Hydrogen Peroxide Activated Matrix Metalloproteinase Inhibitors: A Prodrug Approach

Jourden, Jody L. Major; Cohen, Seth M.

doi:10.1002/anie.201003819

Cited by 112 publications

(93 citation statements)

References 22 publications

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“…To overcome these challenges, we replaced the direct boronic ester protecting group of BSIH and HAPI-BPD with a self-immolative spacer that undergoes a spontaneous elimination after reaction with H 2 O 2 . 17 The new prochelator BHAPI was successfully synthesized in two steps by alkylation of 2-hydroxy acetophenone with 4-bromomethylphenylboronic acid pinacol ester followed by hydrazone bond formation with isonicotinic hydrazide, as shown in Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation

et al. 2012

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A prochelator named BHAPI (N′-(1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyloxy)phenyl)ethylidene)isonitotinohdrazide) based on the structure of experimental metal chelator HAPI (N′-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide) has been synthesized. The prochelator, which shows limited affinity for metal ions, is converted efficiently upon reaction with hydrogen peroxide into its chelator form, which binds di- and trivalent metal ions, including Zn2+, Cu2+ and Fe3+. This work shows that the prochelator has a protective effect on cells under oxidative stress induced by either hydrogen peroxide or the cytotoxic herbicide paraquat. The effect of BHAPI and HAPI on cellular iron status was assessed by monitoring the mRNA level of the transferrin receptor. Whereas the chelator HAPI induces iron deficiency in cultured retinal pigment epithelial cells, the prochelator does not, providing evidence that the differential metal-binding capacity of these compounds observed in vitro is replicated in the cellular context.

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Section: Resultsmentioning

confidence: 99%

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation

et al. 2012

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“…Basic hydrolysis of both the carboxylic and boronate esters of 5 provides the triazole self-immolative prochelator TIP (6) . We chose to use the self-immolative boronic acid protecting group because of synthetic ease and its favorable masking and reaction properties, as we and others have observed previously [26,27]. The free boronic acid of TIP was esterified with pinanediol to afford a protected prochelator TIP-pd ( 8 ).…”

Section: Resultsmentioning

confidence: 99%

A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding

Kielar

Wang

Boyle

et al. 2012

Inorganica Chimica Acta

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“…For example, tumor cells from approximately 60% of patients with AML show elevated ROS; in some cases, a 100-fold elevation is observed 18 . This increased ROS is ripe for exploitation via a pro-drug strategy ( Figure 1 ) 19-21 . In this manuscript we have designed novel pro-drugs that are unreactive until oxidized by hydrogen peroxide.…”

Section: Introductionmentioning

confidence: 99%

Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells

Vadukoot

AbdulSalam

Wunderlich

et al. 2014

Bioorganic & Medicinal Chemistry

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Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl)acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2 μM activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent.

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Hydrogen Peroxide Activated Matrix Metalloproteinase Inhibitors: A Prodrug Approach

Cited by 112 publications

References 22 publications

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation

Prochelator BHAPI protects cells against paraquat-induced damage by ROS-triggered iron chelation

A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding

Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells

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