Alkyl and Alkoxyethyl Antineoplastic Phospholipids

Two series of phosphodiester ether lipid analogs with (N-methylmorpholino)ethyl or (N-methylpiperidino)ethyl polar head groups and long aliphatic or alkoxyethyl chains in the nonpolar portion of the molecule were synthesized as potential antineoplastic agents. The cytotoxic activity of these compounds (<BO>9</BO>−<BO>19</BO>) was evaluated in vitro against a panel of six human tumor xenografts and in two biochemical, mechanism-based screens (cdc2 kinase and cdc25 phosphatase). Analogs <BO>13</BO>, <BO>14</BO>, <BO>17</BO>, and <BO>19</BO> showed activity in the in vitro tests. Specifically, <BO>14</BO> and <BO>17</BO> were more active than the reference compound hexadecylphosphocholine (Miltefosine, He-PC) while <BO>13</BO> and <BO>19 </BO>possessed activity similar to that of the control. Of the analogs tested the one with the highest potency and least toxicity (<BO>17</BO>) has an N-methylpiperidino head group and a C<INF>16</INF> alkyl chain. In the mechanism-based tests <BO>11 </BO>showed weak inhibitory activity in the cdc25 phosphatase screen.