1. Academic Validation
  2. 5-Bromoindirubin 3'-(O-oxiran-2-ylmethyl)oxime: A long-acting anticancer agent and a suicide inhibitor for epoxide hydrolase

5-Bromoindirubin 3'-(O-oxiran-2-ylmethyl)oxime: A long-acting anticancer agent and a suicide inhibitor for epoxide hydrolase

  • Bioorg Med Chem. 2017 Sep 1;25(17):4665-4676. doi: 10.1016/j.bmc.2017.07.009.
Yoshimi Ichimaru 1 Takeshi Fujii 1 Hiroaki Saito 1 Makoto Sano 2 Taketo Uchiyama 1 Shinichi Miyairi 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
  • 2 Division of Pathology, Department of Pathology and Microbiology, School of Medicine, Nihon University, 30-1 Ohyaguchi-Kamimachi, Itabashi-ku, Tokyo 173-8610, Japan.
  • 3 School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan. Electronic address: miyairi.shinichi@nihon-u.ac.jp.
Abstract

Indirubin 3'-oxime (Indox (1b)) suppresses Cancer cell growth (IC50: 15μM towards HepG2 cells) and inhibits cell cycle-related kinases such as cyclin-dependent kinases and glycogen synthase kinase-3β. We have previously reported that the conjugation of 1b with oxirane, a protein-reactive component, enhanced the cytotoxic activity of Indox as determined from the IC50 value (1.7μM) of indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind (1c)). Here we prepared Epox/Ind derivatives with one or two halogen atoms or a methoxy group on the aromatic ring(s) of an Indox moiety and studied the structure-activity relationships of the substituent(s). We found that bromine-substitution at the 5-position on 1c or any Epox/Ind derivative(s) having bromine on the aromatic ring except Epox/6'-Br-Ind was efficient to improving Anticancer activity. Of the 22 Epox/Ind derivatives, 5-bromoindirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/5-Br-Ind (2c)) was the best Anticancer agent in both short- (24h) (IC50: 0.67μM) and extended-duration (72h) cultures. The high Anticancer activity of 2c was partly due to it being a poor substrate and a suicide inhibitor for Epoxide Hydrolase as Epoxide Hydrolase was identified as the Enzyme primarily responsible for the metabolism of 2c.

Keywords

5-Bromoindirubin 3′-(O-oxiran-2-ylmethyl)oxime; Epoxide hydrolase; Long-acting anticancer agent; Structure-activity relationships; Suicide inhibition.

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