S-Farnesyl-Thiopropionic Acid (FTPA) Triazoles as Potent Inhibitors of Isoprenylcysteine Carboxyl Methyltransferase

Abstract

We report the design and synthesis of novel FTPA-triazole compounds as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (Icmt), through a focus on thioether and isoprenoid mimetics. These mimetics were coupled utilizing a copper-assisted cycloaddition to assemble the potential inhibitors. Using the resulting triazole from the coupling as an isoprenyl mimetic resulted in the biphenyl substituted FTPA triazole 10n. This lipid-modified analog is a potent inhibitor of Icmt (IC(50) = 0.8 ± 0.1 μM; calculated K(i) = 0.4 μM).

Scheme 1. Synthesis of Triazole for Sulfur Analogues

Reagents and conditions: (a) Sodium ascorbate, cupric sulfate, ^tBuOH/H₂O, room temperature. (b) LiOH, MeOH; 20–80% over two steps. The number in parentheses indicates Icmt specific activity as percent of AFC control in the presence of 10 μM inhibitor.

Scheme 2. Synthesis of Triazole Substitutions in FTPA

Reagents and conditions: (a) Me₃Al, Cp₂ZrCl₂, (HCO)_n, 0 °C–room temperature, 60%. (b) (i) N-Chlorosuccinimide, Me₂S, DCM, −40 °C–room temperature; (ii) methyl thiopropionate, DIEA, DCM, 0 °C–room temperature, 55% over two steps. (c) NaN₃, DMF, 80 °C, 78%. (d) Sodium ascorbate, cupric sulfate, tBuOH/H₂O, room temperature, 35–97%. (e) LiOH, MeOH, room temperature, 40–90%. The number in parentheses indicates Icmt specific activity as percent of AFC control in the presence of 10 μM inhibitor.

Scheme 3. Triazole Substitutions in FTPA: Use of Biphenyl Alkynes

Reagents and conditions: (a) Sodium ascorbate, cupric sulfate, tBuOH/H₂O, room temperature; 36–78%. (b) LiOH, MeOH, room temperature, 50–96%. The number in parentheses indicates Icmt specific activity as percent AFC control with 10 μM inhibitor.

Figure 1

Mislocalization of GFP-KRas construct upon 10n administration. Jurkat T cells (E 6.1) were treated with vehicle, 25 μM Simvastatin (Sim), or 10n at indicated concentrations for 24 h. Cells were overlaid onto poly-l-lysine-coated coverslips (100 μg/mL), followed by fixation with 3.7% formaldehyde solution for 10 min. Subcellular localization of GFP-KRas was quantified using fluorescence microscopy (Olympus BH-2RFCA).