Adamantyl-substituted retinoid-derived molecules that interact with the orphan nuclear receptor small heterodimer partner: effects of replacing the 1-adamantyl or hydroxyl group on inhibition of cancer cell growth, induction of cancer cell apoptosis, and inhibition of SRC homology 2 domain-containing protein tyrosine phosphatase-2 activity.

Abstract

(E)-4-[3-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure-anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3'-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.

• Authors: Marcia I Dawson, Zebin Xia, Tao Jiang, Mao Ye, Joseph A Fontana, Lulu Farhana, Bhaumik Patel, Li Ping Xue, Mohammad Bhuiyan, Roberto Pellicciari, Antonio Macchiarulo, Roberto Nuti, Xiao-Kun Zhang, Young-Hoon Han, Lutz Tautz, Peter D Hobbs, Ling Jong, Nahid Waleh, Wan-Ru Chao, Gen-Sheng Feng, Yuhong Pang, Ying Su
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 18 Pg. 5650-62 (Sep 25 2008) ISSN: 1520-4804 [Electronic] United States
• PMID: 18759424 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(3-(1-adamantyl)-4-hydroxyphenyl)-3-chlorocinnamic acid
• Antineoplastic Agents
• Cinnamates
• Enzyme Inhibitors
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Adamantane

Topics

• Adamantane (analogs & derivatives, chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cinnamates (chemistry, pharmacology)
• Dimerization
• Enzyme Inhibitors (chemistry, pharmacology)
• Humans
• Models, Molecular
• Neoplasms (pathology)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors)