Summary:
Indirubins are natural alkaloids which derive from the dimerization of two
indole groups (2’-3 connection of the two indolic rings). They belong to the
family of indigoids and they have been traditionally extracted from various
natural sources (plants, mollusks, mammals and bacteria). Nowadays indirubins
are mainly chemically produced via synthetic chemistry.
Natural sources of indirubins have been used since millennia for production of
paint as well as for their therapeutic properties, which were later attributed
to indigoids and mainly indirubin. Studies have proved that indirubins are
potent selective inhibitors of protein kinases, whose activity depends on the
substitution of the aromatic part of the indole groups. Their primary molecular
targets, which have been extensively studied, are the cyclin dependent kinases
(CDKs) and the glycogen synthase kinase (GSK-3). Furthermore it has been
reported that they have presented activity against Auroras and more recently
DYRK kinases and they have also been found to inhibit important regulating
kinases of the JAK/STAT3 pathway.
The aforementioned molecular targets participate in the regulation of the cell
cycle, but also in many other signaling pathways. Therefore, they are involved
in many pathological situations where deregulation of these pathways is
involved. Thus, pharmacological activities of indirubins include amongst other
anticancer, neuroprotective, antiviral, antiparasitic and anti-inflammatory
activity.
Considering the above, it is has become clear that indirubins consist promising
molecules for the discovery of new drugs and they are the key to the
clarification of several intracellular functions and biochemical pathways that
are involved in important pathological conditions.
The main disadvantage of indirudins though, which is a limiting factor of their
bioavailability, is their low water solubility.
The aim of the present master thesis was the further comprehension of the
structure/activity relationship, the development of active and more water
soluble indirubin derivatives. In this context 35 novel indirubin derivatives
were synthesized.
Specifically, a new series of 3’- aminosubstituted derivatives of 5-BIO as well
as analogues with 5’- and 6’- substitutions in the B indole ring were
synthesized. Focusing on the solution of the water solubility problem, we
produced a novel series of a new category of indirubins, the thioindirubins, in
which the A indole ring was replaced with benzothiophene. For this category,
accordingly to the 5-BIO derivatives, analogues which bear substitutions in the
5’- and 6’- positions were synthesized.
Finally, cytotoxic assays were performed for a substantial part of the
synthesized derivatives against melanoma and prostate cell lines (Α2058 and
DU145) and a few of the compounds (5,5’-dibromoindirubin-3’-oxime, 5-bromo-5’
-methoxycarbonylindirubin, 5-bromo-5’-methoxycarbonylindirubin-3’-oxime and 6’
-chlorothioindirubin-3’-oxime) presented significant activity at 10μΜ.
Keywords:
Indirubins, Thioindirubins, Inhibitors, Kinases, Derivatives
