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

Alexander L Ruchelman; Hon-Wah Man; Roger Chen; Wei Liu; Ling Lu; Dorota Cedzik; Ling Zhang; Jim Leisten; Alice Collette; Rama Krishna Narla; Heather K Raymon; George W Muller

doi:10.1016/j.bmc.2011.08.068

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

Bioorg Med Chem. 2011 Nov 1;19(21):6356-74. doi: 10.1016/j.bmc.2011.08.068. Epub 2011 Sep 5.

Authors

Alexander L Ruchelman¹, Hon-Wah Man, Roger Chen, Wei Liu, Ling Lu, Dorota Cedzik, Ling Zhang, Jim Leisten, Alice Collette, Rama Krishna Narla, Heather K Raymon, George W Muller

Affiliation

¹ Drug Discovery Department, Celgene Corporation, 86 Morris Avenue, Summit, NJ 07901, USA. [email protected]

PMID: 21955454
DOI: 10.1016/j.bmc.2011.08.068

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.

MeSH terms

Alkenes / chemical synthesis
Alkenes / chemistry*
Alkenes / pharmacology*
Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Benzene Derivatives / chemical synthesis
Benzene Derivatives / chemistry*
Benzene Derivatives / pharmacology*
Cell Proliferation / drug effects
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / metabolism
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
HCT116 Cells
Humans
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Mice
Models, Molecular
Molecular Dynamics Simulation
Phosphodiesterase Inhibitors / chemical synthesis
Phosphodiesterase Inhibitors / chemistry*
Phosphodiesterase Inhibitors / pharmacology
Structure-Activity Relationship
Tubulin / metabolism
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry*
Tubulin Modulators / pharmacology

Substances

Alkenes
Antineoplastic Agents
Benzene Derivatives
Phosphodiesterase Inhibitors
Tubulin
Tubulin Modulators
Cyclic Nucleotide Phosphodiesterases, Type 4