Wang Resin Catalyzed Green Synthesis of 1,8-Dioxo-octahydroxanthene Derivatives and their in Silico/in vitro Evaluation against SIRT1

Document Type

Peer-Reviewed Article

Publication Date

9-15-2022

Abstract

Because of important role in cancer, sirtuins especially the SIRT1 is viewed as an interesting pharma- cological target for developing potential anticancer agents. Based on our previous studies on sirtuin in- hibitory potential of 1,8-dioxodecahydroacridines we extended our efforts towards exploring the struc- turally relevant 1,8-dioxo-octahydroxanthene derivatives for the similar pharmacological evaluations. The targeted 1,8-dioxo-octahydroxanthenes were conveniently accessed via the sonochemical condensation of a range of (het)aryl aldehydes with 5,5-dimethyl-1,3-cyclohexanedione in water. All these reactions were catalyzed by the sulphonic acid-functionalized Wang resin (Wang-OSO3H) that was recovered and reused for several times without major loss of its catalytic efficiency. This eco-friendly approach afforded the desired products in good to high (87–96%) yields. Initial in silico docking of 1,8-dioxo-octahydroxanthene derivatives possessing a 6-membered aryl ring at the C-9 position into SIRT1 suggested inferior binding interactions in most of the cases (total estimated energy < 82 kcal/mol). While two of these compounds e.g. 3a and 3l showed H-bond interactions through a carbonyl group with the residue ILE347 and ASP348 and a pi-sigma and pi-pi interaction with the residue PHE297 and PHE273 through a methyl group and the C-9 phenyl ring, respectively the size of the C-9 aryl ring seemed to have played a key role in the binding interactions of this class of compounds. Indeed, replacing the 6-membered aryl ring at C-9 by a 5-membered heteroaryl ring e.g. furan or thiophene afforded compounds that showed superior inter- actions (total estimated energy -98.18 and -89.9 kcal/mol) with SIRT1 in silico. The furan analogue 3q showed three H-bond interactions through its two carbonyl groups with the residues HIS363, ILE347 and ASP348 and a pi-pi interaction through the C-9 furan ring. The good in silico interactions of compound 3q were further supported by the initial in vitro assay when this compound showed encouraging inhibition (> 87%) of SIRT1 at 10 μM. The in silico and in vitro studies identified compound 3q along with two other analogues for further pharmacological studies.

Comments

Mandava Bhuvan Tej is a graduate student in the Healthcare Informatics & Health Administration program at Sacred Heart University.

DOI

10.1016/j.molstruc.2022.133313

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