Haloenol pyranones and morpholinones as antineoplastic agents of prostate cancer

Abstract

Haloenol pyran-2-ones and morpholin-2-ones were synthesized and evaluated as inhibitors of cell growth in two different prostate human cancer cell lines (PC-3 and LNCaP). Analogs derived from L- and D-phenylglycine were found to be the most effective antagonists of LNCaP and PC-3 cell growth. Additional studies reveal that the inhibitors induced G2/M arrest and the (S)-enantiomer of the phenylglycine-based derivatives was a more potent inhibitor of cytosolic iPLA(2)β.

Figure 1

Mechanism of serinase inhibition by haloenol pyran-2-ones.

Figure 2

Chemical structures of BEL and haloenol morpholinones.

Figure 3

Changes in morphology (left-40X magnification) and cell cycle (right) of LNCaP cells following treatment with rac-BEL, rac-4, (S)-14a, and (R)-14b.

Figure 4

Inhibitory effects of rac-BEL, rac-4, (S)-14a, and (R)-14b on iPLA₂β activity in rat kidney cytosol in the presence of 4 mM EGTA. Data are represented as the mean ± the S.E.M. of at least 3 separate experiments.

Scheme 1

Synthesis of unsubstituted and monophenyl BEL analogs.

Scheme 2

Synthesis of N-propargyl bromoenol morpholin-2-ones 14–17.

Scheme 3

Synthesis of N-benzyl bromoenol morpholin-2-one 20.