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 (9-19) 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 13, 14, 17, and 19 showed activity in the in vitro tests. Specifically, 14 and 17 were more active than the reference compound hexadecylphosphocholine (Miltefosine, He-PC) while 13 and 19 possessed activity similar to that of the control. Of the analogs tested the one with the highest potency and least toxicity (17) has an N-methylpiperidino head group and a C16 alkyl chain. In the mechanism-based tests 11 showed weak inhibitory activity in the cdc25 phosphatase screen.
Koufaki
M
M
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Athens, Greece.
Polychroniou
V
V
Calogeropoulou
T
T
Tsotinis
A
A
Drees
M
M
Fiebig
H H
HH
LeClerc
S
S
Hendriks
H R
HR
Makriyannis
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010743:Phospholipids / Q000138:chemical synthesis / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013215:Starfish; D014407:Tumor Cells, Cultured; D020687:cdc25 Phosphatases
C100457:(N-methylpiperidino)ethanol hexadecyl phosphonate; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D016213:Cyclins; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D010743:Phospholipids; D010880:Piperidines; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; D020687:cdc25 Phosphatases