ABSTRACT
Based on the efficacy of EHop-016 as an inhibitor of migration and Rac1 activation, a new series of carbazole derivatives has been synthesized. Cytotoxic and anti-migratory effects of these compounds were evaluated in MCF-7 and MDA-MB-231 breast cancer cell lines. Preliminary investigations of their anticancer activity demonstrated that several compounds have moderate antiproliferative effects on cancer cell lines with GI50 values in the range of 13-50⯵M. Furthermore, compounds 3b and 11b inhibit migration activity of metastatic cell line MDA-MB-231 by 32% and 34%, respectively. Compound 11b was shown to inhibit activation of the Rho GTPase Rac1 by 55% at 250â¯nM in both MDA-MB-231 and MDA-MB-435 cell lines. Compared with the IC50 of Rac1 inhibition by lead compound EHop-016 of 1.1⯵M, compound 11b demonstrates 4X improved in vitro efficacy.
Subject(s)
Antineoplastic Agents/chemical synthesis , Carbazoles/chemistry , Drug Design , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Carbazoles/metabolism , Carbazoles/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , MCF-7 Cells , Molecular Docking Simulation , Protein Structure, Tertiary , Structure-Activity Relationship , rac1 GTP-Binding Protein/chemistry , rac1 GTP-Binding Protein/metabolismABSTRACT
Scaffolds composed of a mixture of poly (L-lactic) acid (PLLA) and polyethylene glycol (PEG) biodegradable polymers were prepared by electrospinning. Three-dimensional scaffolds of highly porous non-woven fibers were produced for biomedical applications and coated with calcium phosphate for bone tissue engineering. A mixture (80/20) of PLLA/PEG was dissolved at 5.7%, 7%, 8% and 9% blend solution concentrations. The structure and morphology of the scaffolds were investigated by scanning electron microscopy. Average fiber diameters ranging from 600 nm to 800 nm were obtained as result of the change in viscosity. The low polymer concentration fibers were found to be flat with fused junctions between fibers. For high polymer concentrations fibers they were cylindrical with fibers overlaying each other. For samples deposited at 9% concentration, individual fibers contained pores on their surface with nanometric dimensions. In addition, thin films of calcium deficient hydroxyapatite were prepared by rf magnetron sputtering on silicon substrates heated to temperatures between 300-6000C. These results suggest that it is feasible to fabricate biopolymer scaffolds using methods combining electrospinning and sputtering techniques.
