Sinomenine Derivatives: Synthesis, Antitumor Activity, and Apoptotic Induction in MCF‐7 Cells via IL‐6/PI3K/Akt/NF‐κB Signaling Pathway

Abstract

Natural products have been widely considered as an important resource for new drugs or lead compounds. Sinomenine (SIN) and its derivatives exert antitumor activity via regulation of inflammatory mediators. For these reasons we synthesized three series of SIN derivatives (compounds 4 a-i, 7 a-c and 11 a-c) as antitumor agents from this natural product. All compounds were prepared by modification at the C1 and C4 positions of the A ring, the C4 position of the A ring, and the C6 and C7 positions of the C ring, respectively. All the derivatives were subjected to in vitro antitumor activity against HeLa, A549, HepG-2, MCF-7 and HT-29 cell lines. To observe the apoptotic induction of SIN derivatives and its mechanism, fluorescent staining and western blot assays were carried out for active compound against MCF-7. Based on the screening results, most of the SIN derivatives showed better antitumor activity than SIN. Some of them were found to possess broad-spectrum antitumor activity. Most notably, 11 c exhibited obvious antitumor activity in both cell lines with IC 50 values less than 11 μM. Besides, 11 c induced apoptosis of MCF-7 in a dose-dependent manner. Western blot assay demonstrated that 11 c inhibited IL-6-mediated activation of PI3K/Akt pathway. A docking study revealed that 11 c had stronger binding interaction with the residues of IL-6 than SIN. All these results indicate that 11 c may be a potential anti-breast cancer agent by directly targeting IL-6.

Chanling Gao suppresses colorectal cancer via PI3K/Akt/mTOR pathway modulation and enhances quality of survival

“…We observed CRC metastasis, considering that IL-6 and IL-10 may increase tumor metastasis by regulating the PI3K/Akt/mTOR signaling pathway. 39,40 The left lobe of the liver of nude mice undergoing liver metastasis was taken uniformly, and the number of liver metastatic foci in each group was counted using a stereoscope. When compared to the model group, the number of metastatic foci was significantly reduced in the CLGH and capecitabine groups.…”

Bioactivities and Mechanisms of Action of Sinomenine and Its Derivatives: A Comprehensive Review

“…7, and HT-29) [68]. In the same year, X. Gao et al found that the SIN derivative 7Cc (11) exhibited anti-breast cancer potency with IC50 values of 1.75 and 0.82 μM against MCF-7 and MDA-MB-231, respectively, and the second-highest cytotoxicity against A549 (IC50 = 1.94 μM).…”

“…A year later, Q.Z. Hu and others discovered that SIN derivatives 11c (10) displayed pronounced cytotoxicity through the IL-6/PI3K/Akt and NF-κB signaling pathways, with IC 50 values of 3.76-10.26 µM against cancer cells (HeLa, A549, HepG-2, MCF-7, and HT-29) [68]. In the same year, X. Gao et al found that the SIN derivative 7Cc (11) exhibited anti-breast cancer potency with IC 50 values of 1.75 and 0.82 µM against MCF-7 and MDA-MB-231, respectively, and the second-highest cytotoxicity against A549 (IC 50 = 1.94 µM).…”

The anti-tumor potential of sinomenine: a narrative review

“…However, sinomenine has the disadvantages of unstable physicochemical properties, poor water solubility, short half-life and low bioavailability, which limits its activity against cancer. Therefore, nanocarriers and molecular modification (such as sinomenine hydrochloride, sinomenine ester derivatives, chlorine-containing derivatives and YL064) is considered an effective method to solve these problems ( 5 ). Sinomenine has been successfully loaded into transmitter to enhance its bioactivity and bioavailability ( 6 ).…”