title: Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase.
abstract: Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
authors.forename: Veronica S
authors.initials: VS
authors.lastname: Wills
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA.
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Metzger
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Allen
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Varney
authors.affiliation: Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA; Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Wiemer
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: sarah.holstein@unmc.edu.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Holstein
mesh_terms: D000818:Animals; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D014230:Triazoles; D051231:Farnesyltranstransferase
keywords: Bishomoisoprenoids; Bisphosphonate; GGDP synthase; Inhibition; Isoprenoid biosynthesis; Triazole