Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine‐2,3‐dioxygenase (IDO) as Potential Target for Anticancer Activity

Blunt, Christopher E.; Torcuk, Canan; Liu, Yang; Lewis, William; Siegel, David; Ross, David; Moody, Christopher J.

doi:10.1002/anie.201503323

Cited by 42 publications

(20 citation statements)

References 50 publications

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“…The authors of this work performed corbett assay to show that Aulosirazole exhibits selective toxicity towards solid tumours. The biological activity and unique chemical structure of aulosirazole prompted interest in the chemical synthesis of derivatives which aims to identify antineoplastic agents [38]. We identified LOM612 in an image-based high content screening assay, which monitored the subcellular localization of FOXO proteins.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

et al. 2016

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FOXO factors are tumour suppressor proteins commonly inactivated in human tumours by posttranslational modifications. Furthermore, genetic variation within the FOXO3a gene is consistently associated with human longevity. Therefore, the pharmacological activation of FOXO proteins is considered as an attractive therapeutic approach to treat cancer and age-related diseases. In order to identify agents capable of activating FOXOs, we tested a collection of small chemical compounds using image-based high content screening technology. Here, we report the discovery of LOM612 (compound 1a), a newly synthesized isothiazolonaphthoquinone as a potent FOXO relocator. Compound 1a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a and FOXO1 in U2OS cells in a dose-dependent manner. This activity does not affect the subcellular localization of other cellular proteins including NFkB or inhibit CRM1-mediated nuclear export. Furthermore, compound 1a shows a potent antiproliferative effect in human cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

et al. 2016

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“…In particular, IDO is an essential target for the antitumor activity of the naphthoquinone menadione. 40) Aulosirazole and pronqodine A, a related isothiazolobenzoquinone natural product, are potent inhibitors of human IDO1. 41) Therefore, screening new IDO inhibitors for cancer treatment is still a worth exploring areas.…”

Section: Discussionmentioning

confidence: 99%

“…40) Aulosirazole and pronqodine A, a related isothiazolobenzoquinone natural product, are potent inhibitors of human IDO1. 41) Therefore, screening new IDO inhibitors for cancer treatment is still a worth exploring areas. Our results suggest that regulation of the IDO/ tryptophan catabolism pathway could be regarded as a chemopreventive target for colon cancer, consistent with a recent report, 32) and suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Celastrol Suppresses Tryptophan Catabolism in Human Colon Cancer Cells as Revealed by Metabolic Profiling and Targeted Metabolite Analysis

Wang

Zhao

et al. 2018

Biological & Pharmaceutical Bulletin

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Celastrol is well known for its anti-cancer effects, yet its specific mechanisms against colon cancer are still not fully elucidated. In this study, cytotoxic effect of celastrol against HCT116 colon cancer cells was investigated based on cell viability assay and flow cytometry assay, and the possible mechanism was explored using a strategy combining metabolic profiling and targeted metabolite analysis based on ultra performance liquid chromatography (UPLC)/MS. Celastrol was found to inhibit the growth of colon cancer cells and induce apoptosis. Metabolomics analysis revealed characteristic changes in metabolic profiles of the colon cancer cells, revealing altered levels of amino acids, carnitine, and lipid markers. Most interestingly, with the assistance of targeted metabolite analysis, tryptophan (Trp) level was significantly increased whereas kynurenine (Kyn) level was decreased in colon cancer cells after celastrol treatment, together with markedly declined Kyn/Trp ratios. Western blot analysis revealed that expression of indoleamine 2,3-dioxygenase (IDO), the enzyme catalyzing Trp to generate Kyn, was dramatically inhibited in colon cancer cells after celastrol treatment, with a dose-dependent manner. These results suggest that suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells. This study provided scientific basis for further development of celastrol on treating colon cancer.

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“…Moody and co‐workers reported a direct condensation to afford the desired isothiazoles in their total synthesis of pronqodine A and aulosirazole, naturally occurring isothiazole‐containing quinones with potential anticancer activity (Scheme ) . In the total synthesis of pronqodine A (Scheme , top ), ortho ‐lithiation of a cyclic acetal, trapping with dimethyl disulfide and hydrolysis provided the aldehyde starting material (not shown).…”

Section: Synthesis Of Isothiazolesmentioning

confidence: 99%

Recent Advances in the Synthesis and Reactivity of Isothiazoles

2019

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Isothiazoles represent an important class of five‐membered sulfur heterocycles that are widely utilized in medicinal chemistry and organic synthesis due to the unique properties of two electronegative heteroatoms in a 1,2‐relationship. However, in contrast to other 1,2‐azoles, the facile assembly of isothiazoles has always been considered a substantial challenge. In the last decade, major advances have taken place in the fields of synthesis and functionalization of isothiazoles that make them accessible to a wide range of interested chemists through unprecedented pathways. New condensation methods have emerged that address the challenges posed by unstable thiohydroxylamine. New metal‐catalyzed approaches have been reported that deliver densely decorated isothiazoles bearing various sensitive functional groups. New functionalization strategies have been developed through both cross‐coupling and direct C−H activation chemistry. Finally, the emergence of novel heterocyclic architectures based on isothiazole opens the door for future investigations of this versatile heterocyclic scaffold. This review covers the period from January 2004 to December 2018 and is intended as a sequel to the review on isoxazoles, which represent another class of synthetically‐important 1,2‐azoles (see Adv. Synth. Catal. 2015, 357, 2583–2614).

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Synthesis and Intracellular Redox Cycling of Natural Quinones and Their Analogues and Identification of Indoleamine‐2,3‐dioxygenase (IDO) as Potential Target for Anticancer Activity

Cited by 42 publications

References 50 publications

Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

Discovery of a Novel, Isothiazolonaphthoquinone-Based Small Molecule Activator of FOXO Nuclear-Cytoplasmic Shuttling

Celastrol Suppresses Tryptophan Catabolism in Human Colon Cancer Cells as Revealed by Metabolic Profiling and Targeted Metabolite Analysis

Recent Advances in the Synthesis and Reactivity of Isothiazoles

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