title: 1,1-Diarylalkenes as anticancer agents: dual inhibitors of tubulin polymerization and phosphodiesterase 4.
abstract: 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). 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 20 mg/kg qd.
authors.affiliation: Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. aruchelman@celgene.com
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Ruchelman
authors.forename: Hon-Wah
authors.initials: HW
authors.lastname: Man
authors.forename: Roger
authors.initials: R
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Dorota
authors.initials: D
authors.lastname: Cedzik
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Jim
authors.initials: J
authors.lastname: Leisten
authors.forename: Alice
authors.initials: A
authors.lastname: Collette
authors.forename: Rama Krishna
authors.initials: RK
authors.lastname: Narla
authors.forename: Heather K
authors.initials: HK
authors.lastname: Raymon
authors.forename: George W
authors.initials: GW
authors.lastname: Muller
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000475:Alkenes; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D010726:Phosphodiesterase Inhibitors; D014404:Tubulin; D050257:Tubulin Modulators; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4