Synthesis and antineoplastic properties of an ether glycerophosphonocholine, and analog of ET-18-OCH3-GPC

Biochem Biophys Res Commun. 1992 Sep 16;187(2):603-8. doi: 10.1016/0006-291x(92)91237-k.

Abstract

A glycerophosphonocholine analog of the ether-linked lipid, rac-1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine (ET-18-OCH3-GPC), was synthesized in which the head group is nonhydrolyzable by phospholipase C. The phosphonate analog used in this study is rac-3-octadecyloxy-2-methoxy-propyl-phosphonocholine, C18H37OCH2CH(OCH3)CH2P(O)(O)OCH2CH2N+(CH3)3. The activity of the synthetic phosphonate was tested in the human leukemic cell line, HL-60, and the human undifferentiated cervical carcinoma, C-41. The glycerophosphonocholine inhibited [3H]thymidine uptake by HL-60 cells with an EC50 value of 5-7 microM. The glycerophosphate ET-18-OCH3-GPC had an EC50 value of approximately 2 microM against HL-60 cells. The EC50 values estimated from cell viability experiments were similar to that for [3H]thymidine uptake. The EC50 value for C-41 cells was about 10-15 microM. The data demonstrate that the glycerophosphonocholine is a promising anti-cancer drug for the treatment of both leukemia and solid tumors. Furthermore, the data demonstrate that phospholipase C-catalyzed hydrolysis of ET-18-OCH3-GPC does not play an important role in the cytotoxic action of the ether-linked glycerolipids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • DNA, Neoplasm / biosynthesis
  • Female
  • Glycerylphosphorylcholine / analogs & derivatives*
  • Glycerylphosphorylcholine / chemical synthesis
  • Glycerylphosphorylcholine / pharmacology
  • Glycerylphosphorylcholine / therapeutic use
  • Humans
  • Leukemia / drug therapy
  • Leukemia / metabolism
  • Leukemia / pathology
  • Tumor Cells, Cultured
  • Type C Phospholipases / metabolism
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology

Substances

  • Antineoplastic Agents
  • DNA, Neoplasm
  • 3-octadecyloxy-2-methoxypropylphosphonocholine
  • Glycerylphosphorylcholine
  • Type C Phospholipases