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Granulatimide and isogranulatimide, aromatic alkaloids with G2 checkpoint inhibition activity isolated from the Brazilian ascidian Didemnum granulatum: Structure elucidation and synthesis

TitleGranulatimide and isogranulatimide, aromatic alkaloids with G2 checkpoint inhibition activity isolated from the Brazilian ascidian Didemnum granulatum: Structure elucidation and synthesis
Publication TypeJournal Article
Year of Publication1998
AuthorsBerlinck, RGS, Britton, R, Piers, E, Lim, L, Roberge, M, da Rocha, RM, Andersen, RJ
JournalJournal of Organic Chemistry
Volume63
Pagination9850-9856
Date PublishedDec
Type of ArticleArticle
ISBN Number0022-3263
KeywordsBHK CELLS, CAFFEINE, CELL-CYCLE CHECKPOINTS, DNA-REPLICATION, HELA-CELLS, INDUCED G(2) DELAY, mitosis, PROTEIN-KINASE, RADIOSENSITIZATION, STAUROSPORINE
Abstract

Crude methanol ex-tracts of the ascidian Didemum 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.

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