Indigoids: From natural dyeing agents to selective kinase inhibitors

Indirubin, indigo and isoindigo are the core representatives of a rather small category of bisindole alkaloids referred to as indigoids. Their fascinating history begins before even their exact chemical structure elucidation. These compounds are the colored constituents of the natural dyes indigo and the famous molluscan Tyrian purple, and were used throughout the centuries for textile dyeing. In contrast with indigo dyes, the major constituents of molluscan purple dyes are brominated indigoids.

Nowadays, the use of natural dyes is very limited due to their replacement with less expensive synthetic dyes. Nevertheless, indigoids and especially indirubins have come to the foreplay due to the vast range of biological activities, which in many cases have their origin in traditional medicine. Chronic myelotic leukemia has been treated in the traditional Chinese medicine with the recipe Danggui Longhui Wan, a mixture of 11 herbal medicines. Eventually, the antileukemic activity was attributed to indirubin, which was detected in the mixture as a minor constituent.

A series of derivatives has been developed during the last 15 years aiming to the investigation and amelioration of the indirubin scaffold in terms of activity, selectivity and drugability. Halogenated indirubins are by far one of the most important subcategories of indirubins, with its main representatives 6-bromoindirubin and 6-bromoindirubin-3′-oxime (6BIO) possessing an outstanding selectivity against GSK-3. As proposed from crystallographic studies and molecular modeling studies, the outstanding selectivity of 6BIO to GSK-3β versus CDKs is related to minor differences in the binding pocket of the enzymes. GSK-3β with the relatively small Leu132 provides a more spacious environment for the bromine atom to be inserted in the back of the cavity, whereas in CDKs 1,2 and 5, this area is restricted due to the bulkier Phe80. This presentation attempts to summarize concisely structure/activity relationships among closely related analogues in terms of protein kinase (PK) inhibition and selectivity, while it also focuses on the various biological applications arising from the interactions of halogenated indirubins with molecular targets. Those include effects of halogenated indirubins on stem cells, cardiac, renal and pancreatic cells, effect on leukemia, solid tumors and neurodegeneration.

In most of the cases, all of the above effects can be associated with the interaction of indirubins with important molecular targets such as members of the family of protein kinases (GSK-3, CDKs, DYRK etc). Small variations on the basic skeleton as in the case of halogenated indirubins, have been proven to modulate significantly their biological activity, leading to more active and selective PK inhibitors with fascinating applications as in the field of stem cells. All of the above along with their charming history of natural product research and development, through the ages, places them among the most promising nature-derived drug candidates.