Improved synthesis of indirubin derivatives by sequential build-up of the indoxyl unit: First preparation of fluorescent indirubins

Indirubin, present in extracts of Isatis tinctoria and some other plant species, has promising cytotoxicity against a variety of cell lines by inhibition of cyclin-dependent kinases. Chemical synthesis of its derivatives relies on the combination of isatins and 2,3-dihydro-1H-indol-3-one ('indoxyl') derivatives and usually yields indigo as well as other by-products. Inspection of the hydrolysis of the long-known condensation products of 2-thioxothiazolidin-4-one with isatins gave useful hints for an improved synthesis of indirubins: this reaction does not yield quinoline derivatives but 2-(2,3-dihydro-2-oxo-1H-indol-3-ylidene)-2-sulfanyl acetic acids. By substitution of the sulfanyl group in this oxindoles with anilines and straightforward cyclization under Nazarov conditions, a broad variety of indirubins substituted in the indoxyl ring system are thus available, usually in very good purity and yield. Use of naphthylamines in this reaction sequence yields various fluorescent substances with λ _fl at ca. 630 nm.