Structure-activity relationship of kahalalide F synthetic analogues.
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.
Jiménez
José C
JC
Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain.
López-Macià
Angel
A
Gracia
Carol
C
Varón
Sonia
S
Carrascal
Marta
M
Caba
Josep M
JM
Royo
Miriam
M
Francesch
Andrés M
AM
Cuevas
Carmen
C
Giralt
Ernest
E
Albericio
Fernando
F
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D047630:Depsipeptides; C097897:kahalalide F