Synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6 H)-ones: Evaluating the minimum structure for apoptosis induction by gambogic acid

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 8; pp. 4233 - 4241
• Main Authors: Kuemmerle, Jared, Jiang, Songchun, Tseng, Ben, Kasibhatla, Shailaja, Drewe, John, Cai, Sui Xiong
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15-04-2008; Elsevier Science
• Subjects: 2,3,3a,7a-Tetrahydro-3,6-methanobenzofuran-7(6 H)-ones; Antineoplastic agents; Apoptosis - drug effects; Apoptosis inducer; Benzofurans - chemistry; Biological and medical sciences; Caspases - metabolism; Cell growth inhibition; Cell Line, Tumor; Claisen/Diels–Alder reaction cascade; Enzyme Activation - drug effects; Gambogic acid; General aspects; Humans; Hydrogen - chemistry; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Potential anti-cancer drugs; Structure-Activity Relationship; Xanthones - chemical synthesis; Xanthones - chemistry; Xanthones - pharmacology; Apoptosis inducer; 2,3,3a,7a-Tetrahydro-3,6-methanobenzofuran-7(6 H)-ones; Cell growth inhibition; Claisen/Diels–Alder reaction cascade; Gambogic acid; Potential anti-cancer drugs; Antineoplastic agent; Human; Molecular rigidity; Solid tumor; Cage compound; Liver; Diels Alder addition; Cytotoxicity; Steric hindrance; 2,3,3a,7a-Tetrahydro-3,6-methanobenzofuran-7(6H)-ones; In vitro; Biological activity; Claisen/Diels-Alder reaction cascade; Cell line; Colon; Mammary gland; Chemical synthesis; Tumor cell; Apoptosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.02.084

We have reported the discovery of gambogic acid (GA) as a potent apoptosis inducer and the identification of transferrin receptor as its molecular target. In order to understand the basic pharmacophore of GA for inducing apoptosis and to discover novel and simplified derivatives as potential anti-cancer agents, we explored the synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6
H)-ones (4-oxatricyclo[4.3.1.0]decan-2-ones). Three types of 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6
H)-ones based on xanthone, 2-phenylchromene-4-one and benzophenone, were synthesized using a Claisen/Diels–Alder reaction cascade. All the reactions produced the targeted caged compound as well as its neo-isomer. The caged compounds based on xanthone and 2-phenylchromene-4-one were found to maintain the apoptosis inducing and cell growth inhibiting activity of GA, although with less potency. The caged compounds based on benzophenone were found to be inactive. Our study determined the minimum structure of GA for its apoptosis inducing activity, which could lead to the development of simple derivatives as potential anti-cancer drugs.