Chiral inversion of 2-arylpropionyl-CoA esters by human α-methylacyl-CoA racemase 1A (P504S)—a potential mechanism for the anti-cancer effects of ibuprofen

Woodman, Timothy J.; Wood, Paul M.; Thompson, Andrew S.; Hutchings, T. J.; Steel, G. R.; Jiao, Ping; Threadgill, Michael D.; Lloyd, Matthew D.

doi:10.1039/c1cc10763a

Cited by 39 publications

(54 citation statements)

References 22 publications

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“…Namely, only (S)-NPX is a real inhibitor of arachidonic acid oxygenation 16 (anti-inflammatory effect) but all 2-aryl propionyl derivatives are potent inhibitors of endocannabinoid oxygenation 7 (analgetic effect) and (R)-NPX more actively undergoes chiral metabolism. 8 Our results show the prevailing of the (R,S)-dyad exciplex fluorescence quantum yields (Φexc, up to two times) and the rate constants of the exciplex formation (k4, in half times), as well as the different CIDNP effects of the optical isomers.…”

Section: Conclusion Remarks Concerning Features Of the Behaviour Of mentioning

confidence: 96%

“…7 On the other hand, (R)-NPX is more active in the processes of metabolic inversion, in particular, by cytochrome P450 18 (which also involves ET). 8 For that, according to the results of biochemical research, there is no complete understanding, for example about what kind of physicochemical interactions are responsible for the difference in the action of (S)-and (R)-NPX. 7,16 Taking into consideration the above-mentioned possible involvement of NPX optical isomers in charge transfer processes, it seems promising to use a model one-electron transfer process for studying the chemical nature of the difference between (S)-and (R)-isomers.…”

Section: Impact Of Chirality On the Photoinduced Charge Transfer In Lmentioning

confidence: 99%

“…7 Furthermore, it has been recently observed that the CoA esters of NSAIDs are the substrates of another enzyme, α-methylacyl CoA racemase (AMACR). 8 AMACR levels and activity are associated with certain types of cancer (prostate, colon and others). 9 Today the chiral inversion of optically active NSAIDs by AMACR is considered as a novel mechanism of their anti-cancer activity; it is believed that the enzymatically activated conversion of NSAIDs blocks the other harmful effects of an entire group of enzymes (transferases).…”

Section: Impact Of Chirality On the Photoinduced Charge Transfer In Lmentioning

confidence: 99%

“…54 However, in the case of the chiral inversion of NPX-CoA esters by non-P450 pathways (AMACR and other transferases), the (R)-isomer demonstrates a many times higher activity than that of the (S)-isomers. 8,12,13,55 For (S)-NPX, it is known that it acts as a weak reversible inhibitor of COX 2. 7 Since we believe that our model charge transfer reaction might be reminiscent of donor-acceptor binding, the smaller Φexc of the (S,S)-dyads and the larger ΦLE support the idea of higher (S)-NPX binding reversibility.…”

Section: Conclusion Remarks Concerning Features Of the Behaviour Of mentioning

confidence: 99%

“…9 Today the chiral inversion of optically active NSAIDs by AMACR is considered as a novel mechanism of their anti-cancer activity; it is believed that the enzymatically activated conversion of NSAIDs blocks the other harmful effects of an entire group of enzymes (transferases). 8,[10][11][12][13][14][15] It is worth emphasizing that this activity of NSAIDs also shows high stereoselectivity. 11,12,14 The stereoselectivity of NSAIDs in biological chemistry is investigated, specifically with respect to their main function of the inhibition of COX 2.…”

Section: Impact Of Chirality On the Photoinduced Charge Transfer In Lmentioning

confidence: 99%

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Impact of chirality on the photoinduced charge transfer in linked systems containing naproxen enantiomers

Khramtsova

Sosnovsky

Ageeva

et al. 2016

Phys. Chem. Chem. Phys.

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The model reaction of photoinduced donor-acceptor interaction in linked systems (dyads) has been used to study the comparative reactivity of a well-known antiinflammatory drug, (S)-naproxen (NPX) and its (R)-isomer. (R)-or (S)-NPX in these dyads is linked to (S)-N-methylpyrrolidine (Pyr) using a linear or cyclic amino acid bridge (AA or CyAA), to give (R)-/(S)-NPX-AA-(S)-Pyr flexible and (R)-/(S)-NPX-CyAA-(S)-Pyr rigid dyads. The donor-acceptor interaction is reminiscent of the binding (partial charge transfer, CT) and electron transfer (ET) processes involved in the extensively studied inhibition of the cyclooxygenase enzymes (COXs) by the NPX enantiomers. Besides that, both optical isomers undergo oxidative metabolism by enzymes from the P450 family, which also includes ET. The scheme proposed for the excitation quenching of the (R)-and (S)-NPX excited state in these dyads is based on the joint analysis of the chemically induced dynamic nuclear polarization (CIDNP) and fluorescence data. The 1 H CIDNP effects in this system appear in the back electron transfer in the biradical-zwitterion (BZ), which is formed via dyad photoirradiation. The rate constants of individual steps in the proposed scheme and the fluorescence quantum yields of the local excited (LE) states and exciplexes show stereoselectivity. It depends on the bridge's length, structure and solvent polarity. The CIDNP effects (experimental and calculated) also demonstrate stereodifferentiation. The exciplex quantum yields and the rates of formation are larger for the dyads containing (R)-NPX, which let us suggest a higher contribution from the CT processes with the (R)-optical isomer.

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Section: Conclusion Remarks Concerning Features Of the Behaviour Of mentioning

confidence: 96%

Section: Impact Of Chirality On the Photoinduced Charge Transfer In Lmentioning

confidence: 99%

Section: Impact Of Chirality On the Photoinduced Charge Transfer In Lmentioning

confidence: 99%

Section: Conclusion Remarks Concerning Features Of the Behaviour Of mentioning

confidence: 99%

Section: Impact Of Chirality On the Photoinduced Charge Transfer In Lmentioning

confidence: 99%

See 3 more Smart Citations

Impact of chirality on the photoinduced charge transfer in linked systems containing naproxen enantiomers

Khramtsova

Sosnovsky

Ageeva

et al. 2016

Phys. Chem. Chem. Phys.

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Designing Powerful Biindole‐Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements

Grecchi,

Bonetti,

Emanuele

et al. 2024

Chemistry A European J

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Among inherently chiral selectors of axial stereogenicity, usually resulting in very good enantiodiscrimination performances, the biindole‐based family has the additional advantage of very easy functionalization of the two nitrogen atoms with a variety of substituents with desirable properties. Aiming to evaluate the possibility of exploiting such feature to enhance the enantiodiscrimination ability of the archetype structure, a series of three inherently chiral monomers were designed and synthesized, characterised by a 2,2’‐biindole atropisomeric core conjugated to bithiophene wings enabling fast and regular electrooligomerization, and functionalised at the nitrogen atoms with an ethyl, a methoxyethyl, or a hydroxyethyl substituent. Nitrogen alkylation was also exploited to obtain for the first time the chemical resolution of the biindole selectors without employing chiral HPLC. The enantiodiscrimination ability of the selector series was comparatively evaluated in proof‐of‐concept chiral voltammetry experiments with a “benchmark” chiral ferrocenyl probe as well as with chiral non‐steroidal anti‐inflammatory drugs naproxen and ketoprofen. The large enantiomer potential differences for all probes increased in the ethyl < methoxyethyl ≪ hydroxyethyl sequence of selector substituents, supporting our assumption on the beneficial role of an additional coordination element. The powerful hydroxyethyl selector was also applied to ketoprofen in a commercial drug matrix.

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Inhibition of Human α‐Methylacyl CoA Racemase (AMACR): a Target for Prostate Cancer

et al. 2013

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The enzyme α-methylacyl CoA racemase (AMACR) is involved in the metabolism of branched-chain fatty acids and has been identified as a promising therapeutic target for prostate cancer. By using the recently available human AMACR from HEK293 kidney cell cultures, we tested a series of new rationally designed inhibitors to determine the structural requirements in the acyl component. An N-methylthiocarbamate (Ki=98 nM), designed to mimic the proposed enzyme-bound enolate, was found to be the most potent AMACR inhibitor reported to date.

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Chiral inversion of 2-arylpropionyl-CoA esters by human α-methylacyl-CoA racemase 1A (P504S)—a potential mechanism for the anti-cancer effects of ibuprofen

Cited by 39 publications

References 22 publications

Impact of chirality on the photoinduced charge transfer in linked systems containing naproxen enantiomers

Impact of chirality on the photoinduced charge transfer in linked systems containing naproxen enantiomers

Designing Powerful Biindole‐Based Inherently Chiral Selectors: Enhancing Enantiodiscrimination by Core Functionalization with Additional Coordination Elements

Inhibition of Human α‐Methylacyl CoA Racemase (AMACR): a Target for Prostate Cancer

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