Synthesis and Antitumor Activity of Ether Glycerophospholipids Bearing a Carbamate Moiety at the sn ‐2 Position: Selective Sensitivity Against Prostate Cancer Cell Lines

Analogues of 1‐ O ‐hexadecyl‐ sn ‐3‐glycerophosphonocholine (compounds 1 – 4 ) or sn ‐3‐glycerophosphocholine (compound 5 ) bearing a carbamate or dicarbamate moiety at the sn ‐2 position were synthesized and evaluated for their antiproliferative activity against cancer cells derived from a variety of tissues. Although all of the compounds are antiproliferative, surprisingly the carbamates ( 1 and 2 ) are more effective against the hormone‐independent cell lines DU145 and PC3 than toward other cancer cell lines we examined. This selectivity was not observed with the dicarbamates ( 3 and 4 ). Phosphocholine carbamate analogue 5 is as effective against the prostate cancer cell lines as the corresponding phosphonocholine analogue 1 . Cell death induced by 2′‐(trimethylammonio)ethyl 4‐hexadecyloxy‐3( R )‐ N ‐methylcarbamoyl‐1‐butanephosphonate (carbamate analogue 2 ) appeared to be mediated by apoptosis, as assessed by caspase activation and loss of mitochondrial membrane potential. The in vivo activity of 2 was evaluated in a murine prostate cancer xenograft model. Oral and intravenous administration showed that 2 is effective in inhibiting the growth of PC3 tumors in Rag2M mice. Our studies show that the glycerolipid carbamates reported herein represent a class of prostate‐cancer‐selective cytotoxic agents.