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Antiangiogenic Activity of N-substituted and Tetrafluorinated Thalidomide Analogues

Molecular Pharmacology Section, Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892 [S. S. W. N., E. A. K., W. D. F.]; Pharmaceutical Institute, Poppelsdorf, University of Bonn, Bonn, Germany [M. G.]; Institute of Pharmacy, Pharmaceutical Chemistry [M. W., U. T., T. K. H., K. E.] and Institute of Zoology, Department of Immunobiology [S. H.], University of Leipzig, Leipzig, Germany; and Department of Chemistry, University of Louisville, Louisville, Kentucky [F. A. L.]

Inhibition of angiogenesis is currently perceived as one of the promising strategies in the treatment of cancer. The antiangiogenic property of thalidomide has inspired a second wave of research on this teratogenic drug. Previous studies from our group and others demonstrated that metabolites of thalidomide are responsible for the drug’s pharmacological actions. On the basis of the structures of these metabolites, we synthesized 118 thalidomide analogues. Preliminary screening selected 7 of these 118 analogues for more extensive testing in the current study. In the rat aortic ring assay, all 4 analogues in the N-substituted class and 2 of the 3 analogues in the tetrafluorinated class significantly inhibited microvessel outgrowth at 12.5–200 µM. Thalidomide failed to block angiogenesis at similar concentrations. Subsequently, the effects of these analogues on human umbilical vein endothelial cell proliferation and tube formation were determined. Those analogues showing antiangiogenicity in the rat aortic ring assay also demonstrated antiproliferative action in human umbilical vein endothelial cells. Cell proliferation was not affected by thalidomide. Interestingly, all 7 analogues as well as thalidomide suppressed tube formation. Two tetrafluorinated analogues consistently showed the highest potency and efficacy in all three assays. The in vivo toxicity of representative analogues from each class was also evaluated. Taken together, our results support the further development and evaluation of novel thalidomide analogues as antiangiogenic agents.

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