Introduction: CC-5079, a small molecule inhibitor of tubulin polymerization and phosphodiesterase-4 activity, was evaluated for antiangiogenic and antitumor activities.
Materials And Methods: First, CC-5079 in vitro activity on human umbilical vein endothelial cells (HUVECs), fibroblasts, and MC38 were evaluated by proliferation, migration, and invasion assays. Second, CC-5079 effect on microvessel formation was evaluated ex vivo by chick chorioallantoic membrane (CAM), rat aortic rings assays, and with directed in vivo angiogenesis assay (DIVAA). Third, CC-5079 antitumor effect was determined in treatment of C57BL/6 mice with MC38 tumors. Finally, CC-5079 modulation of MKP1 in HUVECs, human fibroblast, and MC38 were determined by RNA isolation for qRT-PCR.
Results: At the 0.1 μM concentration CC-5079 significantly inhibited HUVEC, fibroblast, and MC38 proliferation and migration (all P < 0.001). At the 0.1 μM concentration, CC-5079 also inhibited HUVEC invasion (P < 0.05) but not fibroblast. In the CAM and rat aortic ring assays, CC-5079 at 0.1 μM inhibited microvessel formation (P < 0.05). By DIVAA, CC-5079 at 1 mg/kg/d continuous delivered inhibited microvessel formation (P < 0.05). Intraperitoneal CC-5079 was well tolerated and inhibited the growth of subcutaneous MC38 at 100 mg/kg/d (P < 0.01). By qRT-PCR, CC-5079 stimulated MKP1 expression in HUVEC and fibroblast.
Conclusion: CC-5079 demonstrated stimulation of MKP1, antiangiogenic, and antitumor properties.
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http://dx.doi.org/10.1016/j.jss.2009.01.031 | DOI Listing |
ChemSusChem
July 2022
Beijing Key Laboratory of Lignocellulosic Chemistry, Beijing Forestry University, Beijing, 100083, P. R. China.
Catechyl lignin (C-lignin) is a naturally occurring linear homogeneous biopolymer composed solely of caffeyl alcohol subunits with cleavable benzodioxane linkages. The inherent structural features of propenylcatechol, a direct depolymerized product of castor seed coats C-lignin, render it a sustainable and promising platform for the synthesis of bioactive molecules. Herein, diversified transformations of propenylcatechol, including C=C bond difunctionalization, β-modification, β,γ-rearrangement, and γ-methyl derivatization, were reported based on known or developed methods.
View Article and Find Full Text PDFBioorg Med Chem
November 2011
Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA.
A series of 1,1-diarylalkene derivatives were prepared to optimize the properties of CC-5079 (1), a dual inhibitor of tubulin polymerization and phosphodiesterase 4 (PDE4). By using the 3-ethoxy-4-methoxyphenyl PDE4 pharmacophore as one of the aromatic rings, a significant improvement in PDE4 inhibition was achieved. Compound 28 was identified as a dual inhibitor with potent PDE4 (IC(50)=54 nM) and antitubulin activity (HCT-116 IC(50)=34 nM and tubulin polymerization IC(50) ∼1 μM).
View Article and Find Full Text PDFJ Surg Res
November 2010
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Introduction: CC-5079, a small molecule inhibitor of tubulin polymerization and phosphodiesterase-4 activity, was evaluated for antiangiogenic and antitumor activities.
Materials And Methods: First, CC-5079 in vitro activity on human umbilical vein endothelial cells (HUVECs), fibroblasts, and MC38 were evaluated by proliferation, migration, and invasion assays. Second, CC-5079 effect on microvessel formation was evaluated ex vivo by chick chorioallantoic membrane (CAM), rat aortic rings assays, and with directed in vivo angiogenesis assay (DIVAA).
Bioorg Med Chem Lett
January 2008
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, and Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
Cancer Res
January 2006
Division of Immunotherapeutics, Celgene Corp., 86 Morris Avenue, Summit, NJ 07901, USA.
We have found that the synthetic compound CC-5079 potently inhibits cancer cell growth in vitro and in vivo by a novel combination of molecular mechanisms. CC-5079 inhibits proliferation of cancer cell lines from various organs and tissues at nanomolar concentrations. Its IC(50) value ranges from 4.
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