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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.

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.

DOI:10.1016/j.bmc.2008.10.024
PMID:18977148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2718708/
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。