title: Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition.
abstract: Cantharidin (1) and its derivatives are of significant interest as serine/threonine protein phosphatase 1 and 2A inhibitors. Additionally, compounds of this type have displayed growth inhibition of various tumour cell lines. To further explore both of these inhibition pathways, a number of amide-acid norcantharidin analogues (15-26) were prepared. Compounds 23 and 24, containing two carboxylic acid residues, showed good PP1 and PP2A activity, with IC(50) values of approximately 15 and approximately 3 mum, respectively. Substituted aromatic amide analogues 45, 48, 49, 52, 53, and 54 also displayed good PP1 and PP2A inhibition, with IC(50) values in the range of 15-10 microM (PP1) and 11-5 microM (PP2A). However, bulky ortho substituents on the aromatic ring caused the aromatic ring to be skewed from the NCO planarity, leading to a decrease in PP1 and PP2A inhibition. A number of analogues, 20, 22, 25 and 46, showed excellent tumour growth inhibition, with 46 in particular being more potent than the lead, norcantharidin 2.
authors.affiliation: Department of Chemistry, School of Environmental & Life Sciences, The University of Newcastle, University Drive, Callaghan, NSW 2308, Australia.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hill
authors.forename: Scott G
authors.initials: SG
authors.lastname: Stewart
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Gordon
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ackland
authors.forename: Jayne
authors.initials: J
authors.lastname: Gilbert
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sauer
authors.forename: Jennette A
authors.initials: JA
authors.lastname: Sakoff
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002193:Cantharidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C069741:norcantharidin; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D002193:Cantharidin