Adamantyl-tethered-biphenylic compounds induce apoptosis in cancer cells by targeting Bcl homologs

Abstract

Bcl homologs prominently contribute to apoptotic resistance in cancer cells and serve as molecular targets in treatment of various cancers. Herein, we report the synthesis of biphenyl-adamantane derivatives by a ligand free palladium on carbon based Suzuki reaction using diisopropylamine as a base for the coupling of adamantane based aryl chloride with a variety of aryl boronic acids. Among the biphenyl derivatives synthesized, compound 3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-3-ol (AMB) displayed cytotoxic activity against hepatocellular carcinoma cell lines without significantly affecting the normal cell lines. Further, AMB caused increased accumulation of the HCC cells in subG1 phase, decreased the expression of Bcl-2, Bcl-xL, cyclin D1, caspase-3, survivin and increased the cleavage of PARP in a time-dependent manner. In silico molecular interaction studies between Bcl homologs and AMB showed that the biphenyl scaffold is predicted to form π-π interactions with Phe-101 and Tyr-105 and the adamantyl fragment is predicted to occupy another hydrophobic region in the kink region of the binding groove. In summary, we report on the synthesis and biological characterization of adamantyl-tethered biphenylic compounds that induce apoptosis in tumor cells most likely by targeting Bcl homologs.

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

“…Furthermore, ACHP treatment suppressed the IL-6 induced activation of these cascades of proteins in H1299 cells. Activation of executioner caspase (caspase 3/7) is the major biochemical event associated with the cells committed to apoptosis [91], and the activated caspase-3 cleaves PARP to induce apoptosis [54,92].…”

“…The three-dimensional structure of ligands (ACHP and HAB) were produced and docked towards the SH2 domain of STAT3 using the LIGANDFIT protocol. The interaction map and binding position of ACHP and HAB were evaluated using the interaction score function in the Ligand Fit module of Discovery Studio as reported previously [54].…”

Synthesis and Bioactivity of Thiosemicarbazones Containing Adamantane Skeletons

“…Since the first adamantane derivative, amantadine, was found to have antiviral [21][22][23] activity, the synthesis and biological activities of adamantane derivatives, which became an interesting topic, were pursued by a lot of researchers. Therefore, many adamantane derivatives were discovered with various biological activities, i.e., antiviral [24][25][26][27][28][29], antimicrobial [27,[29][30][31][32][33][34][35][36][37][38][39], anticancer [32,36,[40][41][42][43][44] activities.…”

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

“…[25] Considering these drawbacks, we used environmentally benign conditions such as water as solvent and tetrabutylammonium bromide (TBAB) as a mild watersoluble catalyst for the synthesis of triazolo-pyridine dicarbonitriles and dihydropyridine carbonitriles. In our effort to explore the pharmacological properties of synthetic small molecules, [26][27][28][29][30] new spiro [1,2,4]triazolo[1,5-a]pyridine dicarbonitriles were synthesized and evaluated for their possible cytotoxic effect towards lung cancer cells and PDE4 inhibitory activity.…”