Semisynthetic neoboutomellerone derivatives as ubiquitin-proteasome pathway inhibitors.
The interesting pharmacological properties of neoboutomellerones 1 and 2 were the basis for the assembly of a small library of analogues consisting of natural products isolated from the plant Neoboutonia melleri and of semisynthetic derivatives. As the two enone systems (C23-C24a and C1-C3) and the two hydroxyls groups (C22 and C26) of neoboutomellerones are required for activity, modifications were focused on these functional groups. Biological evaluation by using a cellular assay for proteasome activity provided clues regarding the mechanism of action of these natural products and synthetic derivatives. Certain neoboutomellerone derivatives inhibited the proliferation of human WM-266-4 melanoma tumor cells at submicromolar concentration and warrant evaluation as anticancer agents.
USR CNRS-Pierre Fabre No. 3388 ETaC, Centre de Recherche et Développement Pierre Fabre, 3 Avenue Hubert Curien, 31035 Toulouse Cedex 01, France.
Joséphine
J
Beck
Yves
Y
Guminski
Christophe
C
Long
Laurence
L
Marcourt
Fadila
F
Derguini
Fabien
F
Plisson
Antonio
A
Grondin
Isabelle
I
Vandenberghe
Stéphane
S
Vispé
Viviane
V
Brel
Yannick
Y
Aussagues
Frédéric
F
Ausseil
Paola B
PB
Arimondo
Georges
G
Massiot
François
F
Sautel
Frédéric
F
Cantagrel
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001688:Biological Products / Q000737:chemistry*; D045744:Cell Line, Tumor; D019665:Euphorbiaceae / Q000737:chemistry; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D025801:Ubiquitin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D001688:Biological Products; D061988:Proteasome Inhibitors; D014315:Triterpenes; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex