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. 2019 Nov 7;24(22):4034.
doi: 10.3390/molecules24224034.

Design, Synthesis and Preliminary Biological Evaluation of Benzylsulfone Coumarin Derivatives as Anti-Cancer Agents

Tao Wang  1   2 , Tao Peng  2 , Xiaoxue Wen  2 , Gang Wang  2 , Yunbo Sun  2 , Shuchen Liu  2 , Shouguo Zhang  2 , Lin Wang  1   2
Affiliations

Design, Synthesis and Preliminary Biological Evaluation of Benzylsulfone Coumarin Derivatives as Anti-Cancer Agents

Tao Wang et al. Molecules. .

Abstract

In this work, a series of benzylsulfone coumarin derivatives 5a-5o were synthesized and characterized. Kinase inhibitory activity assay indicated that most of the compounds showed considerable activity against PI3K. Anti-tumor activity studies of the active compounds were also carried out in vitro on the Hela, HepG2, H1299, HCT-116, and MCF-7 tumor cell lines by MTS assay. The structure-activity relationships (SARs) of these compounds were analyzed in detail. Compound 5h exhibited the most potent activities against the mentioned cell lines with IC50 values ranging from 18.12 to 32.60 μM, followed by 5m with IC50 values of 29.30-42.14 μM. Furthermore, 5h and 5m clearly retarded the migration of Hela cells in vitro. Next, an in silico molecular docking study was conducted to evaluate the binding models of 5h and 5m towards PI3Kα and PI3Kβ. Collectively, the above findings suggested that compounds 5h and 5m might be promising PI3K inhibitors deserving further investigation for cancer treatment.

Keywords: anticancer; benzylsulfone; cell migration; coumarins; molecular docking; phosphoinositide 3-kinase (PI3K).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The design of the new benzylsulfone coumarins (II).
Scheme 1
Scheme 1
Reagents and conditions: (i) HSCH2COOH, NaOH, methanol, r.t., 1 h; (ii) H2O2, acetic acid, 40–45 °C, 4 h; (iii) DCC, DMAP, THF, r.t., 1 h.
Figure 2
Figure 2
Images from a scratch assay experiment at different time points (0 h, 12 h, 24 h) and the cell migration process of Hela cells in response to different concentration of 5h and 5m.
Figure 3
Figure 3
Native ligand (yellow) overlap with its best docked pose (black) in a re-docking protocol. (A) Native ligand of PI3Kα overlap with its best docked pose; (B) Native ligand of PI3Kβ overlap with its best docked pose.
Figure 4
Figure 4
A 2D model of the interaction between rigosertib with the active site of PI3Kα.
Figure 5
Figure 5
A 2D model of the interaction between compound 5h with the active site of PI3Kα.
Figure 6
Figure 6
A 2D model of the interaction between compound 5m with the active site of PI3Kα.
Figure 7
Figure 7
A 2D model of the interaction between rigosertib with the active site of PI3Kβ.
Figure 8
Figure 8
A 2D model of the interaction between compound 5h with the active site of PI3Kβ.
Figure 9
Figure 9
A 2D model of the interaction between compound 5m with the active site of PI3Kβ.
See this image and copyright information in PMC

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