title: Discovery of new pyridoacridine alkaloids from Lissoclinum cf. badium that inhibit the ubiquitin ligase activity of Hdm2 and stabilize p53.
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.
authors.affiliation: Molecular Targets Development Program, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, MD 21702-1201, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Clement
authors.forename: Jirouta
authors.initials: J
authors.lastname: Kitagaki
authors.forename: Yili
authors.initials: Y
authors.lastname: Yang
authors.forename: Carrie J
authors.initials: CJ
authors.lastname: Saucedo
authors.forename: Barry R
authors.initials: BR
authors.lastname: O'Keefe
authors.forename: Allan M
authors.initials: AM
authors.lastname: Weissman
authors.forename: Tawnya C
authors.initials: TC
authors.lastname: McKee
authors.forename: James B
authors.initials: JB
authors.lastname: McMahon
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D010618:Phenanthrolines / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014561:Urochordata / Q000737:chemistry*
chemical_list: D000166:Acridines; D000470:Alkaloids; D004791:Enzyme Inhibitors; D010618:Phenanthrolines; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C475900:pyridoacridine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2