UC Riverside

Asterriquinones display a wide range of biological activity. From antiretroviral and antitumor activity, to anti-diabetes properties and neuroprotection, asterriquinones and their analogs have quickly become a popular target in pharmaceutical research.

The asterriquinone demethylasterriquinone-B1 (DAQ-B1) exhibits insulin mimetic activity in two mouse models of diabetes. It directly activates the tyrosine kinase domain of the insulin receptor and, as a small molecule, is orally active. A substantial amount of SAR work in our and other laboratories identified the key pharmacophore, which includes the quinone. Despite promising early-stage animal studies with compounds of this class, concern about potential long-term toxicity linked to their quinone portion impeded further development. In order to surmount this obstacle, quinone replacements are sought in the synthesis of DAQ-B1 analogs. These replacements include cyclic ketones such as pyrones, pyridones, and cyclohexadienones containing a quarternary center at the 4-position. Two different methods are used in an attempt to synthesize the analogs: a Stille coupling between the desired indole and the halogenated heterocyclic ketone, and a Claisen rearrangement of an (indole)-methyl-kojic acid ether.

Besides exhibiting insulin mimetic activity, DAQ-B1 demonstrates the ability to activate the nerve growth factor (NGF) receptor, which belongs to a class of neurotrophin proteins that support neuronal growth and survival. A fluorinated analog of DAQ-B1, 5E5, activates the TrkA receptor and demonstrates NGF activator activity with 'approximately 200% the effect of a maximal dose of NGF.' A library of fluorinated monoindolylquinones, similar in structure to 5E5, is synthesized from a two step procedure consisting of the acid-catalyzed coupling of fluorinated indoles to 2,5-dichloro-1,4-benzoquinone, followed by methanolysis.