Synthesis and biological activity of isopentenyl diphosphate analogues

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 4; pp. 763 - 770
• Main Authors: Scholte, Andrew A, Eubanks, Lisa M, Poulter, C.Dale, Vederas, John C
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.02.2004; Elsevier Science
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Alkyl and Aryl Transferases - metabolism; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Biological and medical sciences; Diphosphates - chemistry; Farnesyltranstransferase; General aspects; Hemiterpenes - chemical synthesis; Hemiterpenes - chemistry; Hemiterpenes - pharmacology; Inhibitory Concentration 50; Maleates - chemistry; Medical sciences; Molecular Structure; Organophosphorus Compounds - chemical synthesis; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - pharmacology; Pharmacology. Drug treatments; Enzyme; Aliphatic compound; Transferases; Enzyme inhibitor; Dienic compound; Competitive inhibition; Farnesyl-diphosphate farnesyltransferase; di-trans,poly-cis-Decaprenylcistransferase; Stereoselectivity; Lithium Compounds; Structure activity relation; Vinylic compound; Organic salt; Carboxylate; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2003.11.033

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 (≥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 μM. Compound 30 displays competitive inhibition of PFTase with a K i of 287 μM. 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).