INHIBITORS OF PHOSPHATIDYL MYO-INOSITOL CYCLE
The present invention relates to the preparation and biological activity of 3-deoxy-Dmyo-inositol ether lipid analogs as inhibitors of phosphatidylinositol-3-kinase signaling and cancer cell growth. The compounds of the present invention are useful as anti-tumor 5 agents which effectively inhibit the growth of mammalian cells.
1 . A 3-deoxy-D-myo-inositol analog having the formula:
wherein X is O or CH 2 ; R 1 and R 2 are individually, (C 1 -C 25 ) alkyl, (C 6 -C 10 ) aryl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 22 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 7 -C 32 ) aralkyl, (C 7 -C 32 ) alkylaryl, (C 9 -C 32 ) aralkenyl, (C 9 -C 32 ) alkenylaryl or C(O)R 3 ; and R 3 is (C 1 -C 25 ) alkyl (C 6 -C 102 ) aryl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 22 ) alkenyl, (C 5 -C 8 ) cycloalkenyl, (C 7 -C 32 ) aralkyl, (C 7 -C 32 ) alkylaryl, (C 9 -C 32 ) aralkenyl or (C 9 -C 32 )) alkenylaryl; R 4 ad R 5 are individually hydrogen or a phosphate group; or when R 4 or R 5 is not hydrogen, a pharmaceutically acceptable salt thereof.
2 . A method of treating cancer comprising administering a therapeutically effective amount of a compound to a subject according to claim 1 .
3 . The method of claim 2 , wherein said cancer is one that is characterized by cells that over-express the EGF and/or the PDGF receptor, cells that express a mutant ras, or cells that comprise a Bcr/Abl transfection.
4 . The method of claim 3 , wherein said cancer is selected from the group consisting of colon, pancreatic, prostate, head and neck, breast, gastric, renal, brain and CML.