Preparation of an Aminoxyl Analog of the Anticancer Agent Miltefosine George Sosnovsky*, Jan Lukszo**, Robert C. Brasch Department of Chemistry, University of Wisconsin-Milwaukee, Milwaukee. Wisconsin. 53201. USA. and Contrast Media Laboratory. Department of Radiology. School of Medicine. University of California, San Francisco. CA 94143. USA Z. Naturforsch. 51b, 888-890 (1996); received December 11, 1995 Anticancer Agents, Aminoxyl, Nitroxyl, Synthesis The synthesis and a few properties of hexadecyl 2-[N,N-dimethyl-N-(2,2,6.6-tetramethyl- l-oxyl-piperidin-4-yl)ammonio] ethyl phosphate are described. This compound is a spin la beled analog of the antineoplastic drug hexadecylphosphocholine (Miltefosine). Introduction A decade ago in quest of developing new suit able contrast agents for the clinical magnetic reso nance imaging tomography (MRI), among a vari ety of compounds [1-3] also were synthesized two aminoxyls (nitroxyls, “nitroxides”) 1 and 3 con taining quaternary ammonium moieties. While compound 1 was used in a study [4] concerning the membrane permeability of nitroxyl moieties through human erythrocyte membranes, com pound 3 was somewhat neglected and not published. Recently, it came to our attention [5] that hexa decyl (cetyl) phosphocholine (Miltefosine, 2), and related analogs were found [5] to have potent in vitro and in vivo antineoplastic activities against several cancer lines. These results prompted us to disclose the synthesis and the available properties of the nitroxyl labeled analog 3. It is believed that this information would be of interest to the scien tific community participating in the development of anticancer drugs. Results and Discussion The key intermediate N-(2-hydroxyethyl)-N,N- dimethyl-N-(2,2,6,6-tetramethyl-l-oxyl-piperidin- 4-yl)-tetraphenyl borate (7) was synthesized via the known compound N-(2-hydroxyethyl)-N,N-di- methyl-N-(2,2,6,6-tetramethyl-l-oxyl-piperidin-4- yl) ammonium iodide (6) [6]. 6 was prepared from 4-oxo-2,2,6,6-tetramethyl-piperidin-l-oxyl (4) and N-methylethanolamine by the reductive amination reaction mediated by sodium cyanoborohydride. followed by the methylation of the intermediate N-(2-hydroxyethyl)-N-methyl-N-(2,2,6,6-tetra- methyl-l-oxyl-piperidin-4-yl (5) with methyl iodide to give 6. The reaction of 6 with sodium tetraphenylborate gave the desired key intermedi ate 7. The other key intermediate hexadecylphosphate (cetyl phosphate, 8) was obtained by using a known method [7] from cetyl alcohol and phos phorus oxychloride. The condensation of 7 with 8 to give hexyl 2-[N,N-dimethyl-N-(2,2,6,6-tetramethyl-l-oxyl-pi- * Reprint requests to George Sosnovsky. ** Present address: NIH. National Institute of Allergy and Infectious Diseases (NIAID), Laboratory of Molecular Structure. 12441 Parklawn Drive, Rockville, MD 20852. U.S.A. 0932-0776/96/0600-0888 $06.00 © 1996 Verlag der Zeitschrift für Naturforschung. All rights reserved. n