<p>Novel HDAC/Tubulin Dual Inhibitor: Design, Synthesis and Docking Studies of α-Phthalimido-Chalcone Hybrids as Potential Anticancer Agents with Apoptosis-Inducing Activity</p>

Abstract

Introduction: In order to develop novel anticancer HDAC/tubulin dual inhibitors, a novel series of α-phthalimido-substituted chalcones-based hybrids was synthesized and characterized by IR, 1 H NMR, 13 C NMR, mass spectroscopy and X-ray analysis. Methods: All the synthesized compounds were evaluated for their in vitro anticancer activity against MCF-7 and HepG2 human cancer cell lines using MTT assay. To explore the mechanism of action of the synthesized compounds, in vitro β-tubulin polymerization and HDAC 1 and 2 inhibitory activity were measured for the most potent anticancer hybrids. Further, cell cycle analysis was also evaluated. Results: The trimethoxy derivative 7j showed the most potent anticancer activity, possessed the most potent β-tubulin polymerase and HDAC 1 and 2 inhibitory activity and efficiently induced cell cycle arrest at both G2/M and preG1phases in the MCF-7 cell line. Keywords: chalcones, α-phthalimido, anticancer, cell cycle, histone deacetylase inhibitor, tubulin polymerase inhibitor-Cell cycle analysis was done for the most active compounds and it was clear that the tested compounds successfully arrested cell cycle at G2/M phase and induced preG1 apoptosis compared to the reference compounds.-Molecular docking studies were carried out to explore the binding pattern of the most active synthesized compounds toward colchicine binding site in tubulin protein and HDAC2 active site.

Chalcone Derivatives: Role in Anticancer Therapy

“…Chalcones have been shown to exhibit anticancer activity through their inhibitory potential against various targets, such as 5α-reductase [ 187 ], aromatase [ 188 ], histone deacetylase inhibitors (HDAC) [ 189 , 190 ], proteasome [ 191 , 192 ], JAK/STAT signaling pathways [ 193 ], cell division cycle 25 (CD25) [ 194 ], cathepsin-K [ 72 , 195 ], topoisomerase-II [ 196 , 197 ], Wnt [ 198 , 199 ], ROS/MAPK [ 200 ], p38 [ 201 , 202 ] and mTOR [ 203 , 204 ]. However, these studies are not covered in this review because not enough evidence has been provided to indicate that these proteins or pathways are direct targets of chalcones.…”

Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents

“…It has been reported that the combination of SAHA and vincristine (a tubulin inhibitor) could achieve synergistic effects in leukemia, which provides a theoretical basis for designing dual tubulin/HDAC inhibitors. Several groups have reported the discovery of novel tubulin/HDAC dual inhibitors in recent years. ,− For instance, Diana and co-workers designed dual tubulin/HDAC inhibitors that demonstrated potent anticancer activities . Despite these advancements, the therapeutic value of dual tubulin/HADC inhibitors (in particular, dual inhibitors with HDAC-isoform-selectivity) remains to be further explored.…”

Identification of novel leads as potent inhibitors of HDAC3 using ligand-based pharmacophore modeling and MD simulation

“…The results of PLIP analysis of training set compounds and simulated hits showed a concrete relationship between the salient chemical features (Hypo 1) present in training set compounds (FDA approved drugs) and molecular interactions observed in simulated hits in complex with HDAC3. The structural information for five drug molecules such as TSA (5EEF, 16), LBH (5EF8, 1), JNJ-26481585 (6HSK, 2), ACY-1215 (5WGL, 1), and SHH (4LXZ, 11) was retrieved from the crystal structures whereas, for NVP-LAQ824, MS-275 and VPA drugs were obtained from the earlier docking studies 58 – 60 . Total 31 co-crystal structures of these five drugs were downloaded from the protein data bank and analyzed for protein–ligand interactions profiles using PLIP online server and DS.…”