Wang resin catalyzed green synthesis of 1,8-dioxo-octahydroxanthene derivatives and their in silico/in vitro evaluation against SIRT1

Because of important role in cancer, sirtuins especially the SIRT1 is viewed as an interesting pharmacological target for developing potential anticancer agents. Based on our previous studies on sirtuin inhibitory potential of 1,8-dioxodecahydroacridines we extended our efforts towards exploring the structurally 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 interactions (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 mu M. The in silico and in vitro studies identified compound 3q along with two other analogues for further pharmacological studies. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

Due to their important role in cancer, sirtuins, especially SIRT1, are considered as interesting pharmacological targets for developing potential anticancer agents. In this study, a series of structurally relevant 1,8-dioxo-octahydroxanthene derivatives were synthesized using an eco-friendly approach. The interactions between these derivatives and SIRT1 were evaluated through in silico docking and in vitro assays, and one compound showed promising inhibitory activity, warranting further investigation.