1,1-Diarylalkenes as anticancer agents: dual inhibitors of tubulin polymerization and phosphodiesterase 4 |
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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 |
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Institution: | Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. aruchelman@celgene.com |
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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. |
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