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.
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stable analogues of geranylgeranyl diphosphate (GGPP), in which the "natural" all-trans geranylgeranyl portion has been replaced by a (Z,E,E)-geranylgeranyl chain.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.
Minutolo
Filippo
F
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Bertini
Simone
S
Betti
Laura
L
Danesi
Romano
R
Gervasi
Gianbattista
G
Giannaccini
Gino
G
Martinelli
Adriano
A
Papini
Anna Maria
AM
Peroni
Elisa
E
Placanica
Giorgio
G
Rapposelli
Simona
S
Tuccinardi
Tiziano
T
Macchia
Marco
M
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
D004224:Diterpenes; D004791:Enzyme Inhibitors; D011106:Polyisoprenyl Phosphates; D004122:Dimethylallyltranstransferase; C002963:geranylgeranyl pyrophosphate