Hypoxia-selective activation of 5-fluorodeoxyuridine prodrug possessing indolequinone structure: radiolytic reduction and cytotoxicity characteristics

Tanabe, Kazuhito; Makimura, Yuji; Tachi, Yukihiro; Imagawa-Sato, Akemi; Nishimoto, Sei‐ichi

doi:10.1016/j.bmcl.2005.03.013

Cited by 42 publications

(29 citation statements)

References 24 publications

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“…5-Fluoropropynyl-dUMP 14, an improved derivative of 13, has been designed, based on a mechanistic rationale, as a prototype of a new generation of dTMP synthase inhibitors [24]. Novel radiation-activated prodrugs of the antitumour agent 5-FdUrd, possessing an indolequinone structure (IQ-FdUrd) 15, have been designed [25]. IQ-FdUrd has been shown to be a potential prototype compound for radiation-activated antitumour prodrugs that are useful for radiation treatment of tumours [25].…”

Section: Thymidylate Synthase Inhibitorsmentioning

confidence: 99%

“…Novel radiation-activated prodrugs of the antitumour agent 5-FdUrd, possessing an indolequinone structure (IQ-FdUrd) 15, have been designed [25]. IQ-FdUrd has been shown to be a potential prototype compound for radiation-activated antitumour prodrugs that are useful for radiation treatment of tumours [25]. Historically, methotrexate 16 has been an extremely useful and widely prescribed TS inhibitor but it is limited by its toxicity and appears to cause more damage to the cell genome than it gains from inhibition [26].…”

Section: Thymidylate Synthase Inhibitorsmentioning

confidence: 99%

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Fluorine in medicinal chemistry: A review of anti-cancer agents

Isanbor

O’Hagan

2006

Journal of Fluorine Chemistry

1,030

343

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Section: Thymidylate Synthase Inhibitorsmentioning

confidence: 99%

Section: Thymidylate Synthase Inhibitorsmentioning

confidence: 99%

Fluorine in medicinal chemistry: A review of anti-cancer agents

Isanbor

O’Hagan

2006

Journal of Fluorine Chemistry

1,030

343

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“…4 Hence indolequinones have attracted considerable interest in the anticancer arena not only as cytotoxins, but also as bioreductively activated prodrugs. 5–8 In continuation of our studies on the synthesis and biology of indolequinones, we investigated a number of relatively simple tri- and tetra-substituted derivatives initially evaluating their cytotoxicity and also their metabolism by quinone reductase enzymes. 9–16 …”

Section: Introductionmentioning

confidence: 99%

Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells

et al. 2014

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An important determinant of the growth inhibitory activity of indolequinones against pancreatic cancer cells is substitution on the 2-position with 2-unsubstituted derivatives being markedly more potent. A series of indolequinones bearing a range of substituents on nitrogen and at the indolylcarbinyl position was prepared by copper(II)-mediated reaction of bromoquinones and enamines, followed by functional group interconversions. The compounds were then assayed for their ability to inhibit the growth of pancreatic cancer cells. The pKa of the leaving group at the 3-position was shown to influence growth inhibitory activity that is consistent with the proposed mechanism of action of reduction, loss of leaving group and formation of a reactive iminium species. Substitutions on the indole nitrogen were well tolerated with little influence on growth inhibitory activity while substitutions at the 5- and 6- positions larger than methoxy led to decreased activity. The studies presented define the range of substitutions of 2-unsubstituted indolequinones required for optimal growth inhibitory activity.

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“…However, in vivo evaluation indicated that the effect of this compound was not high enough to warrant further clinical studies [193]. Therefore, a series of radiation-activated prodrugs of 5-fluorodeoxyuridine (which is generally more potent than 5-fluorouracil) is now being investigated [194]. Although these prodrugs are activated as efficiently as the prodrugs of 5-fluorouracil, marked in vivo effects have not been detected so far [20].…”

Section: Impact Of Hypoxia On Chemoradiation Responsementioning

confidence: 99%

Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

et al. 2007

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LEARNING OBJECTIVESAfter completing this course, the reader will be able to:1. Argue why hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy.2. Describe how exposure of cells or cell lines to hypoxic conditions has major implications on multiple intracellular pathways.3. Evaluate the importance of investigating chemoradiotherapy combinations in vitro under both normoxic and hypoxic conditions.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit ™ at CME.TheOncologist.com CME CME ABSTRACTAs it is now well established that human solid tumors frequently contain a substantial fraction of cells that are hypoxic, more and more in vitro research is focusing on the impact of hypoxia on the outcome of radiotherapy and chemotherapy. Indeed, the efficacy of irradiation and many cytotoxic drugs relies on an adequate oxygen supply. Consequently, hypoxic regions in solid tumors often contain viable cells that are intrinsically more resistant to treatment with radiotherapy or chemotherapy. Moreover, efforts have been made to exploit hypoxia as a potential difference between malignant and normal tissues. Nowadays, a body of evidence indicates that oxygen deficiency clearly influences some major intracellular pathways such as those involved in cell proliferation, cell cycle progression, apoptosis, cell adhesion, and others. Obviously, when investigating the effects of radiotherapy or chemotherapy or both combined under hypoxic conditions, it is essential to consider the influences of hypoxia itself on the cell. In this review, we first focus on the effects of hypoxia per se on some critical biological pathways. Next, we sketch an overview of preclinical and clinical research on radiotherapy, chemotherapy, and chemoradiation under hypoxic conditions. The Oncologist 2007;12: 690 -712

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Hypoxia-selective activation of 5-fluorodeoxyuridine prodrug possessing indolequinone structure: radiolytic reduction and cytotoxicity characteristics

Cited by 42 publications

References 24 publications

Fluorine in medicinal chemistry: A review of anti-cancer agents

Fluorine in medicinal chemistry: A review of anti-cancer agents

Antitumour indolequinones: synthesis and activity against human pancreatic cancer cells

Review: Implications of In Vitro Research on the Effect of Radiotherapy and Chemotherapy Under Hypoxic Conditions

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