Isolation and characterisation of a prenylated p-terphenyl metabolite of Aspergillus candidus possessing potent and selective cytotoxic activity; studies on mechanism of action.
We describe the discovery and properties of a prenylated p-terphenyl metabolite of the fungus Aspergillus candidus. The compound (1) possesses potent cytotoxic activity against a range of tumour and other hyper-proliferative cell lines. Cell cycle analysis shows that in mouse keratinocyte (BALB/MK) cells treated with 1, the cell cycle is arrested in early S phase, indicative of an antimetabolite effect. Furthermore, cellular cytotoxicity can be reversed by addition of exogenous pyrimidine but not purine nucleosides to the cell culture medium. It is therefore likely that compound 1 selectively inhibits pyrimidine biosynthesis, and it is this property which accounts for its potent cytotoxic properties.
Stead
P
P
Bioprocessing Unit, GlaxoWellcome Medicines Research Centre, Stevenage, Herts, UK.
Affleck
K
K
Sidebottom
P J
PJ
Taylor
N L
NL
Drake
C S
CS
Todd
M
M
Jowett
A
A
Webb
G
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001230:Aspergillus / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004354:Drug Screening Assays, Antitumor; D005285:Fermentation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D013730:Terphenyl Compounds / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C112886:4''-deoxyterprenin; D000903:Antibiotics, Antineoplastic; D001713:Biphenyl Compounds; D013730:Terphenyl Compounds