Phenylfurazan oxide. Chemistry

Burakevich, Joseph V.; Butler, Robert S.; Volpp, G. P.

doi:10.1021/jo00969a016

“…Instead, our results suggest that cellular selectivity may, unexpectedly, be a feature intrinsic to nitrile oxides themselves. For example, the unmasked nitrile oxide JKE-1777, which can be isolated by virtue of oxime stabilization of the nitrile oxide 21 , exhibits selectivity equivalent to masked precursors as assessed by multiple orthogonal assays. We speculate that it may be the transient nature of nitrile oxides that prevents prolonged exposure of cells to this highly reactive electrophilic species and thereby avoids extensive covalent interactions with the proteome.…”

Section: Discussionmentioning

confidence: 99%

“…A possible explanation is that dehydration of the α-nitroketoxime initially yields an unstable monosubstituted furoxan heterocycle ( Figure 6J), the formation of which is dependent on the presence of the oxime group. The furoxan, in turn, can readily undergo a ring-opening isomerization reaction to yield a nitrile oxide 21,22 . While either this furoxan or the isomeric nitrile oxide JKE-1777 could plausibly act as an electrophile, other nitrile oxide precursors that are incapable of forming furoxans are also able to engage GPX4 ( Figures 6H, 6I, and S8C).…”

Section: Proposed Cellular Activation Pathway Of Masked Nitrile Oxidementioning

confidence: 99%

Targeting a Therapy-Resistant Cancer Cell State Using Masked Electrophiles as GPX4 Inhibitors

Eaton

¹

,

Furst

²

,

Ra

³

et al. 2018

Preprint

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We recently discovered that inhibition of the lipid peroxidase GPX4 can selectively kill cancer cells in a therapy-resistant state through induction of ferroptosis. Although GPX4 lacks a conventional druggable pocket, covalent small-molecule inhibitors are able to overcome this challenge by reacting with the GPX4 catalytic selenocysteine residue to eliminate enzymatic activity. Unfortunately, all currently-reported GPX4 inhibitors achieve their activity through reactive chloroacetamide groups. We demonstrate that such chloroacetamide-containing compounds are poor starting points for further advancement given their promiscuity, instability, and low bioavailability. Development of improved GPX4 inhibitors, including those with therapeutic potential, requires the identification of new electrophilic chemotypes and mechanisms of action that do not suffer these shortcomings. Here, we report our discovery that nitrile oxide electrophiles, and a set of remarkable chemical transformations that generates them in cells from masked precursors, provide an effective strategy for selective targeting of GPX4. Our results, which include structural insights, target engagement assays, and diverse GPX4-inhibitor tool compounds, provide critical insights that may galvanize development of improved compounds that illuminate the basic biology of GPX4 and therapeutic potential of ferroptosis induction. In addition, our discovery that nitrile oxide electrophiles engage in highly selective cellular interactions and are bioavailable in their masked forms may be relevant for targeting other currently undruggable proteins, such as those revealed by recent proteome-wide ligandability studies.

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“…Unfortunately, we found that published procedures for the dehydration of αnitroketoximes do not promote this transformation with JKE-1674 19,20 . However, we developed a two-step reaction sequence (Figure S6B) that enables the isolation of a dehydrated analog of JKE-1674, JKE-1777 (Figure 6A), which exhibits an infrared absorbance at 2286 cm -1 characteristic of a nitrile oxide group 21,22 .…”

Section: Dehydration Of Jke-1674 Yields a Nitrile Oxide Electrophile That Binds Gpx4mentioning

confidence: 99%

Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles

Eaton

¹

,

Furst

²

,

Ruberto

³

et al. 2020

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We recently discovered that inhibition of the lipid peroxidase GPX4 can selectively kill cancer cells in a therapy-resistant state through induction of ferroptosis. Although GPX4 lacks a conventional druggable pocket, covalent small-molecule inhibitors are able to overcome this challenge by reacting with the GPX4 catalytic selenocysteine residue to eliminate enzymatic activity. Unfortunately, all currently-reported GPX4 inhibitors achieve their activity through reactive chloroacetamide groups. We demonstrate that such chloroacetamide-containing compounds are poor starting points for further advancement given their promiscuity, instability, and low bioavailability. Development of improved GPX4 inhibitors, including those with therapeutic potential, requires the identification of new electrophilic chemotypes and mechanisms of action that do not suffer these shortcomings. Here, we report our discovery that nitrile oxide electrophiles, and a set of remarkable chemical transformations that generates them in cells from masked precursors, provide an effective strategy for selective targeting of GPX4. Our results, which include structural insights, target engagement assays, and diverse GPX4-inhibitor tool compounds, provide critical insights that may galvanize development of improved compounds that illuminate the basic biology of GPX4 and therapeutic potential of ferroptosis induction. In addition, our discovery that nitrile oxide electrophiles engage in highly selective cellular interactions and are bioavailable in their masked forms may be relevant for targeting other currently undruggable proteins, such as those revealed by recent proteome-wide ligandability studies.

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“…This reactivity pattern was previously shown to proceed in various reaction media, including EtOH-H 2 O mixture. 18 Arguably, the presence of water as a highly polarizable solvent ( = 78.4 at 298 K) promoted dissociation, which was not observed in less polar MeOH ( = 32.7 at 298 K) or EtOH ( = 24.3 at 298 K). At the same time, EtOH is required to dissolve the substrate.…”

Section: Syn Thesismentioning

confidence: 98%

“…It is known, that 4-phenylfuroxan (1a) is capable to undergo the heterocyclic ring cleavage under mild conditions generating nitrile oxide 2a. 18 We decided to use this furoxan reactivity mode to perform tandem ring opening/[3+2] cycloaddition sequence and to prepare a series of (oximino)isoxazoles and -isoxazolines. The accessible 4-phenylfuroxan (1a) 19 and acrylamide as dipolarophile were selected as model substrates.…”

Section: Scheme 2 Synthesis Of Initial 4-arylfuroxans 1abmentioning

confidence: 99%

Divergent Synthesis of Five-Membered Nitrogen Heterocycles via Cascade Reactions of 4-Arylfuroxans

Chaplygin

¹

,

Ananyev

²

,

Ферштат

³

et al. 2020

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A novel method for the synthesis of a diverse series of functionally substituted five-membered heterocyclic compounds via atom-economic, regio-, and diastereoselective one-pot reaction cascade was developed. This approach involves a ring opening in 4-arylfuroxans to α-oximinoarylacetonitrile oxides followed by [3+2] cycloaddition to various dipolarophiles to afford multisubstituted isoxazoles and isoxazolines. Subsequent azole–azole rearrangement of (oximino)isoxazolines/-isoxazoles, which can be conducted in a one-pot manner, results into functionally substituted furazans formation. The developed protocol is operationally simple, proceeds in mild conditions and with high yields of target heterocyclic systems. Overall, this study represents a new mode of isoxazole and 1,2,5-oxadiazole functionalization strategy, which is useful in medicinal and materials chemistry.

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Phenylfurazan oxide. Chemistry

Cited by 20 publications

References 3 publications

Targeting a Therapy-Resistant Cancer Cell State Using Masked Electrophiles as GPX4 Inhibitors

Targeting a Therapy-Resistant Cancer Cell State Using Masked Electrophiles as GPX4 Inhibitors

Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles

Divergent Synthesis of Five-Membered Nitrogen Heterocycles via Cascade Reactions of 4-Arylfuroxans

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