Synthesis of Indoxyl Derivatives and 6-Bromoindirubin Derivatives to treat Parkinson’s Disease

Abstract

Indigoids have been known as dye for centuries. In 1967, it came to be known that indirubin have antitumor properties. Antitumor activity of indirubin comes from inhibiting the binding of ATP to active site of CDKs. Further, studies shows that inhibitors of CDKs are also the inhibitor of GSK-3. 6-Bromoindirubin, a member of indirubin family show selective inhibition of GSK-3 over CDKs. Semi-synthetic 6-BIO gives better bioavailability. GSK-3 controls the autophagy induction by phosphorylating the mTOR associated raptor proteins. 6-BIO inhibits the GSK-3 and hence enhanced autophagy flux. Indirubins are planar molecules and have strong π-π interactions. This leads to low bioavailability. So, how can water solubility and bioavailability of 6-BIO be improved? First, keeping the molecule scaffold of 6-bromoindirubin as it is and substitute the other oxindole facing to solvent to make more water soluble. But not change the 6- bromo – 2-oxindole interacting to GSK-3 active site. It can be achieved by making different indoxyl derivatives substituted at 6 positions and further reacting with isatin to make 6-bromoindirubin derivatives. Second, break the planarity of 6-Bromoindirubin, keeping the 6-bromooxiindole as it is since it interacts with the active site. Derivatize it in such a way that it is watersoluble and can cross the blood-brain barrier.