Synthesis of methoxy- and bromo-substituted indirubins and their activities on apoptosis induction in human neuroblastoma cells

Saito, Hiroaki; Tabata, Keiichi; Hanada, Satoshi; Kanda, Yuko; Suzuki, Takashi; Miyairi, Shinichi

doi:10.1016/j.bmcl.2011.07.011

Cited by 31 publications

(24 citation statements)

References 28 publications

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“…17) Recently, we revealed the cytotoxic activities of various indirubin derivatives against neuroblastoma cells. 18) In this study, we examined the anti-tumor effect of indirubin 3′-epoxide and investigated the significant cytotoxic mechanisms of this compound against neuroblastoma cells.…”

Section: Abstract Neuroblastoma; Indirubin 3′-epoxide; Caspase-indepmentioning

confidence: 99%

Indirubin 3′-Epoxide Induces Caspase-Independent Cell Death in Human Neuroblastoma

Kurita

Hanada

Ichimaru

et al. 2016

Biological & Pharmaceutical Bulletin

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Indirubin inhibits cyclin-dependent kinases by binding to their ATP-binding site, thereby exerting potent cytotoxicity on some tumor cells. We examined the anti-tumor effect of indirubin 3'-epoxide on human neuroblastoma cell lines (IMR-32, SK-N-SH, and NB-39). The results revealed potent cytotoxicity of indirubin 3'-epoxide against the IMR-32 (IC50: 0.16 µM) and SK-N-SH (IC50: 0.07 µM) cells. Furthermore, it also induced an increase of the sub-G1 population in the IMR-32 cells. Examination by Hoechst 33342 staining revealed apoptosis characterized by cell shrinkage, nuclear condensation and nuclear fragmentation in a concentration-dependent manner. Furthermore, annexin V-propidium iodide (PI) double-staining revealed an increase in the percentage of early apoptotic cells following treatment of the cells with indirubin 3'-epoxide without activation of caspases. In addition, significant decreases in the protein level of survivin and poly(ADP-ribose)polymerase (PARP), and increase in that of apoptosis-inducing factor (AIF) were found in the nuclei of the cells. These results suggest that indirubin 3'-epoxide induced caspase-independent apoptosis through mechanisms involving DNA fragmentation and inhibition of DNA repair.

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Section: Abstract Neuroblastoma; Indirubin 3′-epoxide; Caspase-indepmentioning

confidence: 99%

Indirubin 3′-Epoxide Induces Caspase-Independent Cell Death in Human Neuroblastoma

Kurita

Hanada

Ichimaru

et al. 2016

Biological & Pharmaceutical Bulletin

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“…In addition to increased solubility relative to 3'-keto compounds, the 3'-oxime substituted derivatives often exhibit either equivalent or greater cytotoxicity against cancer cell lines in vitro [71,86,[91][92]. The 3'-oxime indirubin derivative 3'-(3,4-dihydroxybutoxy)iminoindirubin or E804, (15d, Fig.…”

Section: Indirubin Is the Active Component In The Traditional Chinesementioning

confidence: 99%

Recent Highlights in the Development of Isatin-Based Anticancer Agents

Vine¹,

Matesic²,

Locke³

et al. 2013

Advances in Anticancer Agents in Medicinal Chemistry

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Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and trisubstitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P-glycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships. Abstract:Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and tri-substitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, Pglycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships.

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“…[5][6][7][8][9][10][11] We reported that 5 0 -methoxyindirubin, but not by indirubin itself, was highly cytotoxic against neuroblastoma cells in comparison with normal cells, human umbilical vein endothelial cells (HUVEC) and normal human dermal fibroblasts (NHDF). 12 More recently, we determined that three of these derivatives, 5-methoxyindirubin, indirubin 3 0 -oxime and 7-methoxyindirubin 3 0 -oxime, suppressed multi-drug resistant gene 1 (MDR1) expression by interaction with a transcription factor, NF-Y, in a tumor cell-type specific manner. 13 It is well known that some anti-tumor agents form a covalent linkage with their biological target(s) such as a specific protein 14 or nucleic acid.…”

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confidence: 99%

“…12 Briefly, indirubin was obtained by reacting isatin and indoxyl acetate in the presence of Na 2 CO 3 in methanol at room temperature. Indirubin was then converted to its 3 0 -oxime by a condensation with hydroxylamine in pyridine at 100°C.…”

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

Ichimaru

Saito

Uchiyama

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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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.

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Synthesis of methoxy- and bromo-substituted indirubins and their activities on apoptosis induction in human neuroblastoma cells

Cited by 31 publications

References 28 publications

Indirubin 3′-Epoxide Induces Caspase-Independent Cell Death in Human Neuroblastoma

Indirubin 3′-Epoxide Induces Caspase-Independent Cell Death in Human Neuroblastoma

Recent Highlights in the Development of Isatin-Based Anticancer Agents

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

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