Stable analogues of geranylgeranyl diphosphate possessing improved geranylgeranyl versus farnesyl protein transferase inhibitory selectivity

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

“…The inhibitory activities of the newly synthesized compounds 4 a,b, 5, and 6, together with those of 1 a,b, 2, and 3, [13] are reported in Table 1 as IC 50 values (concentrations at which GGTase I and FTase activities were inhibited by 50 %).…”

“…Hydrazinolysis of the phthalimido portion afforded free oxyamine 9, which was then subjected to a condensation reaction with the appropriate acid 10 a,b. [13] The diethyl phosphonates thus obtained (11 a,b) were subjected to hydrolysis; treatment with bromotrimethylsilane, 2,4,6-collidine, and aqueous potassium hydroxide, gave compounds 4 a,b as the dipotassium salts.…”

“…The phthalimido derivative 13 thus obtained was subjected to hydrazinolysis to afford free amine 14, which was then condensed with acid 10 b. [13] Final hydrolysis of the diethyl phosphonate 15 afforded the target compound 5 as the dipotassium salt. Compound 6 was prepared as shown in Scheme 3.…”

“…Some of them (1 a,b, 2, and 3, Figure 1) have shown good GGTase inhibitory properties and remarkable GGTase/FTase selectivity levels. [12,13] We subsequently focused our attention on modifying the lipophilic side chain of this class of molecules. In particular, we wanted to observe whether a change in configuration about the C2=C3 double bond of the geranylgeranyl portion could influence the inhibitory activity toward GGTase or FTase.…”

“…The crude residue was triturated with diethyl ether to afford oxyamine 9 as an oil (1.10 g, 3.58 mmol, 89 % yield) that was used for the next step without further purification. 11 a,b: A solution of oxyamine 9 (0.40 g, 1.3 mmol) in anhydrous THF (20 mL) was treated with the appropriate a-substituted phosphonoacetic acid (10 a or 10 b) [13] (1.4 mmol) in the presence of 1-hydroxybenzotriazole (0.27 g, 2.0 mmol) and 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.30 g, 1.6 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. The solvent was then removed under vacuum, and the crude products were purified by silica gel column chromatography by eluting with n-hexane/EtOAc (1:1) to obtain phosphonoacetamidoxy esters 11 a and 11 b.…”