Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer's amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(II), Zn(II)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of beta-amyloid (Abeta) peptide. This was confirmed by Abeta aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Abeta deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics.
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PMID:Design, selection, and characterization of thioflavin-based intercalation compounds with metal chelating properties for application in Alzheimer's disease. 1913 67

Atomization energies at 0 K and enthalpies of formation at 0 and 298 K are predicted for the BH(4-n)X(n)(-) and the BH(3-n)X(n)F(-) compounds for (X = F, Cl, Br, I, NH(2), OH, and SH) from coupled cluster theory (CCSD(T)) calculations with correlation-consistent basis sets and with an effective core potential on I. To achieve near chemical accuracy (+/-1.0 kcal/mol), additional corrections were added to the complete basis set binding energies. The hydride, fluoride, and X(-) affinities of the BH(3-n)X(n) compounds were predicted. Although the hydride and fluoride affinities differ somewhat in their magnitudes, they show very similar trends and are both suitable for judging the Lewis acidities of compounds. The only significant differences in their acidity strength orders are found for the boranes substituted with the strongly electron withdrawing and back-donating fluorine and hydroxyl ligands. The highest H(-) and F(-) affinities are found for BI(3) and the lowest ones for B(NH(2))(3). Within the boron trihalide series, the Lewis acidity increases monotonically with increasing atomic weight of the halogen, that is, BI(3) is a considerably stronger Lewis acid than BF(3). For the X(-) affinities in the BX(3), HBX(2), and H(2)BX series, the fluorides show the highest values, whereas the amino and mercapto compounds show the lowest ones. Hydride and fluoride affinities of the BH(3-n)X(n) compounds exhibit linear correlations with the proton affinity of X(-) for most X ligands. Reasons for the correlation are discussed. A detailed analysis of the individual contributions to the Lewis acidities of these substituted boranes shows that the dominant effect in the magnitude of the acidity is the strength of the BX(3)(-)-F bond. The main contributor to the relative differences in the Lewis acidities of BX(3) for X, a halogen, is the electron affinity of BX(3) with a secondary contribution from the distortion energy from planar to pyramidal BX(3). The B-F bond dissociation energy of X(3)B-F(-) and the distortion energy from pyramidal to tetrahedral BX(3)(-) are of less importance in determining the relative acidities. Because the electron affinity of BX(3) is strongly influenced by the charge density in the empty p(z) lowest unoccupied molecular orbital of boron, the amount of pi-back-donation from the halogen to boron is crucial and explains why the Lewis acidity of BF(3) is significantly lower than those of BX(3) with X = Cl, Br, and I.
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PMID:Lewis acidities and hydride, fluoride, and X- affinities of the BH(3-n)Xn compounds for (X = F, Cl, Br, I, NH2, OH, and SH) from coupled cluster theory. 1969 51