Anhydride modified cantharidin analogues: synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activity

• Published in: Bioorganic & medicinal chemistry letters 2000-08, Vol.10 (15), p.1687-1690
• Main Authors: McCluskey, Adam, Bowyer, Michael C, Collins, Elizabeth, Sim, Alistair T.R, Sakoff, Jennette A, Baldwin, Monique L
• Format: Article
• Language: English
• Subjects: Anhydrides - chemistry; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cantharidin - analogs & derivatives; Cantharidin - chemical synthesis; Cantharidin - pharmacology; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General aspects; Humans; Isoenzymes - antagonists & inhibitors; Medical sciences; Pharmacology. Drug treatments; Phosphoprotein Phosphatases - antagonists & inhibitors; Tumor Cells, Cultured
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00323-1

Two series of anhydride modified cantharidin analogues were synthesised and screened for their phosphatase inhibition (PP1 and PP2A) and cytotoxicity in various cancer cell lines ( Ovarian A2780, ADDP; Osteosarcoma 143B; and Colon HCT116 and HT29). One series was synthesised by a novel, high yielding one-pot hydrogenation-ring-opening-esterification procedure, the other by acid catalysed acetal formation. Analogues 5– 7 and 9 displayed moderate PP2A selectivity (ca. 5- to 20-fold) and inhibition typically in the low μM range (comparable, in some cases to cantharidin). The anticancer activity of these analogues varied with the cell line under study; however, many of them showed selective cytotoxicity for the colon tumour cell lines.