Unprecedented Citrinin Trimer Tricitinol B Functions as a Novel Topoisomerase IIα Inhibitor

被引：53

作者：

Du, Lin ^{[1
]}

Liu, Hong-Chun ^{[2
]}

Fu, Wei ^{[3
]}

Li, De-Hai ^{[1
]}

Pan, Qiu-Ming ^{[2
]}

Zhu, Tian-Jiao ^{[1
]}

Geng, Mei-Yu ^{[2
]}

Gu, Qan-Qun ^{[1
]}

机构：

[1] Ocean Univ China, Sch Med & Pharm, Minist Educ China, Key Lab Marine Drugs, Qingdao 266003, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China

[3] Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 16期

关键词：

MOLECULAR-MECHANISMS; DNA CLEAVAGE; SOLID-STATE; DRUGS; APOPTOSIS; TARGET; DECOMPOSITION; ASSAY;

D O I：

10.1021/jm200511x

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Fifteen citrinin derivatives (1-4,6-16), including two unprecedented citrinin timers tricitrinols A (3) and B (4), were isolated from Penicillium citrinum HGY1-5. The six-membered ring A system is essential for the cytotoxicity of active dimers (1, 2, and 5) and trimers (3 and 4). Tricitrinol B (4) showed extensive cytotoxicity in 17 tumor cells with comparable low-micromolar IC50 values (1-10 mu M) and potential antimultidrug resistance capabilities. Tricitrinol B (4) induced cell apoptosis in HL60 and HCT116 cells via mainly extrinsic pathways and G2/M arrest. Further antitumor mechanism study and computational docking analysis indicated that tricitrinol B (4) works as an intercalating topoisomerase II alpha (topo II alpha) poison, which inhibits the enzyme activity of topo II alpha by interfering predominantly with the topo II alpha-mediated poststrand-passage deavage/religation equilibrium over with the prestrand-passage one and induced DNA damage. Tricitrinol B (4) represents a novel class of topo II alpha-inhibitory skeletons for developing new chemotherapeutic agents.

引用

页码：5796 / 5810

页数：15

共 54 条

[1]

A screen of yeast respiratory mutants for sensitivity against the mycotoxin citrinin identifies the vacuolar ATPase as an essential factor for the toxicity mechanism [J].