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.
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, NY 11367-1597, USA.
Hoe-Sup
HS
Byun
Robert
R
Bittman
Pranati
P
Samadder
Gilbert
G
Arthur
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D002219:Carbamates / Q000737:chemistry*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D010713:Phosphatidylcholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002219:Carbamates; D010713:Phosphatidylcholines