Synthesis of caged 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-ones: Evaluating the minimum structure for apoptosis induction by gambogic acid.
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(6H)-ones (4-oxatricyclo[4.3.1.0]decan-2-ones). Three types of 2,3,3a,7a-tetrahydro-3,6-methanobenzofuran-7(6H)-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.
Kuemmerle
Jared
J
Epicept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Jiang
Songchun
S
Tseng
Ben
B
Kasibhatla
Shailaja
S
Drewe
John
J
Cai
Sui Xiong
SX
D017209:Apoptosis / Q000187:drug effects*; D001572:Benzofurans / Q000737:chemistry*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006859:Hydrogen / Q000737:chemistry*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D001572:Benzofurans; D044004:Xanthones; D006859:Hydrogen; C052659:gambogic acid; D020169:Caspases