Synthesis of Ester Derivatives of Catechin Isolated from Uncaria gambir and their Anticancer Activity

Muhammad Ikhlas Abdjan1,2

Mila Rosyda2

Nanik Siti Aminah2,3,Email

Alfinda Novi Kristanti2,3

Imam Siswanto2,4

Waseem Shehzad5

Hina Siddiqui5

Andika Pramudya Wardana1,2

Indriani6

Mirza Ardella Saputra7

Yoshiaki Takaya8

1Ph.D. Student of Mathematics and Natural Sciences, Faculty of Science and Technology, Universitas Airlangga, Komplek Kampus C UNAIR, Jl. Mulyorejo, 60115, Surabaya, Indonesia.
2Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Komplek Kampus C UNAIR, Jl. Mulyorejo, Surabaya, Indonesia.
3Biotechnology of Tropical Medicinal Plants Research Group, Universitas Airlangga.
4Bioinformatic Laboratory, UCoE Research Center for Bio-Molecule Engineering, Universitas Airlangga, Surabaya, Indonesia.
5H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
6Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Tadulako, Palu, Indonesia.
7Nanotechnology Engineering, Faculty of Advanced Technology and Multidiscipline, Universitas Airlangga, Surabaya 60115, Indonesia.
8Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku, Nagoya, 468-8503 Japan.

Abstract

(+)-Catechin (1) was isolated from the sap of Uncaria gambir and its stereochemistry was confirmed using a polarimeter with an optical rotation value of +17o. Structure modification of compound 1 into several catechin-derived esters was carried out to increase the anticancer activity. Four new catechin-derived esters named catechin-3'-(2,4,6-trichlorobenzoate) (1a), catechin-3'-[2-fluoro-3-(trifluoromethyl)benzoate] (1b), catechin-3'-(4-iodobenzoate) (1c), and catechin-3',4'-[bis(3-chlorobenzoate)] (1d) were successfully synthesized via acetylation reaction of compound 1 with various benzoyl chlorides. All five compounds including (+)-catechin (1) were tested for their anticancer activity against HeLa cell lines using the MTT method. The IC50 values of compounds 1, 1a, 1b, 1c, and 1d were 32.59 ± 0.032, 20.23 ± 0.050, 22.83 ± 0,056, 26.02 ± 0.062, and 15.58 ± 0.035 µg/mL, respectively. A combination of molecular docking and molecular dynamics simulation was performed to observe the interaction between catechin derivatives and the SIRT6 enzyme at the molecular level. Molecular studies showed that compounds 1a and 1b have stable interactions with the SIRT6 enzyme through binding affinity studies based on the MM-PBSA and QM/MM-GBSA approaches. Ultimately, modification of the catechin structure into catechin esters increased the anticancer activity of the parent compound.

Synthesis of Ester Derivatives of Catechin Isolated from Uncaria gambir and their Anticancer Activity