Granulatimide and Isogranulatimide, Aromatic Alkaloids with G2 Checkpoint Inhibition Activity Isolated from the Brazilian Ascidian Didemnum granulatum:  Structure Elucidation and Synthesis

Crude methanol extracts of the ascidian Didemnum granulatum collected in Brazil showed activity in a new screen for G2 cell cycle checkpoint inhibitors. Bioassay-guided fractionation of the extract yielded the known alkaloids didemnimides A ( 1 ) and D ( 2 ), the new alkaloid didemnimide E ( 3 ), and a new G2 checkpoint inhibitor. Two candidate structures for the inhibitor, named granulatimide ( 4 ) and isogranulatimide ( 5 ), have been prepared via a short and efficient biomimetic synthesis involving the photolysis of didemnimide A ( 1 ). The synthesis revealed that the correct structure for the naturally occurring G2 checkpoint inhibitor is isogranulatimide ( 5 ). Granulatimide ( 4 ), the other candidate structure, was also found to be a G2 checkpoint inhibitor, and it was subsequently detected in chromatographic fractions associated with purification of D. granulatum alkaloids. Granulatimide ( 4 ) and isogranulatimide ( 5 ) represent the first examples of a new class of G2 specific cell cycle checkpoint inhibitors and the first ones identified through a rational screening program.