Evaluation of O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyl) 17alpha-hydroxy-5beta-pregnan-20-one as a novel potential antiangiogenic codrug.

Intraocular neovascularization is a complication in a variety of eye diseases, and is a leading cause of visual loss. The purpose of this study was to design and synthesize three novel codrugs of the antiangiostatic steroid, 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) with the cytotoxic agent 5-fluorouracil (5FU) which incorporates either one or two molecules of 5FU attached through carbonate ester linkages at positions O(3), and/or O(21) of the THS molecule. Furthermore, a kinetic study of the O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyL) 17alpha-hydroxy-5beta-pregnan-20-one (THS-BIS-5FU) codrug was carried out. The overall goal of this codrug strategy was to improve sustained drug delivery of both compounds by overcoming their individual solubility problems, and to thus enhance their bioavailability. The codrug was found to be optimal with superior angiostatic activity using the CAM assay compared to the activity of the parent compounds alone. In the hydrolysis studies 5FU was released at a faster rate than THS with an unknown intermediate observed by HPLC, a rationale and proposed structure and mechanism of the unknown THS derivative is provided.