SILICA RESEARCH

J Med Chem. 2001 Mar 1;44(5):834-48.

Syntheses and biological activities of a novel group of steroidal derived inhibitors for human Cdc25A protein phosphatase.

Peng H, Xie W, Otterness DM, Cogswell JP, McConnell RT, Carter HL, Powis G, Abraham RT, Zalkow LH.

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.

Silica gel supported pyrolysis of an azido-homo-oxa steroid led to rearrangement, presumably by a mechanism similar to that of solution phase Schmidt fragmentation, to produce a group of novel inhibitors for the oncogenic cell cycle regulator Cdc25A phosphatase. Cyano-containing acid 17, one of the best inhibitors in this group, inhibited the activity of Cdc25A protein phosphatase reversibly and noncompetitively with an IC(50) value of 2.2 microM. Structure-activity relationships revealed that a phosphate surrogate such as a carboxyl or a xanthate group is required for inhibitory activity, and a hydrophobic alkyl chain, such as the cholesteryl side chain, contributes greatly to the potency. Without the cyano group, acid 26 and xanthate 27 were found to be more selective over Cdc25A (IC(50) = 5.1 microM and 1.1 microM, respectively) than toward CD45 (IC(50) > 100 microM, in each case), a receptor protein tyrosine phosphatase. Several of these inhibitors showed antiproliferative activities in the NCI 60-human tumor cell line screen. These steroidal derived Cdc25 inhibitors provide unique leads for the development of dual-specificity protein phosphatase inhibitors.

J Colloid Interface Sci. 2003 Jul 15;263(2):441-8.

Localized changes in the structural stability of myoglobin upon adsorption onto silica particles, as studied with hydrogen/deuterium exchange mass spectrometry.

Buijs J, Ramstrom M, Danfelter M, Larsericsdotter H, Hakansson P, Oscarsson S.

Division of Ion Physics, Angstrom Laboratory, Uppsala University, Box 534, 75121, Uppsala, Sweden. jos.buijs@biacore.com

A new method is presented for monitoring the conformational stability of various parts of a protein that is physically adsorbed onto nanometer-sized silica particles. The method employs hydrogen/deuterium (H/D) exchange of amide hydrogens, a process that is extremely sensitive to structural features of proteins. The resulting mass increase is analyzed with Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Higher structural specificity is obtained by enzymatically cleaving the adsorbed proteins prior to mass spectrometric analysis. The mass increases of four peptic fragments of myoglobin are followed as a function of the H/D exchange time. The four peptic fragments cover 90% of the myoglobin structure. Two of the peptic fragments, located in the middle of the myoglobin sequence and close to the heme group, do not show any adsorption-induced changes in their structural stability, whereas the more stable C- and N-terminal fragments are destabilized. Interestingly, for the N-terminal fragment, comprising residues 1-29, two distinct and equally large conformational populations are observed. One of these populations has a stability similar to that in solution (-23 kJ/mol), whereas the other population is highly destabilized upon adsorption (-11 kJ/mol).