Synthesis and Biological Evaluation of Radioiodinated Phospholipid Ether Stereoisomers

Mark A. Rampy, Anatoly N. Pinchuk, Jamey P. Weichert, R. W.Scott Skinner, Susan J. Fisher, Richard L. Wahl, Milton D. Gross, Raymond E. Counsell

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4 Scopus citations


Radioiodinated phospholipid ethers have shown the remarkable ability to selectively accumulate in a variety of animal tumors as well as in human tumor xenografts. It has been suggested that this tumor avidity may arise as a consequence of metabolic differences between tumor and corresponding normal tissue. One such compound, 1-0-[12-(m-iodophenyl)dodecyl]-2-0-methyl-rac-glycero-3-phosphocholine (NM-294), contains a chiral center at the sn-2 position. The unnatural S- and natural R-enantiomers (4 and 5, respectively) of NM-294 were synthesized in order to provide further information on the mechanism(s) responsible for the tumor avidity of phospholipid ethers. In vitro cytotoxicity studies demonstrated a lack of stereospecificity. Biodistribution studies in rats bearing the Walker 256 tumor demonstrated the S- and R-isomers to have similar tissue uptake at 24 and 48 h after administration. Tumor-to-blood ratios at 24 h were 11.1 and 11.0 for the S- and R-isomers, respectively. In addition, γ-camera scintigrams of tumor-bearing rats at various time points after iv administration of the S- and R-isomers did not show any qualitative differences in the distribution of radioactivity. Prior studies have shown that rac-NM-294 was not a substrate for phosphatidylcholine specific phospholipase C, but was a substrate for two forms of phospholipase D (PLD). Therefore, metabolism studies with 4 and 5 with various forms of PLD were performed. PLD from cabbage demonstrated a degree of stereoselectivity. In the presence of 1% ethanol, the R-isomer was metabolized to the greatest extent, followed by rac-NM-294 and the S-isomer. PLD isolated from Streptomyces chromofuscus failed to demonstrate any stereoselectivity. The results suggest that the mechanism(s) of retention of these compounds in tumors may not involve a highly stereoselective component.

Original languageEnglish
Pages (from-to)3156-3162
Number of pages7
JournalJournal of Medicinal Chemistry
Issue number16
StatePublished - Aug 1 1995


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