Design, Green Synthesis, and Biological Evaluation of Novel Triaryl‐Tethered Acryloyl Derivatives as New Generation β‐Tubulin Inhibitors for Hepatocellular Carcinoma Treatment

Abstract

ABSTRACT Inhibition of β‐tubulin polymerization has been set as promising therapeutic strategy for cancer therapy. Accordingly, a new set of triaryl‐tethered acetohydrazide‐acryloyl derivatives were designed and synthesized. The antiproliferative influence was evaluated against liver Huh‐7 cell line using MTT colorimetric method with Doxorubicin as a positive control. Compounds 3b , 4f , 4i, and 4j showed excellent cytotoxic activity against Huh‐7 cell line. Among the investigated compounds, 2‐(naphthalene‐2‐yloxy)acetohydrazide having 2‐(4‐methyl)‐3‐(3,4,5‐trimethoxybenzamido)acryloyl moiety (compound 4i ) was the most active one with an IC 50 value of 2.46 µM. In addition, all compounds were further evaluated in vitro for their β‐tubulin polymerization inhibition activity. Results found that compound 4i showed high activity against β‐tubulin polymerization with an IC 50 value of 2.29 µM, surpassing the activity of the reference Podophyllotoxin (IC 50 = 4.45 µM). Further studies revealed the ability of the promising compound 4i to induce apoptosis and halt the cellular cycle at G2/M phase. Furthermore, the apoptosis‐inducing activity of naphthalene‐tethered acryloyl moiety 4i was correlated to the downregulation of Bcl‐2 as well as elevation of both Bax and c aspase 9 as concluded from RT‐PCR immunoassay measurements. Finally, molecular docking studies were also performed to explain the displayed inhibitory activities.