Lupane derivatives from Lophopetalum wallichii with farnesyl protein transferase inhibitory activity.
Chloroform-soluble extracts of the stems and of the mixed stems and stem bark of Lophopetalum wallichii were found to be inhibitory in a farnesyl protein transferase (FPTase) bioassay system. During the course of activity-guided fractionation, the known lupane-type triterpenes, ochraceolide A (1), ochraceolide B (2), betulin, and lupeol and the new lupane lactone, dihydro ochraceolide A (4), were isolated. The stereochemistry of the epoxide group of ochraceolide B (2) was determined by preparation of both epoxide isomers [2, and the new semisynthetic derivative, 20-epi-ochraceolide B (3)] from 1. The structure of 4 was established by reduction of 1 with sodium borohydride. Compounds 1 and 2 exhibited significant inhibitory activity in the FPTase assay (IC50 values of 1.0 and 0.7 microgram/mL, respectively). Lupeol was found to be weakly active (IC50 65.0 micrograms/mL) in this test system, whereas no significant inhibition was detected for betulin or compounds 3 or 4. When evaluated against a panel of human cancer cells in culture, compounds 1 and 4 were modestly cytotoxic. Compounds 2 and 3 were not active in the panel.
Sturm
S
S
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago 60612, USA.
Gil
R R
RR
Chai
H B
HB
Ngassapa
O D
OD
Santisuk
T
T
Reutrakul
V
V
Howe
A
A
Moss
M
M
Besterman
J M
JM
Yang
S L
SL
Farthing
J E
JE
Tait
R M
RM
Lewis
J A
JA
O'Neill
M J
MJ
Farnsworth
N R
NR
Cordell
G A
GA
Pezzuto
J M
JM
Kinghorn
A D
AD
D019883:Alkyl and Aryl Transferases; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018547:Plant Stems / Q000737:chemistry*; D010946:Plants, Medicinal / Q000737:chemistry*; D014166:Transferases / Q000037:antagonists & inhibitors*; D014315:Triterpenes / Q000302:isolation & purification* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D014315:Triterpenes; D014166:Transferases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase