Synthesis and anticancer activity of novel bisindolylhydroxymaleimide derivatives with potent GSK-3 Inhibition

Florence Mccarthy,Kevin O'Shea,Michael Cahill,Hannah Winfield

doi:10.3390/ecmc-4-05639

Abstract

Glycogen synthase kinase-3 (GSK-3) refers to a group of multifaceted serine/threonine protein kinases that, in mammals, exist as two isoforms (GSK-3a and GSK-3b). Both isoforms share very similar homology but represent contrasting pharmacology. The quest for targeted GSK-3 inhibition has recently become a mainstay for pharmaceutical companies due to the enzymes’ role in a multitude of under-addressed disease states including cancer, Alzheimer’s and bipolar disorder. Herein, we describe the synthesis and evaluation of novel indole derivatives as anticancer agents. A bisindolyl template has been derived, starting from a substituted maleimide, through the introduction of an oxygen atom to the headgroup (hydroxymaleimide). Assessing the bioactivity of these derivatives through kinase assays allowed for the identification of substituent derived selectivity. Following on from this, indole substitution was completed and assessed with the identification of unique selectivity patterns in the GSK-3 and CDK kinase assays. Subsequent evaluation of anticancer activity utilising the NCI-60 cell screen showed growth inhibitory profiles towards a multitude of cell lines including: SNB-75 CNS cancer, A498 and UO-31 renal, MDA MB435 melanoma and a panel of leukemia cell lines. Achieving selective kinase inhibition through modulation of this bisindolyl template is evident and will inform future selective clinical candidates.

Highlights

Route to incorporate individual indole functionality was devised in order to probe the influence of the indole nitrogen on anticancer and kinase activity
Compounds 1, 3 – 4, 6 – 9 and 11 – 14 were chosen in order to scope the breadth of structural diversity and kinase inhibition. These compounds were initially screened at a 10 μM dose against 60 cancer cell lines
Cell lines with sub-micromolar GI50 values include SNB-75 (CNS), MDA-MB-435, A498 and HS-578 T cancer cell lines showing the spread of activity

Summary

Introduction

7-Azaindole incorporation will seek to ameliorate bioactivities and, in turn, achieve more selective kinase inhibition. Synthesis of a related hydroxymaleimide was undertaken in order to probe the effect of oxygen insertion into the headgroup and the effect of indole substitution. By contrast, converting to 2 reduced CDK activity completely with significant inhibition only evident in PIM1 kinase and GSK-3α/β .

Results

Conclusion