Synthesis and antitumor activity of ether glycerophospholipids bearing a carbamate moiety at the sn-2 position: selective sensitivity against prostate cancer cell lines.
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| Abstract |
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.
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| Authors | Hoe-Sup Byun, Robert Bittman, Pranati Samadder, Gilbert Arthur |
| Journal | ChemMedChem (ChemMedChem) Vol. 5 Issue 7 Pg. 1045-52 (Jul 05 2010) ISSN: 1860-7187 [Electronic] Germany |
| PMID | 20533503 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Chemical References |
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