Title

Small-molecule inhibitors of cell migration and their molecular targets

Date of Completion

January 2009

Keywords

Chemistry, Biochemistry|Chemistry, Organic

Degree

Ph.D.

Abstract

A range of normal and disease processes are dependent on the movement of cells. Some of these processes include tissue repair, organismal development, immune function and inflammation, blood vessel formation, and cancer cell invasion and metastasis. We have discovered a large number of small-molecule inhibitors of cell migration of varying potency in a high-throughput screen for modulators of cell movement. Among the more potent compounds we have identified are NSC 295642, a Cu(II) complex of the Schiff base product of condensation of S-benzyl dithiocarbazate and 2-acetylpyridine, and locostatin, a 3,4-disubstituted oxazolidinone. We prepared a number of analogs of NSC 295642, which has cell-selective, nanomolar anti-migratory activity, varying both the ligand structure and the chelated metal. We found that the S-benzyl groups for the bioactive Cu(II) and Zn(II) complexes are oriented transoid relative to the central metal-coordinated rings, while the conformation is cisoid in the inactive Ni(II) complex. Investigating the biological function of Raf kinase inhibitor protein (RKIP), the target of locostatin, we found that it positively regulates cell adhesion to substratum while negatively regulating adhesion of cells to one another. We also found that RKIP suppresses metastasis of several cancer cell lines through downregulation of matrix metalloproteinases. ^