title: Comparative inhibition of prostate cell invasion by conformationally flexible and constrained bis(2,6-dioxopiperazine)s.
abstract: Inhibition of the migration of human prostate cancer PC-3 cells by a series of 18 conformationally flexible and constrained bis(2,6-dioxopiperazine)s including selected bis(morpholinomethyl) derivatives was investigated in vitro using the Matrigel invasion assay. The anti-invasion effects were compared to the cytotoxic effects of these experimental drugs. The parent conformationally mobile ICRF-159 (razoxane) and its dextrorotatory isomer ICRF-187 (dexrazoxane) inhibited invasion at concentrations that were at least 19-fold lower than their cytotoxic concentrations. This indicates that the anti-invasion effect was achieved independent of cytotoxicity. Seven conformationally constrained compounds were found to have no appreciable anti-invasive activity. Generally, the morpholinomethyl pro-drug derivatives of seven of the dioxopiperazines, exhibited either anti-invasive or cytotoxic activities that were reduced or unchanged relative to the parent molecules. In summary, certain bis(2,6-dioxopiperazine)s exhibit a promising and selective anti-invasion effect in human prostate cells. This activity seems to require a flexible linker allowing for multiple conformational possibilities of the dioxopiperazine rings.
authors: OHIO STATE UNIV,COLL PHARM,COLUMBUS,OH 43210. OHIO STATE UNIV,COLL MED,DEPT PATHOL,COLUMBUS,OH 43210.
authors: M
authors: M
authors: Wientjes
authors: R
authors: R
authors: Stephens
authors: A
authors: A
authors: Koolemansbeynen
authors: S
authors: S
authors: Eturi
authors: D
authors: D
authors: Witiak