Indirubin 3′-(O-oxiran-2-ylmethyl)oxime: A novel anticancer agent

Abstract

Indirubin is a potent inhibitor of cell cycle-related protein kinases by binding to the ATP-binding site and thus is a promising compound for development as an antitumor drug. We prepared indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind), in which the ATP-binding site orientated part was attached by non-specific alkylating group. The IC50 value of Epox/Ind at 1.7 μM in HepG2 cells is comparable to that of cisplatin (4.0 μM). Furthermore, Epox/Ind was shown to be metabolized by a HepG2 cell lysate into indirubin 3'-(O-2,3-dihydroxypropyl)oxime (E804), the sole extractable metabolite. The lower toxicity of this metabolite may explain the lack of cytotoxicity of 1 μM Epox/Ind observed in HepG2 cells beyond an initial loss of viability in the first 24h of treatment.

Evaluation of the Developmental Toxicity Induced by E804 in Zebrafish Embryos

“…Indirubin is the an active compound of Chinese herb of indigo blue, which can be used for the treatment of chronic diseases such as chronic myelogenous leukemia, and hepatitis, influenza, and encephalitis (Han, 1994;Wang et al, 2014;Gaboriaud-Kolar et al, 2015). Previous researches have shown that indirubin and its derivatives possessed many biological activities, including anticancer (Ichimaru et al, 2015;Zhang et al, 2015), anti-inflammatory (Mok et al, 2014;Kwok et al, 2016), anti-leukemia, and antivirus effects. The targets of indirubin and its derivatives have been widely studied.…”

Inhibitory Effects of Indirubin-3′-oxime Derivatives on Lipid Accumulation in 3T3-L1 Cells

“…In addition, 5-methoxyindirubin-3′-oxime (2) and 6-bromoindirubin-3′-oxime (7) inhibited the expression of the lipolysis and the lipid metabolism-related genes Atgl, Hsl, Pparα, and Ucp2, which was not significantly different from the expression levels in undifferentiated cells. Although the precise structure-activity relationships and inhibition mechanisms have not yet been clarified, these results provide new directions for designing 5-and/or 6-substituted indirubins 19,20,23) that could potentially be applied to the prevention of obesity. Further studies are warranted to elucidate the direct association between the inhibition of lipid accumulation and the structure of indirubin-3′-oximes.…”

“…16) Indirubin derivatives have also been reported to inhibit protein kinases, such as cyclin-dependent kinases and glycogen synthase kinase-3. [17][18][19][20] Our previous studies have also reported that some of these derivatives exhibit beneficial pharmacological effects, such as anti-cancer and anti-inflammatory activities. [21][22][23][24] Interestingly, indirubin-3′-oxime has been demonstrated to inhibit the differentiation of adipocytes.…”

Is an Inhibitor or Blocker of Inactivation of Glycogen Synthase Kinase- 3β (GSK-3β) a Reliable Agent for Cancer Chemotherapy?

“…We determined the antiproliferative activity to evaluate the biological significance of newly developed indirubin derivatives as anti-cancer agents. We successfully developed an effective compound (IC 50 : 1.7 μM) with anti-proliferative activity that is comparable with that of cis-platin, a powerful anticancer agent [8].…”