Synthesis and biological evaluation of radioiodinated phospholipid ether stereoisomers.

Abstract

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-O-[12-(m-iodophenyl)dodecyl]-2-O-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, gamma-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.

• Authors: M A Rampy, A N Pinchuk, J P Weichert, R W Skinner, S J Fisher, R L Wahl, M D Gross, R E Counsell
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 38 Issue 16 Pg. 3156-62 (Aug 04 1995) ISSN: 0022-2623 [Print] United States
• PMID: 7636878 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Iodine Radioisotopes
• Phospholipid Ethers
• NM 294
• Phospholipase D

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Brassica (enzymology)
• Carcinoma 256, Walker (metabolism)
• Female
• Iodine Radioisotopes (pharmacokinetics)
• Neoplasm Transplantation
• Phospholipase D (metabolism)
• Phospholipid Ethers (chemical synthesis, pharmacokinetics, pharmacology)
• Radionuclide Imaging
• Rats
• Rats, Sprague-Dawley
• Stereoisomerism
• Streptomyces (enzymology)
• Structure-Activity Relationship
• Substrate Specificity
• Tumor Cells, Cultured