D-3-deoxy-3-substituted myo-inositol analogues as inhibitors of cell growth.
A number of unnatural D-3-deoxy-3-substituted myo-inositols were synthesized and their effects on the growth of wild-type NIH 3T3 cells and oncogene-transformed NIH 3T3 cells were studied. The compounds were found to exhibit a diversity of growth-inhibitory activities and showed selectivity in inhibiting the growth of some transformed cells as compared with wild-type cells. Remarkably, D-3-deoxy-3-azido-myo-inositol exhibited potent growth-inhibitory effects toward v-sis-transformed NIH 3T3 cells but had little effect on the growth of wild-type cells. The growth-inhibitory effects of the myo-inositol analogues were antagonized by myo-inositol. Since [3H]-3-deoxy-3-fluoro-myo-inositol was shown to be taken up by cells and incorporated into cellular phospholipids, we suggest that these unnatural myo-inositol analogues may act as antimetabolites in the phosphatidylinositol intracellular signalling pathways. Because cells transformed by oncogenes often exhibit elevated phosphatidylinositol turnover, the inhibition of signalling pathways that mediate oncogene action could offer new opportunities for controlling the growth of cancer cells.
Powis
G
G
Department of Pharmacology, Mayo Clinic, Rochester, MN 55905.
Aksoy
I A
IA
Melder
D C
DC
Aksoy
S
S
Eichinger
H
H
Fauq
A H
AH
Kozikowski
A P
AP
D016475:3T3 Cells; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D007294:Inositol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D010743:Phospholipids / Q000378:metabolism; D015290:Second Messenger Systems
D010743:Phospholipids; D007294:Inositol; D002118:Calcium