Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione

Hori, Hitoshi; Nagasawa, Hideko; Uto, Yoshihiro; Ohkura, Kazuto; Kirk, Kenneth L.; Uehara, Yoshimasa; Shimamura, Mariko

doi:10.1016/j.bbapap.2003.11.011

Cited by 9 publications

(4 citation statements)

References 60 publications

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“…A receptor of fusicoccin, which is closely related to cotylenin A, has been reported to be a member of the 14-3-3 protein family, which are commonly found in a wide range of signaling and regulatory pathways. Many hypoxia-targeting drugs have been developed and the design of these drugs is also practicable [3,18]. To develop more effective candidates, we synthesized many fusicoccin derivatives with antitumor activity, based on the structure-activity relationship of cotylenin derivatives.…”

Section: Discussionmentioning

confidence: 99%

A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts

Kawakami¹,

Hattori²,

Inoue³

et al. 2012

ACAMC

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Malignant cells in solid tumors survive under prolonged hypoxia and can be a source of resistance to current cancer therapies. Tumor hypoxia is also associated with a more malignant phenotype and poor survival in cancer patients. Recent progress in our understanding of the biology of tumor cells under hypoxia has led to increased attention on targeting hypoxia for cancer therapy. We report here that a novel fusicoccin derivative (ISIR-042), but not its parent or related compounds such as fusicoccin A and cotylenin A, is more cytotoxic to hypoxic cells than to normoxic cells. The hypoxia-induced accumulation of hypoxia-inducible factor (HIF)-1α and the phosphorylation of Akt were effectively inhibited by treatment with ISIR-042, suggesting that the preferential cytotoxicity toward hypoxic cells is associated with a reduction of HIF-1α and Akt activation. ISIR-042 inhibited the growth of human pancreatic cancer MIAPaCa-2 cells while sparing normal endothelial cells, and significantly inhibited the growth of MIAPaCa-2 cells as xenografts without apparent adverse effects. Pancreatic cancer cells expressing CD24 and CD44 exhibited characteristics of stem cells. Treatment with gemcitabine increased this stem cell-enriched population, and this effect was significantly inhibited by ISIR-042, suggesting that ISIR- 042 preferentially inhibits stem/progenitors in pancreatic cancer cell lines compared with chemotherapeutic agents. These results suggest that ISIR-042 may be a potential therapeutic agent for hypoxic tumors such as pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts

Kawakami¹,

Hattori²,

Inoue³

et al. 2012

ACAMC

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“…As shown in Table 2 , all of the furan-2-yl(phenyl)methanone derivatives were subjected to the in vitro PTK inhibitory activity testing using the PTK assay, as previously reported [ 13 ]. Some of the new derivatives exhibited promising activity, which in some cases, was identical to, or even better than that of genistein, a positive reference compound in the same model.…”

Section: Resultsmentioning

confidence: 99%

“…A variety of tumor types have dysfunctional growth factor receptor tyrosine kinases, which result in inappropriate mitogenic signaling. PTKs are, therefore, attractive targets in the search for therapeutic agents, not only against cancer, but also in many other diseases [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and In Vitro Protein Tyrosine Kinase Inhibitory Activity of Furan-2-yl(phenyl)methanone Derivatives

et al. 2011

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A series of novel furan-2-yl(phenyl)methanone derivatives were synthesized, and their structures were established on the basis of 1H-NMR, 13C-NMR and mass spectral data. All the prepared compounds were screened for their in vitro protein tyrosine kinase inhibitory activity and several new derivatives exhibited promising activity, which, in some cases, was identical to, or even better than that of genistein, a positive reference compound. The preliminary structure-activity relationships of these compounds were investigated and are discussed.

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“…We present here our design, syntheses, and biological evaluation of new 2-nitroimidazole-based antiangiogenic hypoxic cell radiosensitizers that incorporate the 2-aminomethylene-4-cyclopentene-1,3-dione moiety as an antiangiogenic pharmacophoric descriptor. 8 …”

Section: Introductionmentioning

confidence: 99%

Design of antiangiogenic hypoxic cell radiosensitizers: 2-Nitroimidazoles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety

Uto

Nagasawa

Jin

et al. 2008

Bioorganic & Medicinal Chemistry

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We designed chiral 2-nitroimidazole derivatives containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety as antiangiogenic hypoxic cell radiosensitizers. Based on results of molecular orbital calculations, the 2-aminomethylene-4-cyclopentene-1,3-dione moiety is expected to show high electrophilicity comparable to that of the 2-methylene-4-cyclopentene-1,3-dione moiety included in TX-1123 and tyrphostin AG17. We evaluated the antiangiogenic and radiosensitizing effects of the new compounds, along with other biological properties including their activities as hypoxic cytotoxicities and protein tyrosine kinase (PTK) inhibitory activities. Among the compounds tested, 5 (TX-2036) proved to be the strongest antiangiogenic hypoxic cell radiosensitizer. All the other chiral 2-nitroimidazole derivatives having 2-aminomethylene-4-cyclopentene-1,3-dione moiety tested were also antiangiogenic hypoxic cell radiosensitizers. The PTK inhibitory activity of 5 (TX-2036) showed this to be a promising and potent EGFR kinase inhibitor, having an IC 50 value of lower than 2 μM. This compound also was an Flt-1 kinase Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. inhibitor having an IC 50 value of lower than 20 μM. Our results show that these chiral 2-nitroimidazole derivatives that contain the 2-amnomethlene-4-cyclopentene-1,3-dione moiety as a potent antiangiogenic pharmacophoric descriptor are promising lead candidates for the development of antiangiogenic hypoxic cell radiosensitizers. NIH Public Access

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Design of hypoxia-targeting protein tyrosine kinase inhibitor using an innovative pharmacophore 2-methylene-4-cyclopentene-1,3-dione

Cited by 9 publications

References 60 publications

A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts

A Novel Fusicoccin Derivative Preferentially Targets Hypoxic Tumor Cells and Inhibits Tumor Growth in Xenografts

Synthesis and In Vitro Protein Tyrosine Kinase Inhibitory Activity of Furan-2-yl(phenyl)methanone Derivatives

Design of antiangiogenic hypoxic cell radiosensitizers: 2-Nitroimidazoles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety

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