Studies On The Design, Synthesis And Biological Activity Of Xanthone Derivatives

One of the successful and effective approaches in the search for new drugs is to synthesize novel compounds by simple chemical modification on the basis of natural leading compounds in the drug research industry. Xanthone derivatives with oxygenated heterocyclic compounds are widely distributed in plants and microoganisms. They have a broad spectrum of biological activities, such as antitumor, antifungal, antioxidative, and anti-hyperlipidemia. In this paper, sixty-two xanthone derivatives were designed and synthesized by introducing different pharmacophores to the xanthone scaffold. All of them were reported firstly and the structures were determined by 1H NMR and LC-MS. At the same time their pharmacological activities were evaluated as antitumor and XO inhibitors.1. Design, synthesis and antitumor activity of novel xanthone derivativesThe malignant tumor is a highly prevalent disease that poses an increasing public health threat worldwide. It is reported that xanthone could act as efficient DNA intercalators and topoisomerase inhibitors, dispalying interesting anticancer activity. On the other hand,1,2,3-triazoles are favorite groups in various fields of drug design. Especially, their potent antitumor effect gains our great interest.According to the combination principles in drug design, two series of novel xanthone derivatives containing 1,4-disubstituted -1,2,3- -triazole were designed and synthesized. The xanthone frameworks were achieved by using Eaton's Reagent, which were gotten propargylation in 3-OH by reacting with propargyl bromide. "Click reaction" was successfully employed for the synthesis of the designed target compounds. The reaction of corresponding benzylbromide with sodium azide and terminal alkynes yielded target compounds in the presence of Na-ascorbate (5 mol%) and CUSO45H2O (1 mol%) with high yield. All the prepared compounds were screened for their activities against human hepatoma carcinoma cell line (Bel-7402) and cervical carcinoma cell line (Hela) using the MTT colorimetric method. All of the derivatives showed moderate cytotoxic effects. A preliminary SAR study of was performed.2. Design, synthesis of some xanthone derivatives as potent XO inhibitorsXanthine oxidase (XO) is a key enzyme in catabolic sequence of the purine nucleotide metabolism, which catalyzes the last two steps in the purine degradation pathway prior to formation of uric acid. So the levels of plasma uric acid can be kept under control by way of inhibiting the activity of XO.In our previous study, it was found that mangiferin displayed good XO inhibitory activity. To explore compounds with better acvitity, twenty compounds were designed and synthesized based on the mangiferin structure.2,4,5-trimethoxybenzoic acid was taken as the starting material, through halogenation reaction, Friedel-Crafts reaction, intramolecular cyclization, demethylation, protection, benzylation and deprotection, a series of xanthone derivatives were synthesized and evaluated for their xanthine oxidase inhibition activity in vitro. Compounds 8a,8c,8g,8i and 8r demonstrated potent inhibitory activities against XO with IC50 values lower than 10μM, which were much better than allopurinol (IC50=24.40±0.50μM). Molecular docking studies of compounds 8i and 8r were performed, which showed that 8i and 8r could insert into the narrow tunnel towards the Mo (Ⅳ) complex, and overlapped properly with molybdenum-pterin active site with the configuration of "L". Moreover, additional hydrogen binding between the carboxyl group of Lys1045 and the nitrogen atom of compound 8r occurred.