Synthesis and biological activity of isopentenyl diphosphate analogues.
A series of analogues of isopentenyl diphosphate (IPP) having a dicarboxylate moiety in place of the diphosphate were synthesized and investigated as inhibitors of undecaprenyl diphosphate (UPP) synthase and protein farnesyltransferase (PFTase). PFTase is involved in control of cell proliferation and is known to be inhibited by certain maleic acid derivatives bearing long alkyl substituents (> or =12 carbons, e.g., chaetomellic acid). UPP synthase is a potential target for antimicrobial agents and utilizes isopentenyl diphosphate (IPP) as a substrate. A number of dicarboxylate-containing IPP analogues were prepared in 2-5 steps from commercially available starting materials with good overall yield (20-78%). These syntheses involved the conjugate addition of an organocuprate to dimethyl acetylenedicarboxylate (DMAD) followed by basic ester hydrolysis. The E-pentenylbutanedioic acid 32 showed inhibition of UPP synthase with an IC(50) of 135 microM. Compound 30 displays competitive inhibition of PFTase with a K(i) of 287 microM.
Scholte
Andrew A
AA
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Eubanks
Lisa M
LM
Poulter
C Dale
CD
Vederas
John C
JC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011756:Diphosphates / Q000737:chemistry; D051231:Farnesyltranstransferase; D045782:Hemiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008298:Maleates / Q000737:chemistry; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D011756:Diphosphates; D045782:Hemiterpenes; D008298:Maleates; D009943:Organophosphorus Compounds; C004809:isopentenyl pyrophosphate; C030272:maleic acid; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C023266:undecaprenyl pyrophosphate synthetase