353491-46-0Relevant academic research and scientific papers
Synthesis and structure determination of kahalalide F
Lopez-Macia,Jimenez,Royo,Giralt,Albericio
, p. 11398 - 11401 (2001)
Kahalalide F, the only member of the family of peptides called kahalalides, isolated from the sacoglossan mollusc Elysia rufescens and the green alga Bryopsis sp., with important bioactivity, is in clinical trials for treatment of prostate cancer. An efficient solid-phase synthetic approach is reported. Kahalalide F presents several synthetic difficulties: (i) An ester bond between two Β-branched and sterically hindered amino acids; (ii) a didehydroamino acid; and (iii) a rather hydrophobic sequence with two fragments containing several Β-branched amino acids in a row, one of them terminated with a saturated aliphatic acid. The cornerstones of our strategy were (i) a quasiorthogonal protecting system with allyl, tert-butyl, fluorenyl, and trityl-based groups, (ii) azabenzotriazole coupling reagents, (iii) formation of the didehydroamino acid residue on the solid phase, and (iv) cyclization and final purification in solution. HPLC, high-field NMR, and biological activity studies showed that the correct stereochemistry of the natural product is that proposed by Rinehart et al. whereas the stereochemistry proposed by Scheuer et al. is tha of a biologically less active diastereoisomer.
Structure-activity relationship of Kahalalide F synthetic analogues
Jiménez, José C.,López-Macià, Angel,Gracia, Carol,Varón, Sonia,Carrascal, Marta,Caba, Josep M.,Royo, Miriam,Francesch, Andrés M.,Cuevas, Carmen,Giralt, Ernest,Albericio, Fernando
supporting information; experimental part, p. 4920 - 4931 (2009/09/06)
Kahalalide F (KF) is a natural product currently under phase II clinical trials. Here, we report the solid phase synthesis of 132 novel analogues of kahalalide F and their in vitro activity on a panel of up to 14 cancer cell lines. The structure-activity relationship of these analogues revealed that KF is highly sensitive to backbone stereotopical modification but not to side chain size modification. These observations suggest that this compound has a defined conformational structure and also that it interacts with chiral compounds through its backbone and not through its side chains. The N-terminal aliphatic acid appears to be a hydrophobic buoy in a membrane-like environment. Moreover, significant improvement of the in vitro activity was achieved.
