Heteroatom-Substituted Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid

Abstract

(E)-4-[3'-(1-Adamantyl)-4'-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell cycle arrest and apoptosis of cancer cells. Because its pharmacologic properties-solubility, bioavailability, and toxicity-required improvement for translation, structural modifications were made by introducing nitrogen atoms into the cinnamyl ring and replacing its E-double bond with XCH(2) (X = O, N, and S) with the objective of enhancing these properties without impacting apoptosis-inducing activity. Analogues having nitrogen atoms in heterocyclic rings corresponding to the cinnamyl phenyl ring displayed equal or higher biological activities. The pyrimidine and pyridine analogues were more soluble in both phosphate-buffered saline and water. While the 2,5-disubstituted pyridine analogue was the most potent inducer of KG-1 acute myeloid leukemia cell apoptosis, on the basis of apoptotic activity in KG-1 cells and solubility, the 2,5-disubstituted pyrimidine proved to be the more promising candidate for treatment of acute myeloid leukemia.

Diastereoselective Multicomponent Reaction in Water: Synthesis of 2-Azapyrrolizidine Alkaloid Analogues

“…Plants containing pyrrolizidine alkaloids are being used as important herbs in traditional chinese medicine which is popular in China and widely accepted the world over (Figure ). Substituting one or more ring carbons with heteroatoms is known to significantly modify biological properties …”

Analogues of Orphan Nuclear Receptor Small Heterodimer Partner Ligand and Apoptosis Inducer (E)-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic Acid. 2. Impact of 3-Chloro Group Replacement on Inhibition of Proliferation and Induction of Apoptosis of Leukemia and Cancer Cell Lines

“…The general route to the 3-substituted analogues of 8 involved constructing a series of ( E )-cinnamate intermediates by a Mizoroki–Heck vinyl–aryl coupling of 3,4-disubstituted phenyl halides with ethyl acrylate or by a Wittig reaction , on 3,4-disubstituted benzaldehydes. After suitable functionalization followed by the Suzuki–Miyaura diaryl coupling, suitably-functionalized cinnamates with 3-(1-adamantyl)-4-benzyloxyphenylboronic acid ( 34 ) were used to introduce the central diaryl bond (Schemes and ).…”

“…GST-bound SHP was expressed and purified as described previously . One-dimensional 1 H NMR spectra were recorded with 128 transients and a sweep width of 12376 Hz using a Bruker Avance 600 MHz NMR spectrometer equipped with a TCI cryoprobe so that the sample temperature was maintained at 11 °C.…”

“…Docking of analogues to the SHP homology model 6 derived from the USP LBD− phospholipid complex structure (PDB entry 1G2N) using BioMed Cache version 6.2 (Fujitsu Ltd., Beaverton, OR) was assessed as we previously described. 15 The binding pocket site was derived by selecting all neighboring residues within 4 Å (radius) of the USP ligand 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine, which had been docked to the SHP model. 6 Both the ligand and side chains of pocket residues were allowed to be flexible during the docking process.…”

Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective

“…This ligand-dependent activation was shown to repress certain CYP enzymes involved in bile acid regulation. Additional studies are also exposing further potential synthetic ligands that could be utilized to modulate SHP activity and its repressive functions (Xia et al, 2011, 2012). …”