5,5′-Substituted Indirubin-3′-oxime Derivatives as Potent Cyclin-Dependent Kinase Inhibitors with Anticancer Activity

Abstract

To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3'-oxime derivatives with combined substitutions at the 5 and 5' positions. A molecular docking study predicted the binding of derivatives with OH or halogen substitutions at the 5' position to the ATP binding site of CDK2, revealing the critical interactions that may explain the improved CDK2 inhibitory activity of these derivatives. Among the synthesized derivatives, the 5-nitro-5'-hydroxy analogue 3a and the 5-nitro-5'-fluoro analogue 5a displayed potent inhibitory activity against CDK2, with IC(50) values of 1.9 and 1.7 nM, respectively. These derivatives also showed antiproliferative activity against several human cancer cell lines, with IC(50) values of 0.2-3.3 microM. A representative analogue, 3a, showed greater than 500-fold selectivity for CDK relative to selected kinase panel and potent in vivo anticancer activity.

MLS-2384, a new 6-bromoindirubin derivative with dual JAK/Src kinase inhibitory activity, suppresses growth of diverse cancer cells

“…32,38,39 Potent anticancer activities of bromoindirubins have been reported in human cancer cells. 32,[39][40][41][42] ReseaRCh PaPeR…”

A Colorful History: The Evolution of Indigoids

“…The selection of 5-or 7-substituted isatins opened the door to the creation of new libraries of synthetic analogs possessing diverse substituents at the 5-and 7-positions (156)(157)(158)(159)(160). Interestingly, the versatility of the method is conserved when starting from azaisatin or 3-acetoxy-5-or 6-substituted-indoles, leading, respectively, to azaindirubins (161,162) and di-substituted indirubins (158,163,164). Overall, the general synthesis scheme can be represented as depicted in Scheme 37.…”

“…20), also exhibit potent inhibition against CDK2/cyclin E in vitro, and in addition, an induction of apoptosis and in vivo efficacy (157,164). …”

Recent Highlights in the Development of Isatin-Based Anticancer Agents

“…A number of these derivatives with various substitution patterns exhibit sub-micromolar and/or high-nanomolar IC 50 values against human cancer cell lines in vitro (Fig. (7), compounds 14-16) [69][70][71][72][73]. Indirubins exert their cytotoxic action via a number of modes [74] and they are recognised for their ATP-competitive inhibition of both CDK1 and CDK2 [75][76][77] and induction of apoptosis through cell cycle arrest at G2/M, as a result of inhibition of GSK3 [78], c-Src kinase and NF-κB activation and expression [79][80] as well as the activation of the aryl hydrocarbon receptor [81][82].…”

“…Indirubins exert their cytotoxic action via a number of modes [74] and they are recognised for their ATP-competitive inhibition of both CDK1 and CDK2 [75][76][77] and induction of apoptosis through cell cycle arrest at G2/M, as a result of inhibition of GSK3 [78], c-Src kinase and NF-κB activation and expression [79][80] as well as the activation of the aryl hydrocarbon receptor [81][82]. Based on a range of mechanistic and crystallographic studies of indirubins with GSK3 and CDK2, a vast number of indirubin derivatives have been synthesised and their biological activity and specificity evaluated [76,[83][84]. A number of recent studies have identified numerous alternative modes for the cytotoxic and antiangiogenic actions displayed by indirubin and some of its derivatives.…”