3-Substituted-3-hydroxy-2-oxindole, an Emerging New Scaffold for Drug Discovery with Potential Anti-Cancer and other Biological Activities

Natural products and small molecules inspired by them are enjoying a resurgence of interest because they intersect biological space effectively and selectively. On account of their unprecedented structural diversity and biological activities oxindole natural products continue to attract the interest of chemists and biologists alike. Quarternary or spirocyclic 3-alkyl(aryl)-3-hydroxy-2-oxindole scaffold is at the core of several natural products with a wide spectrum of biological activities. Convolutamydines, arundaphine, donaxaridine, maremycins, paratunamide, celogentin K, TMC-95AD, neuroprotectin B, flustraminol A and B, 3-hydroxy welwitindolinones and pyrrolidinoindoline-type alkaloid, CPC-1 are some examples of a growing list of bioactive 3-substituted-3-hydroxy-2-oxindole natural products. Simultaneous with the extraordinary progress in the development of selective synthetic methods, a number of drug discovery programs have now started to recognize the importance of this ‘privileged’ scaffold, because of the potent anti-oxidant, anti-cancer, anti- HIV, neuroprotective and other biological properties and diverse modes of action of this class of natural products and analogs inspired by them. There is strong impetus for the continued synthesis of novel diversity libraries based on the 3- substituted-3-hydroxy-2-oxindole core for the potential treatment of proliferative and other diseases and a clear understanding of underlying cellular pathways involved. In fact, this process is well underway as exemplified by the recent synthesis of novel spirocyclic tetrahydrofuran- and isoxazolidine-2-oxindole libraries capable of achieving growth inhibition of lung adenocarcinoma (A549) cells, hepatocellular carcinoma (HepG2) cells and human breast cancer cell line, MCF-7. This review covers the isolation, diverse structure, activity, synthesis, and known medicinal chemistry of 3- substituted-3-hydroxy-2-oxindoles.