Alkaloids as aldose reductase inhibitors, with special reference to berberine

Aldose reductase is the rate-limiting enzyme of the polyol pathway that leads to conversion of glucose to sorbitol. Its increased activity, which results in abnormal activation of the polyol pathway, is implicated in the development of long-term complications of diabetes mellitus. Different plant species and their active components have shown potent in vitro and in vivo aldose reductase inhibitory activity. Among different phyto-constituents, alkaloids that contain isoquinoline/bis(isoquinoline)and related ring structures (such as berberine, palmatine, coptisine, and jateorrhizine) have shown very potent aldose reductase inhibitory activity. The structural activity relationship has revealed the importance of hydrophobic and hydrophilic groups of isoquinoline/bis(isoquinoline)for binding to an enzyme. The dioxymethylene group in the D ring (hydrophobic group) of these alkaloids binds tightly to the site adjacent to the anionic binding site (active site), while the methoxyl groups (polar) bind to the site adjacent to the nicotinamide ring of the coenzyme. On the basis of these findings, it may be proposed that the presence of isoquinoline/bis(isoquinoline)ring structures is the most important requirement for alkaloids to behave as potent aldose reductase inhibitors. Thus, other plants may also be screened for the same activity. The present review discusses these isoquinoline/bis(isoquinoline)-based alkaloids as aldose reductase inhibitors that may be used to manage diabetic complications and may substitute for the chemically synthesized aldose reductase inhibitors.