Synthesis of a New Phenyl Chlormethine-Quinazoline Derivative, a Potential Anti-Cancer Agent, Induced Apoptosis in Hepatocellular Carcinoma Through Mediating Sirt1/Caspase 3 Signaling Pathway

Abstract

Quinazoline derivatives display multiple pharmacological activities and target various biological receptors. Based on the skeleton of quinazoline core, we designed and synthesized three new quinazoline-phenyl chlormethine conjugates (I-III) bearing a Schiff base (C = N) linker, and investigated their anti-tumor effects on HepG2-xenografted tumor and human cancer cell line HepG2. Among these compounds, compound II showed better inhibitory effect against HepG2 cells. In the present study, TUNEL staining, western blot, molecular docking, and siRNA were used to investigate the inhibitory mechanism of compound II towards hepatoma. Compound II inhibited HepG2-xenografted tumor growth in nude mice. Moreover, Compound II not only up-regulated Bax/Bcl-2 ratio and active-caspase 3 level, but also down-regulated Sirt1 expression and its activity, as well as PGC-1a expression. Furthermore, compound II also significantly suppressed the promotion of HepG2 cell proliferation, as evidenced by MTT assay and lactate dehydrogenase (LDH) release assay. Of note, the cytotoxicity of Compound II on HepG2 cells mainly via regulating Sirt1/caspase 3 signaling pathway, consisting with the results in vivo. Intriguingly, z-DEVD-FMK, a caspase 3 inhibitor, almost abolished the inhibitory effects of compound II. Of note, knockdown of caspase 3 by siRNA significantly reversed the inhibitory effect of compound II on HepG2. Interestingly, compound II directly bonded to Sirt1, indicating that Sirt1 might be a promising therapeutic target of compound II. In summary, our findings reveal that compound II, a new synthetical phenyl chlormethine-quinazoline derivative, contributes to the apoptosis of HepG2 cells both in vivo and in vitro through mediating Sirt1/caspase 3 singling pathway. These findings demonstrate that compound II may be a new potent agent against hepatocellular carcinoma.

a Versatile Schiff Base Chemosensor for the Determination of Trace Co2+, Ni2+, Cu2+, and Zn2+ in the Water and Its Bioimaging Applications

“…To apply the chemosensor L in living cells for the fluorescence imaging detection of Zn 2+ , we first tested the cytotoxicity of L against HepG2 cells using the MTT assay . The results showed that L had a low cell inhibitory rate (Figure S48) and could be used as a biocompatible probe for the cellular imaging of Zn 2+ .…”

Caspase‐3: A primary target for natural and synthetic compounds for cancer therapy

“…Many caspase‐3 activation‐mediated apoptosis inducers for potential cytotoxicity have been reported till date (Jain et al., 2012, 2013, 2019; Jain, Pattnaik, et al., 2017; Kumar et al., 2021; Lv et al., 2020; Vaidya et al., 2020a, 2020b; Vaidya, Pathak, et al., 2020). Numerous SAR and QSAR studies were reported in favor to search of these compounds (Mansouri et al., 2020; Jain, Vaidya, et al., 2017; Şenkardeş et al., 2021; Vaidya et al., 2014).…”

Epigenetics of Sirtuins: Relevance to Hepatocellular Carcinoma

“…In addition, potential quinazoline derivatives, as tumor-targeting drugs, target multiple receptors. A previous study has demonstrated that a newly synthesized phenylchloromethine-quinazoline derivative with SIRT1 as its target effectively promotes the apoptosis of hepatocellular carcinoma in vivo and in vitro [111].…”