Determination of the Dissociation Constants of Urocanic Acid Isomers in Aqueous Solutions

Juusola, Pekka M.; Minkkinen, Pentti; Leino, Lasse; Laihia, Jarmo K.

doi:10.1007/s00706-007-0687-1

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…They are presented in Tables 1 and 2 in the logarithmic form. Protonation constants for both ligands are in a satisfactory accordance with the literature data, obtained solely by UV-vis (lit., 19 3.43 and 5.80 for trans-UCA, and 2.7 and 6.65 for cis-UCA). The pK a values determined by potentiometry are also close to those obtained in our UV-vis titrations.…”

Section: Resultsmentioning

confidence: 97%

“…The blue line represents linear dependence for ligands binding Ni(II) monodentately by the imidazole nitrogen (blue circles) described by the equation: log K Ni NiL = 0.225pK H HL + 1.380, valid for the 0.1 M ionic strength. 19,20 Ligands with chelating groups (red squares) show stability enhancement. Data shown are for histidine 22 (1), 4-(2-methylaminoethyl)imidazole 23 (2), histamine 24 (3), 2,2'-biimidazole 25 (4), imidazole-4-acetate 25 (5), 4(5)-aminoimidazole-5(4)-carboxamide 25 (6), 5-chloro-1-methylimidazole 20 (7), trans-UCA (8), cis-UCA (9), imidazole 20,24 (10), N-(2,3,5,6-tetrafluorophenyl)imidazole 20 (11), 4'-(imidazol-1-yl)acetophenone 20 (12), acetylhistidine 26 (13) and 1-methylimidazole 20 (14).…”

Section: Dalton Transactions Papermentioning

confidence: 99%

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cis-Urocanic acid as a potential nickel(ii) binding molecule in the human skin

et al. 2014

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5cis-Urocanic acid, a derivative of histidine, is one of essential components of human skin. We found that it can bind nickel(II) ions in a pH-dependent manner, with the dissociation constant in the low millimolar range, as revealed by potentiometry, and confirmed by isothermal titration calorimetry and UV-vis spectroscopy. The binding occurs within the physiological skin pH range. Considering the fact that cisurocanic acid is present in the human skin in concentrations as high as millimolar, this molecule may be a 10 physiologically important player in nickel trafficking in the human organism.

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Section: Resultsmentioning

confidence: 97%

Section: Dalton Transactions Papermentioning

confidence: 99%

cis-Urocanic acid as a potential nickel(ii) binding molecule in the human skin

et al. 2014

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“…This new mode of action of cis-UCA, which we have named as the protodynamic action, constitutes a novel concept of anticancer therapy. The transportation and release of protons into the cytosol is based on the unique second acid dissociation constant (pKa 2 ) of cis-UCA [ 9 ], and it is inherently independent of enzymes and membrane receptors.…”

Section: Introductionmentioning

confidence: 99%

Molecular targets for the protodynamic action of cis-urocanic acid in human bladder carcinoma cells

et al. 2010

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Backgroundcis-urocanic acid (cis-UCA) is an endogenous amino acid metabolite capable of transporting protons from the mildly acidic extracellular medium into the cell cytosol. The resulting intracellular acidification suppresses many cellular activities. The current study was aimed at characterizing the molecular mechanisms underlying cis-UCA-mediated cytotoxicity in cultured cancer cells.Methods5367 bladder carcinoma cells were left untreated or treated with cis-UCA. Cell death was assessed by measuring caspase-3 activity, mitochondrial membrane polarization, formation and release of cytoplasmic histone-associated DNA fragments, and cellular permeabilization. Cell viability and metabolic activity were monitored by colorimetric assays. Nuclear labelling was used to quantify the effects of cis-UCA on cell cycle. The activity of the ERK and JNK signalling pathways was studied by immunoblotting with specific antibodies. Phosphatase activity in cis-UCA-treated cells was determined by assay kits measuring absorbance resulting from the dephosphorylation of an artificial substrate. All statistical analyses were performed using the two-way Student's t-test (p < 0.05).ResultsHere we report that treatment of the 5637 human bladder carcinoma cells with 2% cis-UCA induces both apoptotic and necrotic cell death. In addition, metabolic activity of the 5637 cells is rapidly impaired, and the cells arrest in cell cycle in response to cis-UCA. Importantly, we show that cis-UCA promotes the ERK and JNK signalling pathways by efficiently inhibiting the activity of serine/threonine and tyrosine phosphatases.ConclusionsOur studies elucidate how cis-UCA modulates several cellular processes, thereby inhibiting the proliferation and survival of bladder carcinoma cells. These anti-cancer effects make cis-UCA a potential candidate for the treatment of non-muscle invasive bladder carcinoma.

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“…, submitted). The mode of action is based on the second acid dissociation constant (pK a2 ) of cis‐ UCA [7]. As cis‐ UCA is a natural compound with no known serious side‐effects, protodynamic therapy is a promising new treatment approach for various malignancies.…”

Section: Introductionmentioning

confidence: 99%

“…Our previous results showed the antiproliferative effects of cis -UCA on several human tumour cell lines in culture, and on human melanoma xenograft transplants in mice in vivo (Laihia et al , submitted). The mode of action is based on the second acid dissociation constant (pK a2 ) of cis-UCA [7]. As cis-UCA is a natural compound with no known serious side-effects, protodynamic therapy is a promising new treatment approach for various malignancies.…”

Section: Introductionmentioning

confidence: 99%

Protodynamic therapy for bladder cancer: in vitro results of a novel treatment concept

Laihia¹,

Pylkkänen²,

Laato

et al. 2009

BJU International

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paclitaxel for 2 h, to simulate drug exposure on intravesical instillation. The combination of cis-UCA and chemotherapeutic agents was also studied. Cell viability was measured with a colorimetric assay. RESULTScis-UCA inhibited proliferation and suppressed the survival of cells at an extracellular pH ≤ pK a2 of 6.65 but to a lesser degree at pH > pK a2 , as suggested by the protodynamic theory. cis -UCA caused dosedependent, irreversible termination of cell proliferation. The number of viable surviving BC cells decreased by > 85% with 2% cis-UCA ( P < 0.001). Viable cells disappeared completely with 4% and 6% cis-UCA after a 2-h treatment, and by 90% with 6% cis-UCA within a 15-min exposure. These effects were associated with distinct morphological changes. The other drugs tested had a clearly lower effect on cell survival. Interestingly, when combined, cis-UCA markedly enhanced the cytotoxic effect of epirubicin. CONCLUSIONcis -UCA is a potent antiproliferative agent in bladder cancer cell cultures. As our previous non-clinical studies showed that cis-UCA is locally and systemically well tolerated, protodynamic therapy with cis -UCA is a promising intravesical treatment for bladder cancer. KEYWORDSurinary bladder neoplasms, cell proliferation, drug pulse therapies, combined antineoplastic agents Study Type -Therapy (controlled) Level of Evidence 3b OBJECTIVETo present a novel treatment approach for urinary bladder cancer, protodynamic therapy, which comprises inhibition of cancer cell proliferation by intracellular acidification; cis-urocanic acid ( cis-UCA) was investigated as a protodynamic drug in bladder cancer cell cultures and compared with conventional chemotherapeutic agents. MATERIALS AND METHODSThe moderately differentiated cell line 5637 and the poorly differentiated T24 cell line were exposed to cis-UCA for 0.25-2 h, and to epirubicin, doxorubicin, cisplatin and

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Determination of the Dissociation Constants of Urocanic Acid Isomers in Aqueous Solutions

Cited by 11 publications

References 31 publications

cis-Urocanic acid as a potential nickel(ii) binding molecule in the human skin

cis-Urocanic acid as a potential nickel(ii) binding molecule in the human skin

Molecular targets for the protodynamic action of cis-urocanic acid in human bladder carcinoma cells

Protodynamic therapy for bladder cancer: in vitro results of a novel treatment concept

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