1,1-Diarylalkenes as anticancer agents: Dual inhibitors of tubulin polymerization and phosphodiesterase 4

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 21; pp. 6356 - 6374
• Main Authors: Ruchelman, Alexander L., Man, Hon-Wah, Chen, Roger, Liu, Wei, Lu, Ling, Cedzik, Dorota, Zhang, Ling, Leisten, Jim, Collette, Alice, Narla, Rama Krishna, Raymon, Heather K., Muller, George W.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-11-2011; Elsevier
• Subjects: Alkenes - chemical synthesis; Alkenes - chemistry; Alkenes - pharmacology; amino acids; Animals; Anticancer; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitubulin; Benzene Derivatives - chemical synthesis; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Combretastatin A-4 (CA-4); Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism; derivatization; General aspects; HCT-116; HCT116 Cells; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Models, Molecular; Molecular Dynamics Simulation; pharmacology; Pharmacology. Drug treatments; Phosphodiesterase 4 (PDE4); Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; polymerization; solubility; Structure-Activity Relationship; tubulin; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Tumor necrosis factor-α (TNF-α); Antitubulin; HCT-116; Anticancer; Combretastatin A-4 (CA-4); Tumor necrosis factor-α (TNF-α); Phosphodiesterase 4 (PDE4); Antineoplastic agent; Solid tumor; Nitrile; Cytotoxicity; Esterases; Phosphoric diester hydrolases; Modeling; Phosphodiesterase 4 inhibitor; Structure activity relation; 3',5'-Cyclic-AMP phosphodiesterase; Vinylic compound; Molecular model; Colon; Chemical synthesis; Antimitotic; Tumor cell; Tumor necrosis factor α; Human; 3',5'-Cyclic-nucleotide phosphodiesterase; Ether; Enzyme; Aminoamide; Rodentia; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Malignant tumor; In vitro; In vivo; α-Aminoacid; Vertebrata; Chemotherapy; Mammalia; Treatment; Cell line; Mouse; Animal; Hydrolases; 3',5'-cyclic AMP phosphodiesterase; Cancer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.08.068

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 (IC50=54nM) and antitubulin activity (HCT-116 IC50=34nM and tubulin polymerization IC50 ∼1μM). While the nitrile group at the alkene terminus was generally required for potent antiproliferative activity, its replacement was tolerated if there was a hydroxyl or amino group on one of the aryl rings. Conveniently, this group could also serve as a handle for amino acid derivatization to improve the compounds’ solubility. The glycinamide analog 45 showed significant efficacy in the HCT-116 xenograft model, with 64% inhibition of tumor growth upon dosing at 20mg/kg qd.