Spongolactams, farnesyl transferase inhibitors from a marine sponge: isolation through an LC/MS-guided assay, structures, and semisyntheses.
Novel nitrogenous diterpenoids, spongolactams A-C (1-3), were isolated as trace components of an Okinawan marine sponge, Spongia sp., by an LC/MS-guided assay for farnesyl transferase (FTase) inhibitors. Their structures were elucidated by spectroscopic analyses. To evaluate their structures and biological activity, the metabolites were semisynthesized from the known furanoditerpene 5, obtained from the same sponge. Three related compounds 4, 13, and 16 were also semisynthesized. The IC50 values against FTase for 1-3 were 23, 130, and >260 microM, respectively, while the IC50 values against a human tumor cell line were 2.0, 3.5, and 20 microM, respectively. The structure-activity relationships within the six compounds suggest some positive correlation between FTase inhibitory and cytotoxic activities.
Mori
Daisuke
D
Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Kimura
Yuko
Y
Kitamura
Shigeyuki
S
Sakagami
Youji
Y
Yoshioka
Yukio
Y
Shintani
Tomoaki
T
Okamoto
Tetsuji
T
Ojika
Makoto
M
D002853:Chromatography, Liquid; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D013058:Mass Spectrometry; D012441:Saccharomyces cerevisiae / Q000201:enzymology
D004791:Enzyme Inhibitors; D007769:Lactams; D051231:Farnesyltranstransferase