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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
Author(s) -
Minutolo Filippo,
Bertini Simone,
Betti Laura,
Danesi Romano,
Gervasi Gianbattista,
Giannaccini Gino,
Martinelli Adriano,
Papini Anna Maria,
Peroni Elisa,
Placanica Giorgio,
Rapposelli Simona,
Tuccinardi Tiziano,
Macchia Marco
Publication year - 2006
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200500010
Subject(s) - prenylation , chemistry , stereochemistry , docking (animal) , side chain , derivative (finance) , biochemistry , enzyme , organic chemistry , financial economics , economics , medicine , nursing , polymer
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stable analogues of geranylgeranyl diphosphate (GGPP), in which the “natural” all‐trans geranylgeranyl portion has been replaced by a (Z,E,E)‐geranylgeranyl chain.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 C2C3 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.