A Theoretical Investigation of <i>p</i>-Hydroxyphenacyl Caged Phototrigger Compounds:  An Examination of the Excited State Photochemistry of <i>p</i>-Hydroxyphenacyl Acetate

Chen, Xuebo; Ma, Chensheng; Kwok, Wai Ming; Guan, Xiangguo; Du, Yong; Phillips, David Lee

doi:10.1021/jp064490e

Cited by 20 publications

(34 citation statements)

References 53 publications

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“…In earlier publications, k 1 described the formation of GTP from NPEcaged GTP, which is slower than the process observed here. The pHP-caged GTP used here forms GTP within 500 ps after photolysis, much faster than it takes to record the first spectrum (Ϸ40 ms) (23,24). Thus, we now observe with k 1 an additional process of the Ras⅐GAP system that was masked by the slow caged compound in earlier measurements.…”

Section: Resultsmentioning

confidence: 47%

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The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy

Kötting

Kallenbach

Suveyzdis

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

112

142

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Members of the Ras superfamily of small G proteins play key roles in signal transduction pathways, which they control by GTP hydrolysis. They are regulated by GTPase activating proteins (GAPs). Mutations that prevent hydrolysis cause severe diseases including cancer. A highly conserved ''arginine finger'' of GAP is a key residue. Here, we monitor the GTPase reaction of the Ras⅐RasGAP complex at high temporal and spatial resolution by time-resolved FTIR spectroscopy at 260 K. After triggering the reaction, we observe as the first step a movement of the switch-I region of Ras from the nonsignaling ''off'' to the signaling ''on'' state with a rate of 3 s ؊1 . The next step is the movement of the ''arginine finger'' into the active site of Ras with a rate of k2 ‫؍‬ 0.8 s ؊1 . Once the arginine points into the binding pocket, cleavage of GTP is fast and the protein-bound Pi intermediate forms. The switch-I reversal to the ''off'' state, the release of Pi, and the movement of arginine back into an aqueous environment is observed simultaneously with k3 ‫؍‬ 0.1 s ؊1 , the rate-limiting step. Arrhenius plots for the partial reactions show that the activation energy for the cleavage reaction is lowered by favorable positive activation entropy. This seems to indicate that protein-bound structured water molecules are pushed by the ''arginine finger'' movement out of the binding pocket into the bulk water. The proposed mechanism shows how the high activation barrier for phosphoryl transfer can be reduced by splitting into partial reactions separated by a Pi-intermediate.enzyme catalysis ͉ FTIR spectroscopy ͉ GTPases ͉ phosphate ͉ proteins

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Section: Resultsmentioning

confidence: 47%

“…The GTPase reaction is commonly started by a laser flash, using photolabile caged GTP. Here, para-hydroxyphenacyl (pHP)-GTP, instead of nitrophenylethyl (NPE)-GTP, is used because the release of GTP is much faster: 500 ps in contrast to Ϸ500 ms (23,24). This now allows possible reaction steps preceding catalysis to be monitored.…”

mentioning

confidence: 99%

The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy

Kötting

Kallenbach

Suveyzdis

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

112

142

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“…Likewise, the instability of 7e to acid precluded its conversion to 2-methoxy-pHP diethyl phosphate which, instead, was obtained by the Sn2 bromide displacement from α-bromo-2-methoxy-4-hydroxyacetophenone, the method previously reported for most pHP phosphates. 10b …”

Section: Resultsmentioning

confidence: 99%

“…7 Similar photoinduced ring contraction reactions have been hallmarks of FR, WR, and pWR reactions, particularly α-diazocycloalkanones. 8 These similarities plus recent mechanism studies of the photo-Favorskii reaction 3c,7b,9,10 have added significantly to our understanding of the rearrangement reaction, inviting a more in depth comparison between the pFR and the more well-established pWR. 2,11 …”

Section: Introductionmentioning

confidence: 99%

2-Diazo-1-(4-hydroxyphenyl)ethanone: a versatile photochemical and synthetic reagent

Senadheera

Evans

Toscano

et al. 2014

Photochem Photobiol Sci

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α-Diazo arylketones are well-known substrates for Wolff rearrangement to phenylacetic acids through a ketene intermediate by either thermal or photochemical activation. Likewise, α-substituted p-hydroxyphenacyl (pHP) esters are substrates for photo-Favorskii rerrangements to phenylacetic acids by a different pathway that purportedly involves a cyclopropanone intermediate. In this paper, we show that the photolysis of a series of α-diazo-p-hydroxyacetophenones and p-hydroxyphenacyl (pHP) α-esters both generate the identical rearranged phenylacetates as major products. Since α-diazo-p-hydroxyacetophenone (1a, pHP N2) contains all the necessary functionalities for either Wolff or Favorskii rearrangement, we were prompted to probe this intriguing mechanistic dichotomy under conditions favorable to the photo-Favorskii reangement, i.e., photolysis in hydroxylic media. An investigation of the mechanism for conversion of 1a to p-hydroxyphenyl acetic acid (4a) using time-resolved infrared (TRIR) spectroscopy clearly demonstrates the formation of a ketene intermediate that is subsequently trapped by solvent or nucleophiles. The photoreaction of 1a is quenched by oxygen and sensitized by triplet sensitizers and the quantum yields for 1a–c range from 0.19 to a robust 0.25. The lifetime of the triplet, determined by Stern-Volmer quenching, is 15 ns with a rate for appearance of 4a of k = 7,1 × 106 s−1 in aq. acetonitrile (1:1 v:v). These studies establish that the primary rearrangement pathway for 1a involves ketene formation in accordance with the photo-Wolff rearrangement. Furthermore we have also demonstrated the synthetic utility of 1a as an esterification and etherification reagent with a variety of substituted α-diazo-p-hydroxyacetophenones, using them as synthons for efficiently coupling it to acids and phenols to produce pHP protect substrates.

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“…For pHP, the reactive excited state is a π,π* triplet that is favored only in hydroxylic solvents, especially H 2 O [15,45–46 48]. In non-hydroxylic solvents, the (n,π*) 3 dominates which leads to the classical α- and β-homolytic cleavage and H-abstraction reactions.…”

Section: Discussionmentioning

confidence: 99%

Photorelease of phosphates: Mild methods for protecting phosphate derivatives

Senadheera¹,

Yousef²,

Givens³

2014

Beilstein J. Org. Chem.

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SummaryWe have developed a new photoremovable protecting group for caging phosphates in the near UV. Diethyl 2-(4-hydroxy-1-naphthyl)-2-oxoethyl phosphate (14a) quantitatively releases diethyl phosphate upon irradiation in aq MeOH or aq MeCN at 350 nm, with quantum efficiencies ranging from 0.021 to 0.067 depending on the solvent composition. The deprotection reactions originate from the triplet excited state, are robust under ambient conditions and can be carried on to 100% conversion. Similar results were found with diethyl 2-(4-methoxy-1-naphthyl)-2-oxoethyl phosphate (14b), although it was significantly less efficient compared with 14a. A key step in the deprotection reaction in aq MeOH is considered to be a Favorskii rearrangement of the naphthyl ketone motif of 14a,b to naphthylacetate esters 25 and 26. Disruption of the ketone-naphthyl ring conjugation significantly shifts the photoproduct absorption away from the effective incident wavelength for decaging of 14, driving the reaction to completion. The Favorskii rearrangement does not occur in aqueous acetonitrile although diethyl phosphate is released. Other substitution patterns on the naphthyl or quinolin-5-yl core, such as the 2,6-naphthyl 10 or 8-benzyloxyquinolin-5-yl 24 platforms, also do not rearrange by aryl migration upon photolysis and, therefore, do not proceed to completion. The 2,6-naphthyl ketone platform instead remains intact whereas the quinolin-5-yl ketone fragments to a much more complex, highly absorbing reaction mixture that competes for the incident light.

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A Theoretical Investigation of p-Hydroxyphenacyl Caged Phototrigger Compounds: An Examination of the Excited State Photochemistry of p-Hydroxyphenacyl Acetate

Cited by 20 publications

References 53 publications

The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy

The GAP arginine finger movement into the catalytic site of Ras increases the activation entropy

2-Diazo-1-(4-hydroxyphenyl)ethanone: a versatile photochemical and synthetic reagent

Photorelease of phosphates: Mild methods for protecting phosphate derivatives

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