How Acidic Is Carbonic Acid?

Pines, Dina; Ditkovich, Julia; Mukra, Tzach; Miller, Yifat; Kiefer, Philip M.; Daschakraborty, Snehasis; Hynes, James T.; Pines, Ehud

doi:10.1021/acs.jpcb.5b12428

Cited by 78 publications

(101 citation statements)

References 69 publications

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“…This proton transfer (PT) reaction within a hydrogen (H)-bonded complex was found to be barrierless and very rapid, consistent with the strong thermodynamic driving force inferred from the difference in acid strengths of H 2 CO 3 and the base’s conjugate acid CH 3 NH 3 + , a reactivity result of relevance for our proposal described in more detail elsewhere, 4 that H 2 CO 3 has the potential of being a major protonating agent of, for example, nitrogen bases in the blood. 5 …”

Section: Introductionsupporting

confidence: 80%

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution II: Solvent Coordinate-Dependent Reaction Path

et al. 2016

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The protonation of methylamine base CH3NH2 by carbonic acid H2CO3 within a hydrogen (H)-bonded complex in aqueous solution was studied via Car–Parrinello dynamics in the preceding paper (Daschakraborty, S.; Kiefer, P. M.; Miller, Y.; Motro, Y.; Pines, D.; Pines, E.; Hynes, J. T. J. Phys. Chem. B 2016, DOI: 10.1021/acs.jpcb.5b12742). Here some important further details of the reaction path are presented, with specific emphasis on the water solvent’s role. The overall reaction is barrierless and very rapid, on an ∼100 fs time scale, with the proton transfer (PT) event itself being very sudden (<10 fs). This transfer is preceded by the acid–base H-bond’s compression, while the water solvent changes little until the actual PT occurrence; this results from the very strong driving force for the reaction, as indicated by the very favorable acid-protonated base ΔpKa difference. Further solvent rearrangement follows immediately the sudden PT’s production of an incipient contact ion pair, stabilizing it by establishment of equilibrium solvation. The solvent water’s short time scale ∼120 fs response to the incipient ion pair formation is primarily associated with librational modes and H-bond compression of water molecules around the carboxylate anion and the protonated base. This is consistent with this stabilization involving significant increase in H-bonding of hydration shell waters to the negatively charged carboxylate group oxygens’ (especially the former H2CO3 donor oxygen) and the nitrogen of the positively charged protonated base’s NH3+.

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Section: Introductionsupporting

confidence: 80%

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution II: Solvent Coordinate-Dependent Reaction Path

et al. 2016

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“…18 This statement is supported by the rapid, activationless character of the PT reaction that we will find within. Nonetheless, the intrinsic PT reaction for H 2 CO 3 with nitrogen bases such as methylamine is key for its chemistry in a biochemical context.…”

Section: Introductionsupporting

confidence: 52%

“…34,35 Thus, Δp K a ∼ 7 for the reaction: H 2 CO 3 is a far stronger acid than is CH 3 NH 3 + . This Δp K a is already past the transition, near Δp K a ∼ 5 16,18,31–33 between activated and activation-less PT. This Δp K a ∼ 7 acidity difference corresponds to a strongly favorable reaction free energy asymmetry ∼ −10 kcal/mol for the PT reaction.…”

Section: Introductionmentioning

confidence: 87%

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution I: Acid and Base Coordinate and Charge Dynamics

et al. 2016

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Protonation by carbonic acid H2CO3 of the strong base methylamine CH3NH2 in a neutral contact pair in aqueous solution is followed via Car–Parrinello molecular dynamics simulations. Proton transfer (PT) occurs to form an aqueous solvent-stabilized contact ion pair within 100 fs, a fast time scale associated with the compression of the acid–base hydrogen-bond (H-bond), a key reaction coordinate. This rapid barrierless PT is consistent with the carbonic acid-protonated base pKa difference that considerably favors the PT, and supports the view of intact carbonic acid as potentially important proton donor in assorted biological and environmental contexts. The charge redistribution within the H-bonded complex during PT supports a Mulliken picture of charge transfer from the nitrogen base to carbonic acid without altering the transferring hydrogen’s charge from approximately midway between that of a hydrogen atom and that of a proton.

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“…The CO 2 + H 2 O ↔ H 2 CO 3 equilibrium lays heavily to the left in favor of dissolved CO 2 , and the true concentration of H 2 CO 3 is very much lower than the combined value. Thus, the acidity of H 2 CO 3 is far greater, and the basicity of HCO 3 − is much lower than its apparent pKa would imply . The relatively low [Pi] (and soluble monoesters thereof) in plasma (~1 m m ) compared to intracellular levels (>10 m m ) should result in the spontaneous activation half‐life of laromustine being nearly equivalent within plasma and normal cells, despite the plasma being ~0.2 pH units more alkaline (pH 7.4 versus 7.2).…”

Section: Resultsmentioning

confidence: 99%

“…Deaths at the higher dosage levels are due to drug toxicity. The approximate ED 50 and LD 50 values are indicated. Panel (d), Cancer cells frequently utilize aerobic glycolysis (the Warburg effect) as their major energy producing pathway even in the presence of sufficient oxygen for normal aerobic glucose oxidation.…”

Section: Introductionmentioning

confidence: 99%

pH‐dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)hydrazine prodrugs

et al. 2017

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Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short-lived chloroethylating agent with anticancer activity. The short half-life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl-based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells. K E Y W O R D Salkylation, cross-linking, intracellular pH, laromustine, methyl isocyanate, MGMT, phosphate, sulfonylhydrazine, targeted chemotherapy

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How Acidic Is Carbonic Acid?

Cited by 78 publications

References 69 publications

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution II: Solvent Coordinate-Dependent Reaction Path

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution II: Solvent Coordinate-Dependent Reaction Path

Reaction Mechanism for Direct Proton Transfer from Carbonic Acid to a Strong Base in Aqueous Solution I: Acid and Base Coordinate and Charge Dynamics

pH‐dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)hydrazine prodrugs

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