title: Synthesis of stable analogues of geranylgeranyl diphosphate possessing a (Z,E,E)-geranylgeranyl side chain, docking analysis, and biological assays for prenyl protein transferase inhibition.
abstract: Herein, we report the synthesis of novel stable analogues of geranylgeranyl diphosphate (GGPP), in which the "natural" all-trans geranylgeranyl portion has been replaced by a (Z,E,E)-geranylgeranyl chain. The change in configuration and consequent change in the relative position of the polar portion with the lipophilic side chain did not improve the properties of the E,E,E analogues in their inhibition of geranylgeranyl protein transferase I (GGTase I). However, a significant level of GGTase I inhibition and selectivity for GGTase I over farnesyl transferase (FTase) was maintained the unsubstituted phosphonoacetamidoxy derivative 4 a. This has shed light on the relative importance of the configuration at the C2=C3 double bond among GGPP derivatives. Moreover, the biological activities of all the compounds reported herein, in particular the preferential FTase inhibitory activity shown by compound 6, were in good agreement with the results of docking analysis.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Simone
authors.initials: S
authors.lastname: Bertini
authors.forename: Laura
authors.initials: L
authors.lastname: Betti
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Gianbattista
authors.initials: G
authors.lastname: Gervasi
authors.forename: Gino
authors.initials: G
authors.lastname: Giannaccini
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Papini
authors.forename: Elisa
authors.initials: E
authors.lastname: Peroni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Placanica
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
mesh_terms: D004122:Dimethylallyltranstransferase / Q000037:antagonists & inhibitors*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011106:Polyisoprenyl Phosphates / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D004224:Diterpenes; D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; D004122:Dimethylallyltranstransferase; C002963:geranylgeranyl pyrophosphate