ABSTRACT
Respiratory failure due to pulmonary metastasis is the major cause of death for patients with osteosarcoma. However, the molecular basis for metastasis of osteosarcoma is poorly understood. Recently, ezrin, a member of the ERM family of proteins, has been associated with osteosarcoma metastasis to the lungs. The small molecule NSC 668394 was identified to bind to ezrin, inhibit in vitro and in vivo cell migration, invasion, and metastatic colony survival. Reported herein are the design and synthesis of analogues of NSC 668394, and subsequent functional ezrin inhibition studies. The binding affinity was characterized by surface plasmon resonance technique. Cell migration and invasion activity was determined by electrical cell impedance methodology. Optimization of a series of heterocyclic-dione analogues led to the discovery of compounds 21k and 21m as potential novel antimetastatic agents.
Subject(s)
Antineoplastic Agents/chemical synthesis , Cytoskeletal Proteins/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bone Neoplasms/metabolism , Bone Neoplasms/pathology , Cell Line, Tumor , Cell Movement , Cytoskeletal Proteins/antagonists & inhibitors , Drug Design , Humans , Osteosarcoma/metabolism , Osteosarcoma/pathologyABSTRACT
A series of pyridine complexes are prepared of the general form TpW(NO)(PMe3)(pyr) where pyr is either pyridine or a substituted pyridine. Depending on substitution pattern, the pyridine can be either N- or eta2-coordinated, and the role of the pyridine substituents and metal oxidation state in determining this equilibrium is explored. For eta2-pyridine complexes, the substituent pattern and solubility characteristics also determine the ratio of coordination diastereomers. Rates of both intra- and interfacial linkage isomerizations are explored along with the pyridine rotational barrier. This study is supported by DFT calculations and X-ray data and includes characterization of both eta2-pyridine and eta2-pyridinium complexes.