Martin Victor Miles

Synthesis of 4,5,8-trimethoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid, an analogue of rhein with improved systemic exposure in the guinea pig

N,N-Diethyl(2-methoxy-4-methyl)benzamide 4 has been lithiated and treated with 2,5-dimethoxybenz-aldehyde to give 3-(2′,5′-dimethoxyphenyl)-7-methoxy-5-methylisobenzofuran-1(3H)-one 5. Reduction and cyclisation gives 4,5,8-trimethoxy-2-methylanthracen-10-ol 7 which is oxidised to give 4,5,8-trimethoxy-2-methylanthraquinone 8. Demethylation gives the natural product helminthosporin 9, oxidation gives 4,5,8-trimethoxy-9,10-dioxo-9,10-dihydroanthracene-2-carboxylic acid an analogue of the osteoarthritis drug rhein. Alternatively, dimethylrhein methyl ester 12 may be iodinated and the iodine displaced with methoxide to provide a large-scale synthesis of 3. Plasma concentration data in the guinea pig were obtained for 3, diacetylrhein, dimethylrhein and 4,5-dimethyl-8-fluororhein after oral dosing.

Anthraquinones related to rhein inhibit glucose uptake into chondrocytes. A mechanism for anti-osteoarthritis drugs?

Abstract Rhein has been shown to inhibit the uptake of glucose into Ehrlich Ascites tumor cells. In this paper we show that a wide range of antrhaquinones related to rhein can also inhibit glucose uptake into chondrocytes, many significantly more than the parent molecule.