从类似巴氏 Lissoclinum 中发现新的吡啶吖啶生物碱，其可抑制 Hdm2 的泛素连接酶活性并稳定 p53。
Discovery of new pyridoacridine alkaloids from Lissoclinum cf. badium that inhibit the ubiquitin ligase activity of Hdm2 and stabilize p53.
作者信息
Clement Jason A, Kitagaki Jirouta, Yang Yili, Saucedo Carrie J, O'Keefe Barry R, Weissman Allan M, McKee Tawnya C, McMahon James B
机构信息
Molecular Targets Development Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702-1201, USA.
出版信息
Bioorg Med Chem. 2008 Dec 1;16(23):10022-8. doi: 10.1016/j.bmc.2008.10.024. Epub 2008 Oct 14.
Abstract
Compounds that stabilize p53 could suppress tumors providing a additional tool to fight cancer. Mdm2, and the human ortholog, Hdm2 serve as ubiquitin E3 ligases and target p53 for ubiquitylation and degradation. Inhibition of Hdm2 stabilizes p53, inhibits cell proliferation and induces apoptosis. Using HTS to discover inhibitors, we identified three new alkaloids, isolissoclinotoxin B, diplamine B, and lissoclinidine B from Lissoclinum cf. badium. Lissoclinidine B inhibited ubiquitylation and degradation of p53, and selectively killed transformed cells harboring wild-type p53, suggesting this compound could be used to develop new treatments.
摘要
能够稳定p53的化合物可抑制肿瘤，为抗癌提供了一种额外的工具。Mdm2及其人类同源物Hdm2作为泛素E3连接酶，将p53作为泛素化和降解的靶点。抑制Hdm2可稳定p53，抑制细胞增殖并诱导凋亡。通过高通量筛选（HTS）来发现抑制剂，我们从类似巴氏 Lissoclinum cf. badium中鉴定出三种新生物碱，异 Lissoclinotoxin B、双胺B和 Lissoclinidine B。Lissoclinidine B抑制p53的泛素化和降解，并选择性杀死携带野生型p53的转化细胞，表明该化合物可用于开发新的治疗方法。
相似文献
1
Discovery of new pyridoacridine alkaloids from Lissoclinum cf. badium that inhibit the ubiquitin ligase activity of Hdm2 and stabilize p53.从类似巴氏 Lissoclinum 中发现新的吡啶吖啶生物碱，其可抑制 Hdm2 的泛素连接酶活性并稳定 p53。
Bioorg Med Chem. 2008 Dec 1;16(23):10022-8. doi: 10.1016/j.bmc.2008.10.024. Epub 2008 Oct 14.
2
Additional cytotoxic pyridoacridine alkaloids from the ascidian Cystodytes violatinctus and biogenetic considerations. 来自于短尾下纲的石房蛤毒素和生物合成的考虑。
J Nat Prod. 2013 Sep 27;76(9):1801-5. doi: 10.1021/np400284z. Epub 2013 Aug 20.
3
Targeting tumor cells expressing p53 with a water-soluble inhibitor of Hdm2.用一种水溶性Hdm2抑制剂靶向作用于表达p53的肿瘤细胞。
Mol Cancer Ther. 2008 Aug;7(8):2445-54. doi: 10.1158/1535-7163.MCT-08-0063.
4
Inhibiting Hdm2 and ubiquitin-activating enzyme: targeting the ubiquitin conjugating system in cancer.抑制Hdm2和泛素激活酶：靶向癌症中的泛素共轭系统
Ernst Schering Found Symp Proc. 2008(1):171-90. doi: 10.1007/2789_2008_108.
5
Sebastianines A and B, novel biologically active pyridoacridine alkaloids from the Brazilian ascidian Cystodytes dellechiajei.塞巴斯蒂宁A和B，从巴西海鞘德氏囊海鞘中提取的新型生物活性吡啶吖啶生物碱。
J Org Chem. 2002 Jul 26;67(15):5429-32. doi: 10.1021/jo011174h.
6
Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells.HDM2泛素连接酶活性的小分子抑制剂可稳定并激活细胞中的p53。
Cancer Cell. 2005 Jun;7(6):547-59. doi: 10.1016/j.ccr.2005.04.029.
7
Structures and antimicrobial activities of pyridoacridine alkaloids isolated from different chromotypes of the ascidian Cystodytes dellechiajei.从不同色型的被囊动物 Cystodytes dellechiajei 中分离得到的吡啶并吖啶生物碱的结构和抗菌活性。
J Nat Prod. 2010 Jun 25;73(6):1044-8. doi: 10.1021/np900751k.
8
5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2.5-脱氮黄素衍生物作为 HDM2 介导的 p53 泛素化抑制剂。
Bioorg Med Chem. 2013 Nov 15;21(22):6868-77. doi: 10.1016/j.bmc.2013.09.038. Epub 2013 Sep 25.
9
p53 promotes its own polyubiquitination by enhancing the HDM2 and HDMX interaction.p53 通过增强 HDM2 和 HDMX 的相互作用来促进自身的多泛素化。
Protein Sci. 2018 May;27(5):976-986. doi: 10.1002/pro.3405. Epub 2018 Mar 25.
10
Differentiation of Hdm2-mediated p53 ubiquitination and Hdm2 autoubiquitination activity by small molecular weight inhibitors.通过小分子抑制剂区分Hdm2介导的p53泛素化和Hdm2自身泛素化活性。
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14734-9. doi: 10.1073/pnas.212428599. Epub 2002 Oct 29.
引用本文的文献
1
A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins.靶向泛素连接酶以稳定肿瘤抑制蛋白的治疗前景
Cancers (Basel). 2025 Feb 13;17(4):626. doi: 10.3390/cancers17040626.
2
The Benzoxazole Heterocycle: A Comprehensive Review of the Most Recent Medicinal Chemistry Developments of Antiproliferative, Brain-Penetrant, and Anti-inflammatory Agents.苯并恶唑杂环：抗增殖、穿透血脑屏障和抗炎药物的最新药物化学发展的综合综述。
Top Curr Chem (Cham). 2024 Oct 21;382(4):33. doi: 10.1007/s41061-024-00477-6.
3
Identification of unique highly hetero-substituted benzenes as chemical weapons of springtails by a combination of trace analytical methods with DFT calculations and synthesis.通过痕量分析方法与密度泛函理论计算及合成相结合，鉴定独特的高度杂取代苯为跳虫的化学武器。
Chem Sci. 2024 Sep 2;15(37):15332-8. doi: 10.1039/d4sc03182b.
4
Promising bioactive compounds from the marine environment and their potential effects on various diseases.来自海洋环境的有前景的生物活性化合物及其对各种疾病的潜在影响。
J Genet Eng Biotechnol. 2022 Jan 26;20(1):14. doi: 10.1186/s43141-021-00290-4.
5
Biological Activity of Naturally Derived Naphthyridines.天然衍生的萘啶类化合物的生物活性。
Molecules. 2021 Jul 16;26(14):4324. doi: 10.3390/molecules26144324.
6
Development of a High-throughput NanoBRET Screening Platform to Identify Modulators of the RAS/RAF Interaction.高通量 NanoBRET 筛选平台的开发，用于鉴定 RAS/RAF 相互作用的调节剂。
Mol Cancer Ther. 2021 Sep;20(9):1743-1754. doi: 10.1158/1535-7163.MCT-21-0175. Epub 2021 Jun 22.
7
Regulation of p53 by E3s.E3 对 p53 的调控。
Cancers (Basel). 2021 Feb 11;13(4):745. doi: 10.3390/cancers13040745.
8
Bioactive compounds from marine invertebrates as potent anticancer drugs: the possible pharmacophores modulating cell death pathways.海洋无脊椎动物中的生物活性化合物作为有效的抗癌药物：可能的药效团调节细胞死亡途径。
Mol Biol Rep. 2020 Sep;47(9):7209-7228. doi: 10.1007/s11033-020-05709-8. Epub 2020 Aug 14.
9
Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?靶向耐药肿瘤：TRIM 蛋白-p53 轴是否可行？
Int J Mol Sci. 2019 Apr 10;20(7):1776. doi: 10.3390/ijms20071776.
10
Clogging the Ubiquitin-Proteasome Machinery with Marine Natural Products: Last Decade Update.用海洋天然产物堵塞泛素-蛋白酶体机制：过去十年的进展。
Mar Drugs. 2018 Nov 26;16(12):467. doi: 10.3390/md16120467.
本文引用的文献
1
Identification of inhibitors for MDM2 ubiquitin ligase activity from natural product extracts by a novel high-throughput electrochemiluminescent screen.通过新型高通量电化学发光筛选从天然产物提取物中鉴定MDM2泛素连接酶活性抑制剂。
J Biomol Screen. 2008 Mar;13(3):229-37. doi: 10.1177/1087057108315038. Epub 2008 Feb 12.
2
Living with p53, dying of p53.因p53而生，因p53而死。
Cell. 2007 Aug 24;130(4):597-600. doi: 10.1016/j.cell.2007.08.005.
3
p53 in health and disease.健康与疾病中的p53
Nat Rev Mol Cell Biol. 2007 Apr;8(4):275-83. doi: 10.1038/nrm2147.
4
Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction.基于结构的螺环氧化吲哚类化合物设计，作为MDM2-p53相互作用的强效、特异性小分子抑制剂。
J Med Chem. 2006 Jun 15;49(12):3432-5. doi: 10.1021/jm051122a.
5
The P53 pathway: what questions remain to be explored?P53 信号通路：还有哪些问题有待探索？
Cell Death Differ. 2006 Jun;13(6):1027-36. doi: 10.1038/sj.cdd.4401910.
6
Unleashing the power of p53: lessons from mice and men.释放p53的力量：来自小鼠和人类的启示。
Genes Dev. 2006 Jan 15;20(2):125-31. doi: 10.1101/gad.1397506.
7
Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells.HDM2泛素连接酶活性的小分子抑制剂可稳定并激活细胞中的p53。
Cancer Cell. 2005 Jun;7(6):547-59. doi: 10.1016/j.ccr.2005.04.029.
8
Cytotoxic effect of a non-peptidic small molecular inhibitor of the p53-HDM2 interaction on tumor cells.一种p53-HDM2相互作用的非肽类小分子抑制剂对肿瘤细胞的细胞毒性作用。
World J Gastroenterol. 2005 May 21;11(19):2927-31. doi: 10.3748/wjg.v11.i19.2927.
9
Novel antisense anti-MDM2 mixed-backbone oligonucleotides: proof of principle, in vitro and in vivo activities, and mechanisms.新型反义抗MDM2混合骨架寡核苷酸：原理验证、体外和体内活性及作用机制
Curr Cancer Drug Targets. 2005 Feb;5(1):43-9. doi: 10.2174/1568009053332663.
10
Assay for ubiquitin ligase activity: high-throughput screen for inhibitors of HDM2.泛素连接酶活性测定：HDM2抑制剂的高通量筛选
J Biomol Screen. 2004 Dec;9(8):695-703. doi: 10.1177/1087057104267956.
Zotero 插件