Synthesis, cytotoxicity evaluation and molecular docking studies on 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone derivatives

Nopawit Khamto; Lada Chaichuang; Puracheth Rithchumpon; Worrapong Phupong; Phuangthip Bhoopong; Suriya Tateing; Wilart Pompimon; Natthawat Semakul; Ni-Orn Chomsri; Puttinan Meepowpan

doi:10.1039/d1ra05445g

Synthesis, cytotoxicity evaluation and molecular docking studies on 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone derivatives

RSC Adv. 2021 Sep 22;11(50):31433-31447. doi: 10.1039/d1ra05445g. eCollection 2021 Sep 21.

Authors

Nopawit Khamto^{1

2}, Lada Chaichuang^{1

2}, Puracheth Rithchumpon^{1

2}, Worrapong Phupong³, Phuangthip Bhoopong⁴, Suriya Tateing⁵, Wilart Pompimon⁶, Natthawat Semakul^{1

7}, Ni-Orn Chomsri⁸, Puttinan Meepowpan^{1

7}

Affiliations

¹ Department of Chemistry, Faculty of Science, Chiang Mai University 239 Huay Kaew Road Chiang Mai 50200 Thailand pmeepowpan@gmail.com.
² Graduate School, Chiang Mai University 239 Huay Kaew Road Chiang Mai 50200 Thailand.
³ School of Science, Walailak University 222 Thaiburi Nakhon Si Thammarat 80161 Thailand.
⁴ School of Allied Health Science, Walailak University 222 Thaiburi Nakhon Si Thammarat 80161 Thailand.
⁵ Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University 239 Huay Kaew Road Chiang Mai 50200 Thailand.
⁶ Laboratory of Natural Products, Centre for Innovation in Chemistry, Faculty of Science, Lampang Rajabhat University Lampang 52100 Thailand.
⁷ Center of Excellence in Materials Science and Technology, Chiang Mai University 239 Huay Kaew Road Chiang Mai 50200 Thailand.
⁸ Agricultural Technology Research Institute (ATRI), Rajamangala University of Technology Lanna 202 Pichai District Lampang 52100 Thailand.

Abstract

2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC, 1) was isolated from seeds of Syzygium nervosum A.Cunn. ex DC. exhibiting intriguing biological activities. Herein, thirty three DMC derivatives including 4'-O-monosubstituted-DMC (2), 7-O-acylated-4-hydroxycoumarin derivatives (3), stilbene-coumarin derivatives (4), 2',4'-disubstituted-DMC (5), and flavanone derivatives (6), were synthesised through acylation, alkylations, and sulfonylation. These semi-synthetic DMC derivatives were evaluated for in vitro cytotoxicity against six carcinoma cell lines. It was found that most derivatives exhibited higher cytotoxicity than DMC. In particular, 4'-O-caproylated-DMC (2b) and 4'-O-methylated-DMC (2g) displayed the strongest cytotoxicity against SH-SY5Y with IC₅₀ values of 5.20 and 7.52 μM, respectively. Additionally, 4'-O-benzylated-DMC (2h) demonstrated the strongest cytotoxicity against A-549 and FaDu with IC₅₀ values of 9.99 and 13.98 μM, respectively. Our structure-activity relationship (SAR) highlights the importance of 2'-OH and the derivatisation pattern of 4'-OH. Furthermore, molecular docking simulation studies shed further light on how these bioactive compounds interact with cyclin-dependent kinase 2 (CDK2).