2-(Acyloxy)ethylphosphonate analogues of prenyl pyrophosphates: synthesis and biological characterization.
2-(Acyloxy)ethylphosphonate analogues of geranyl, farnesyl, and geranylgeranyl pyrophosphate have been prepared. Horner-Wadsworth-Emmons condensation of different terpene aldehydes with an unsymmetrical bisphosphonate was the key step in syntheses of the phosphonates bearing alpha,beta-unsaturated acyloxy groups. After preparation of the respective phosphonic acids through reaction with TMSBr, both acids and esters were tested for their effects on DNA synthesis in human-derived myeloid and lymphoid leukemia cell lines. The phosphonate esters varied substantially in their ability to impair proliferation of the different cell lines, but testing against one possible target, farnesyl protein transferase (FPTase), revealed little impact at concentrations ranging up to 10 microM. Because the corresponding 2,3-dihydro compounds showed similar biological activity, conjugate addition would not appear to be involved in the toxicity.
Cermak
D M
DM
Department of Chemistry, University of Iowa, Iowa City 52242-1294, USA.
Wiemer
D F
DF
Lewis
K
K
Hohl
R J
RJ
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D011756:Diphosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017368:Protein Prenylation / Q000187:drug effects; D013329:Structure-Activity Relationship
D011756:Diphosphates; D004247:DNA; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase