Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugs

Hay, Michael P.; Sykes, Bridget M.; Denny, William A.; O’Connor, Charmian J.

doi:10.1039/a904067f

Cited by 47 publications

(59 citation statements)

References 19 publications

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“…[79,90,120] As expected from the stabilization of the partial positive charge at the benzylic position in the transition state,t he introduction of am ethyl substituent at the benzylic substituent was also shown to significantly accelerate the elimination of the quinone methide intermediate (compare formulas 44 and 46 with formulas 43 and 45). [78,89] Ap henyl substituent similarly accelerates the rate of disassembly. [125] …”

Section: Linking Core Leaving Groups and Substituents At The Benzylicmentioning

confidence: 94%

“…Indeed, self-immolative spacers containing aromatic rings substituted with strong electronwithdrawing functional groups, such as NO 2 (formulas 3, 6, 11) and CO 2 Me (formulas 10, 27), exhibit ahalf-life of self-immolation larger than their unsubstituted analogues [53,78,120] (see Table 1S). Indeed, self-immolative spacers containing aromatic rings substituted with strong electronwithdrawing functional groups, such as NO 2 (formulas 3, 6, 11) and CO 2 Me (formulas 10, 27), exhibit ahalf-life of self-immolation larger than their unsubstituted analogues [53,78,120] (see Table 1S).…”

Section: Methodsmentioning

confidence: 99%

“…[78,91,120] In fact, electrondonating groups (e.g.OMe) should increase the energy of the HOMO of the aromatic ring and correspondingly strengthen the HOMO-LUMO interaction between the bonding p ring molecular orbital and the non-bonding s*C À LG orbital (LG = leaving group). [78,91,120] In fact, electrondonating groups (e.g.OMe) should increase the energy of the HOMO of the aromatic ring and correspondingly strengthen the HOMO-LUMO interaction between the bonding p ring molecular orbital and the non-bonding s*C À LG orbital (LG = leaving group).…”

Section: Substituents On the Aromatic Corementioning

confidence: 99%

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Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chemical bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller molecules. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chemistry, analytical chemistry, and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic experiments and fully exploit the rich perspectives of self-immolative spacers.

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Section: Linking Core Leaving Groups and Substituents At The Benzylicmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Substituents On the Aromatic Corementioning

confidence: 99%

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Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

et al. 2015

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“…Reduction of prodrugs and subsequent release of the corresponding PERK inhibitors was measured following radiolytic reduction (40 Gy) of anoxic solutions of prodrugs in formate buffer with subsequent analysis by LC‐MS . Strongly reducing species (aquated electron, e − (aq) and formate radical, CO 2 ⋅− ) are produced by radiolysis which result in reduction of the nitroimidazole group.…”

Section: Resultsmentioning

confidence: 99%

Hypoxia‐Activated Prodrugs of PERK Inhibitors

Liew

Singleton

Wong

et al. 2019

Chemistry An Asian Journal

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Tumour hypoxia plays an important role in tumour progression and resistance to therapy. Under hypoxia unfolded proteins accumulate in the endoplasmic reticulum (ER) and this stress is relieved through the protein kinase R‐like ER kinase (PERK) signalling arm of the unfolded protein response (UPR). Targeting the UPR through PERK kinase inhibitors provides tumour growth inhibition, but also elicits on‐mechanism normal tissue toxicity. Hypoxia presents a target for tumour‐selective drug delivery using hypoxia‐activated prodrugs. We designed and prepared hypoxia‐activated prodrugs of modified PERK inhibitors using a 2‐nitroimidazole bioreductive trigger. The new inhibitors retained PERK kinase inhibitory activity and the corresponding prodrugs were strongly deactivated. The prodrugs were able to undergo fragmentation following radiolytic reduction, or bioreduction in HCT116 cells, to release their effectors, albeit inefficiently. We examined the effects of the prodrugs on PERK signalling in hypoxic HCT116 cells. This study has identified a 2‐substituted nitroimidazole carbamate prodrug with potential to deliver PERK inhibitors in a hypoxia‐selective manner.

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“…11). It has to be noted that elimination is likely to occur after four-electron reduction to the hydroxylamine [64] rather than after six-electron reduction to the amine as often reported in the literature.…”

Section: Nitroaromaticsmentioning

confidence: 92%

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

Groot¹,

Damen²,

Scheeren

2001

CMC

114

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In order to improve current chemotherapeutic treatment and diminish severe side effects, several prodrug strategies have evolved to achieve site-specific delivery of cytotoxic anticancer agents. This review concentrates on recent developments of antitumor prodrug monotherapy with prodrugs that are designed for direct recognition of tumor-associated factors, such as hypoxia, tumor-associated enzymes and receptors. Firstly, oxygen deficiency in the core of solid tumors leads to enhanced activity of reducing enzymes, like for example nitroreductases, which can be used for site- specific conversion of prodrug to drug. Secondly, some enzymes are present in elevated levels in tumor tissue: beta-glucuronidase leaks from necrotic areas within tumors, while tumor cells for invasive and metastatic activities need several tumor-associated proteases, like plasmin. These enzymes form an attractive target for designing selective prodrugs. Finally, tumor-selective expression of receptors can be exploited for the delivery of antitumor agents. Low molecular weight binding motifs for these receptors can be coupled to cytotoxic drugs in order to obtain tumor-homing conjugates. At present, receptor-binding motifs for a number of receptors that are required for angiogenesis are used for prodrug monotherapy. There exists an increasing body of literature, which describes the complex interplay not only between tumor-associated enzymes, but also between these enzymes and tumor-associated receptors in the process of tumor invasion and metastasis, indicating the feasibility of targeting cytotoxic drugs to these key players in tumor growth. This paper reviews the development and evaluation of anticancer prodrugs, and their application in the various prodrug monotherapy approaches.

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Substituent effects on the kinetics of reductively-initiated fragmentation of nitrobenzyl carbamates designed as triggers for bioreductive prodrugs

Cited by 47 publications

References 19 publications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Self‐Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications

Hypoxia‐Activated Prodrugs of PERK Inhibitors

Anticancer Prodrugs for Application in Monotherapy Targeting Hypoxia, Tumor-Associated Enzymes, and Receptors

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