Prediction of pKa values of phenolic and nitrogen-containing compounds by computational chemical analysis compared to those measured by liquid chromatography

Hanai, Toshihiko; Koizumi, Koshiro; Kinoshita, Toshio; Arora, Rohit; Ahmed, Farrukh Rafiq

doi:10.1016/s0021-9673(96)01009-6

Cited by 51 publications

(22 citation statements)

References 9 publications

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“…As in Fig. 2D, for substituted phenyl sulfones the in vitro cleavage rates (Table 1) show an excellent Hammett correlation with σ constants for substituents on the phenyl sulfone modulator reported for pK a values of substituted phenols (18) and fit the equation log k 1 = −2.08 + 1.49σ (R 2 = 0.995). Predictable, fine-tuning of in vitro β-elimination rates can thus be achieved by varying the substituent on a phenyl sulfone modulator.…”

supporting

confidence: 60%

“…As with the in vitro rates, in vivo release rates show the same excellent correlation with σ, but they are two-to threefold faster. This excellent structure-activity relationship, together with the availability of σ constants over 60 substituted phenols (18), predicts that fine-tuning of in vivo β-elimination release rates should be easily attainable. From Fig.…”

mentioning

confidence: 95%

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Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Santi

Schneider

Reid

et al. 2012

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

177

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Conjugation to macromolecular carriers is a proven strategy for improving the pharmacokinetics of drugs, with many stable polyethylene glycol conjugates having reached the market. Stable conjugates suffer several limitations: loss of drug potency due to conjugation, confining the drug to the extracellular space, and the requirement for a circulating conjugate. Current research is directed toward overcoming such limitations through releasable conjugates in which the drug is covalently linked to the carrier through a cleavable linker. Satisfactory linkers that provide predictable cleavage rates tunable over a wide time range that are useful for both circulating and noncirculating conjugates are not yet available. We describe such conjugation linkers on the basis of a nonenzymatic β-elimination reaction with preprogrammed, highly tunable cleavage rates. A set of modular linkers is described that bears a succinimidyl carbonate group for attachment to an amine-containing drug or prodrug, an azido group for conjugation to the carrier, and a tunable modulator that controls the rate of β-eliminative cleavage. The linkers provide predictable, tunable release rates of ligands from macromolecular conjugates both in vitro and in vivo, with half-lives spanning from a range of hours to >1 y at physiological pH. A circulating PEG conjugate achieved a 56-fold half-life extension of the 39-aa peptide exenatide in rats, and a noncirculating s.c. hydrogel conjugate achieved a 150-fold extension. Using slow-cleaving linkers, the latter may provide a generic format for once-a-month dosage forms of potent drugs. The releasable linkers provide additional benefits that include lowering C max and pharmacokinetic coordination of drug combinations. metronomic chemotherapy | implant M any drugs and drug candidates are suboptimal or ineffective because of a short duration of action. For example, peptides and proteins with promising therapeutic value often have serum half-lives of only minutes to hours. One solution to this problem involves conjugation to carriers such as polyethylene glycol (PEG), the Fc portion of IgG, serum albumin, and other longlived macromolecules. The large carriers retard kidney filtration and hence increase plasma half-life of the attached drug. Much success has been realized thus far with PEG as the macromolecular carrier. PEG is nontoxic and nonimmunogenic, and the plasma half-life is a function of hydrodynamic size. Conjugation of drugs to PEG with molecular mass ∼40 kDa has been successfully used with peptides, nucleic acids, and small molecules and can afford half-lives of up to ∼7 d in humans; as of 2011, 10 PEGylated peptide-based drugs were approved by the Food and Drug Administration (FDA) and ∼40 were in clinical trials (1, 2).All of the currently marketed PEG-protein conjugates are permanently PEGylated. Attachment of large PEG moieties often reduces activity of the drug, and higher concentrations of conjugate are necessary to achieve the required biological activity. A further limitation is that permanen...

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supporting

confidence: 60%

mentioning

confidence: 95%

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Santi

Schneider

Reid

et al. 2012

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

177

View full text Add to dashboard Cite

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“…[21] Determination of the pH-value of the acidic aqueous solution necessary for protonation of the thin films of 4 gave values around À0.2 when aqueous HCl solutions were used. The found pH-value is in stark contrast to the common pK a -value of pyridine (i.e., 5.25-5.62), [20] but these differences can be readily explained by matrix effects (hydrophobic matrix vs. hydrophilic acid) resulting in an encumbered penetration of the acid into the polymer film. [22] Indeed, by increasing the hydrophilic character of the thin films via blending with polyethylene glycol (PEG) the corresponding value could be increased from À0.2 to approximately 0.2 for a blend containing 20 wt.-% of PEG (cf.…”

Section: Photophysical Properties In the Solid Statementioning

confidence: 83%

“…[19] To give an example, 2-methylpyridine exhibits pK a -values between 4.85 and 6.21 depending on the methodology of determination. [20] However, in pure organic solvents such as THF apparent pK a -values of 34 have been reported. [19d] Additionally, when operating in organic solvents also the relative solvent basicity has to be taken into account.…”

Section: Solvent Dependencementioning

confidence: 99%

The Effect of Protonation on the Optical Properties of Conjugated Fluorene–Pyridine Copolymers

Kappaun

Horner

Kelterer

et al. 2008

Macro Chemistry & Physics

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A series of conjugated alternating and statistical copolymers of fluorene and pyridine are synthesized and characterized. The compounds under investigation, namely poly[2,7-(9,9-dihexylfluorenyl)-alt-(2,6-pyridinyl)] and poly[2,7-(9,9-dihexylfluorenyl)-stat-(2,6-pyridinyl)], are prepared by a Suzuki-type cross-coupling reaction starting from commercially available materials utilizing the recently described catalyst trans-bis(dicyclohexylamine) palladiumdiacetate (''DAPCy''). The target compounds are investigated by nuclear magnetic resonance and infrared spectroscopy, matrix-assisted laser desorption ionization time-of-flight mass spectrometry, thermal analysis, UV-Vis absorption spectroscopy, and luminescence measurements in solution and in the solid state. Special emphasis is placed on studying the consequences of protonation on the photophysical properties of the described materials. Achieving a concise microscopic understanding of the effects of protonation on the absorption and luminescence characteristics is crucial for potential applications in, e.g., optical sensors. To that aim, the results of the systematic studies of the photophysical properties are explained by quantum mechanical calculations.

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“…The results obtained were close to the literature values particularly when the authors used zwitterion buffers (TRIS, MES). Recently, the pK A values of several aromatic compounds determined by CE [8][9] have been compared to those measured by liquid chromatography.…”

Section: Introductionmentioning

confidence: 99%

Determination of weak (2.0–2.5) dissociation constants of non-UV absorbing solutes by capillary electrophoresis

et al. 1998

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SummaryCapillary electrophoresis (CE) has proved to be a fast and convenient method for the determination of the dissociation constants of non-UV absorbing solutes in the acidic pK A range (2.0-2.5). The electroosmotic flow was reversed by washing the capillary with 0.2% polybren aqueous solution. A series of background electrolytes was prepared with phenylphosphonic acid (pK A = 1.29) and [3-alanine (pK A = 3.55) with the same ionic strength and a high buffer capacity in order to improve the repeatability (0.1-0.2 %) of the electrophoretic mobility and to determine the values of pK A accurately. This procedure was applied to the determination of the dissociation constants of several alkyl-alkylphosphonic acids whose pKA values have not yet been published in the literature. In this work, their dissociation constants have been found to vary between 1.91 and 2.34 for alkyl-methylphosphonic acids and between 2.10 and 2.38 for alkyl-ethylphosphonic acids.

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Prediction of pKa values of phenolic and nitrogen-containing compounds by computational chemical analysis compared to those measured by liquid chromatography

Cited by 51 publications

References 9 publications

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

Predictable and tunable half-life extension of therapeutic agents by controlled chemical release from macromolecular conjugates

The Effect of Protonation on the Optical Properties of Conjugated Fluorene–Pyridine Copolymers

Determination of weak (2.0–2.5) dissociation constants of non-UV absorbing solutes by capillary electrophoresis

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