Discovery and SAR of methylated tetrahydropyranyl derivatives as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT).

A series of tetrahydropyranyl (THP) derivatives has been developed as potent inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT) for use as anticancer agents. Structural modification of the submicromolar hit compound 3 led to the potent 3-methoxy substituted analogue 27. Further SAR development around the THP ring resulted in an additional 10-fold increase in potency, exemplified by analogue 75 with an IC(50) of 1.3 nM. Active and potent compounds demonstrated a dose-dependent increase in Ras cytosolic protein. Potent ICMT inhibitors also reduced cell viability in several cancer cell lines with growth inhibition (GI(50)) values ranging from 0.3 to >100 µM. However, none of the cellular effects observed using ICMT inhibitors were as pronounced as those resulting from a farnesyltransferase inhibitor.

Open, microfluidic flow cell for studies of interfacial processes at gas-liquid interfaces.

Interfacial processes involving peripheral proteins depend on the composition and packing density of the interfacial lipid molecules. As a biological membrane model, lipid monolayers at the gas-liquid interface allow independent control of these parameters. However, measuring protein adsorption to monolayers has been difficult. To aid in this and other studies of the interfacial processes, we have developed an open, microfluidic flow cell with which surface physical properties can be controlled and monitored in well-defined lipid monolayers while varying aqueous-phase composition. Using this apparatus, we implement a recently described fluorescence method (Momsen, W. E.; Mizuno, N. K.; Lowe, M. E.; Brockman, H. L. Anal. Biochem. 2005, 346, 139-49) to characterize the adsorption/desorption of glucagon to 1,2-dioleoyl-sn-glycerol monolayers at 27 mN/m. Analysis of the data gives reasonable and self-consistent results for kinetic and thermodynamic constants. Varying the packing density of 1,2-dioleoyl-sn-glycerol does not alter the extent of glucagon adsorption, but comparable measurements with 1-steaoryl-2-oleoyl-sn-glycero-3-phosphocholine show a critical dependence. Because it allows a high degree of control of both lipid monolayer properties and aqueous-phase composition, this microfluidic flow cell should find wide applicability in many areas of research into interfacial processes.

Aqueous solubilization of highly fluorinated molecules by semifluorinated surfactants.

The physical and chemical properties of organic compounds are deeply affected by the introduction of fluorinated substituents. Perfluorinated and highly fluorinated organic molecules are both hydrophobic and lipophobic. This makes the recognition and the binding of fluorinated molecules extremely difficult to achieve through classical elements of molecular recognition. Here we show that semifluorinated water-soluble block copolymers can generate micellar structures having a fluorous phase-based inner core in aqueous solution. Furthermore, we show that these micelles can be used to encapsulate and bind highly fluorinated molecules through association in the internal fluorous phase (fluorophobic effect). We report that semifluorinated block copolymers can be used for the aqueous solubilization of the widely diffused gaseous anesthetic sevoflurane, thereby suggesting the possibility of the intravenous delivery of this commonly used anesthetic.