","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}

引用次数: 0

Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer 发现以AZD9291为基础的新型缺氧激活、硝基咪唑构建的治疗人肺癌的多靶点激酶抑制剂

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117384

Tingting Jia , Ruoyang Miao , Jiankang Zhang , Huajian Zhu , Chong Zhang , Linghui Zeng , Yanmei Zhao , Weiyan Cheng , Jiaan Shao

{"title":"Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer","authors":"Tingting Jia , Ruoyang Miao , Jiankang Zhang , Huajian Zhu , Chong Zhang , Linghui Zeng , Yanmei Zhao , Weiyan Cheng , Jiaan Shao","doi":"10.1016/j.bmc.2023.117384","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117384","url":null,"abstract":"<div>A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4–6-fold (IC50 < 10 nM), indicating its hypoxia-selectivity. A14′s high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, A14 exhibited good bio-reductive property and could bind with nucleophilic amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, A14 shows promise as a multi-target kinase inhibitor for cancer therapy.</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117384"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1828276","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}

引用次数: 1

Synthesis and biological evaluation of sulfonylpyridine derivatives as potential anti-chlamydia agents 磺酰基吡啶衍生物作为潜在的抗衣原体药物的合成及生物学评价

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117401

Jiachen Feng, Luana Janaína de Campos, Mohamed A. Seleem , Martin Conda-Sheridan

{"title":"Synthesis and biological evaluation of sulfonylpyridine derivatives as potential anti-chlamydia agents","authors":"Jiachen Feng, Luana Janaína de Campos, Mohamed A. Seleem , Martin Conda-Sheridan","doi":"10.1016/j.bmc.2023.117401","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117401","url":null,"abstract":"<div>Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection in the United States and the world. This pathogen can cause health problems ranging from trachoma (blindness) to damage of the fallopian tubes or ectopic pregnancy, which can be life-threatening if not treated properly. To this day, there is no chlamydia-specific drug on the market. Previously, we reported the activity and basic structure–activity relationships (SAR) of sulfonylpyridine molecules that possess antichlamydial action. Based on those results, we prepared a new series of derivatives. Our data indicate the new analogs can halt the growth of C. trachomatis. The lead compound, 22, was more active than our previous molecules and did not affect the growth of S. aureus and E. coli, suggesting bacterial selectivity. We performed docking studies on the presumed target, the cylindrical protease of Chlamydia. The in-silico studies partially explained the in vitro biological result as well as predicted a possible binding pose in the binding pocket. The top compound displayed a good cytotoxicity profile towards mammalian cell lines and was stable in both serum and stimulated gastric fluid. The presented data suggests the sulfonylpyridines are promising and selective anti-chlamydial compounds that merit further structural optimization.</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117401"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1695612","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}

引用次数: 0

Research progress of STAT3-based dual inhibitors for cancer therapy 基于stat3的肿瘤双抑制剂研究进展

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117382

Xiaojuan Yang, Lu Xu, Li Yang, Shaohong Xu

{"title":"Research progress of STAT3-based dual inhibitors for cancer therapy","authors":"Xiaojuan Yang, Lu Xu, Li Yang, Shaohong Xu","doi":"10.1016/j.bmc.2023.117382","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117382","url":null,"abstract":"<div>Signal transducer and activator of transcription 3 (STAT3), a transcription factor, regulates gene levels that are associated with cell survival, cell cycle, and immune reaction. It is correlated with the grade of malignancy and the development of various cancers and targeting STAT3 protein is a potentially promising therapeutic strategy for tumors. Over the past 20 years, various compounds have been found to directly inhibit STAT3 activity via different strategies. However, numerous difficulties exist in the development of STAT3 inhibitors, such as serious toxic effects, poor therapeutic effects, and intrinsic and acquired drug resistance. STAT3 inhibitors synergistically suppress cancer development with additional anti-tumor drugs, such as indoleamine 2,3-dioxygenase 1 inhibitors (IDO1i), histone deacetylase inhibitors (HDACi), DNA inhibitors, pro-tumorigenic cytokine inhibitors (PTCi), NF-κB inhibitors, and tubulin inhibitors. Therefore, individual molecule- based dual-target inhibitors can be the candidate alternative or complementary treatment to overcome the disadvantages of just STAT3 or other targets as a monotherapy. In this review, we discuss the theoretical basis for formulating STAT3-based dual-target inhibitors and also summarize their structure–activity relationships (SARs).</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117382"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1812597","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}

引用次数: 0

Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics 发现mTOR抑制剂与NO供体的新型杂交体作为潜在的抗肿瘤治疗药物

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117402

Xin Gao , Fang Zhao , Yang Wang , Xiaodong Ma , Huayi Chai , Jingjing Han , Fang Fang

{"title":"Discovery of novel hybrids of mTOR inhibitor and NO donor as potential anti-tumor therapeutics","authors":"Xin Gao , Fang Zhao , Yang Wang , Xiaodong Ma , Huayi Chai , Jingjing Han , Fang Fang","doi":"10.1016/j.bmc.2023.117402","DOIUrl":"https://doi.org/10.1016/j.bmc.2023.117402","url":null,"abstract":"<div>Nitric oxide (NO) may be beneficial to overcoming drug resistance resulting from mutation of mTOR kinases and bypass mechanisms. In this study, a novel structural series of hybrids of mTOR inhibitor and NO donor were designed and synthesized via structure-based drug design (SBDD). Throughout the 20 target compounds, half of the compounds (13a, 13b, 19a-19d, 19f-19j) demonstrated attractive mTOR inhibitory activity with IC50 at single-digit nanomolar level. In particular, 19f exerted superior anti-proliferative activity against HepG2, MCF-7, HL-60 cells (HepG2, IC50 = 0.24 μM; MCF-7, IC50 = 0.88 μM; HL-60, IC50 = 0.02 μM) to that of the clinical investigated mTOR inhibitor MLN0128, and show mild cytotoxicity against normal cells with IC50 over 10 μM. 19a, with the most potent mTOR inhibitory activity in this series (IC50 = 3.31 nM), also displayed attractive cellular potency. In addition, 19f treatment in HL-60 reduces the levels of Phos-Akt and Phos-S6 in a dose-dependent manner, and releases NO in cells. In summary, 19f deserves further development as a novel mTOR-based multi-target anti-cancer agent.</div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"91 ","pages":"Article 117402"},"PeriodicalIF":3.5,"publicationDate":"2023-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1812599","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}

引用次数: 1

Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy EZH2/BRD4双抑制剂的设计、合成及机制研究

IF 3.5 3区医学

Bioorganic & Medicinal Chemistry Pub Date : 2023-08-15 DOI: 10.1016/j.bmc.2023.117386

Xinye Chen, Cheng Wang, Dehua Lu, Heng Luo, Shang Li, Fucheng Yin, Zhongwen Luo, Ningjie Cui, Lingyi Kong, Xiaobing Wang

引用次数: 1