An Adamantyl-Substituted Retinoid-Derived Molecule That Inhibits Cancer Cell Growth and Angiogenesis by Inducing Apoptosis and Binds to Small Heterodimer Partner Nuclear Receptor:  Effects of Modifying Its Carboxylate Group on Apoptosis, Proliferation, and Protein-Tyrosine Phosphatase Activity

Abstract

Apoptotic and antiproliferative activities of small heterodimer partner (SHP) nuclear receptor ligand (E)-4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC), which was derived from 6-[3'-(1-adamantyl)-4'-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN), and several carboxyl isosteric or hydrogen bond-accepting analogues were examined. 3-Cl-AHPC continued to be the most effective apoptotic agent, whereas tetrazole, thiazolidine-2,4-dione, methyldinitrile, hydroxamic acid, boronic acid, 2-oxoaldehyde, and ethyl phosphonic acid hydrogen bond-acceptor analogues were inactive or less efficient inducers of KG-1 acute myeloid leukemia and MDA-MB-231 breast, H292 lung, and DU-145 prostate cancer cell apoptosis. Similarly, 3-Cl-AHPC was the most potent inhibitor of cell proliferation. 4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorophenyltetrazole, (2E)-5-{2-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]ethenyl}-1H-tetrazole, 5-{4-[3'-(1-adamantyl)-4'-hydroxyphenyl]-3-chlorobenzylidene}thiazolidine-2,4-dione, and (3E)-4-[3'-(1-adamantyl)-2-chloro-4'-hydroxy-4-biphenyl]-2-oxobut-3-enal were very modest inhibitors of KG-1 proliferation. The other analogues were minimal inhibitors. Fragment-based QSAR analyses relating the polar termini with cancer cell growth inhibition revealed that length and van der Waals electrostatic surface potential were the most influential features on activity. 3-Cl-AHPC and the 3-chlorophenyltetrazole and 3-chlorobenzylidenethiazolidine-2,4-dione analogues were also able to inhibit SHP-2 protein-tyrosine phosphatase, which is elevated in some leukemias. 3-Cl-AHPC at 1.0 microM induced human microvascular endothelial cell apoptosis but did not inhibit cell migration or tube formation.

Synthesis, crystal structure, superoxide scavenging activity, anticancer and docking studies of novel adamantyl nitroxide derivatives

“…The incorporation of an adamantyl moiety into various molecules resulted in compounds with relatively high lipophilicity, which could modify or improve the biological availability [9]. It has been reported that retinoid compounds substituted with adamantyl showed a proapoptotic and antiangiogenesis activity in solid tumors, with an improved pharmacological profile [10]. In addition, the adamantylbased 1,4-hydroquinone was reported as potent tyrosine kinase inhibitor, which was 3-fold more potent at inducing the downregulation of the chronic myelogenous leukemia-specific tyrosine kinase (p210 bcr/abl ) [11].…”

Novel naphthalimide derivatives as potential apoptosis-inducing agents: Design, synthesis and biological evaluation

“…It was recognized that dysfunction of the apoptosis machinery was a hallmark of cancer [12][13][14], and induction of apoptosis was arguably the most potent defense against cancer [5]. Therefore, much attention was paid to the design and discovery of apoptotic inducers during recent years [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], and promising results have been obtained in this way. Compounds 2 [5] and 3 [34] were the representative reported apoptotic inducers (Fig.…”

Insights into the binding mode and mechanism of action of some atypical retinoids as ligands of the small heterodimer partner (SHP)

“…Thus, the combination of these studies gives rise to an intriguing scenario where small molecules oppositely regulate SHP functions. In line with these observations, further studies by Dawson and coworkers reported the importance of the carboxylic moiety of 1 and 2 for the apoptotic activity and, more recently, an interaction model of these compounds at the proposed ligand binding site of SHP has been suggested, though pending for further experimental appraisals [31, 32]. …”