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The C–F bond activation of perfluorobenzene and perfluoropyridine have been achieved by means of the complex [Pt2(μ-S)2(dppp)2], where dppp denotes 1,3-bis(diphenylphosphino)propane. The reaction with the first substrate requires a long time (five days) and high temperature (reflux in toluene) to yield [Pt(o-S2C6F4)(dppp)] and [Pt3(μ3-S)2(dppp)3]F2, and involves replacement of two fluorides in the orthoposition. In contrast, the reaction with perfluoropyridine is much faster (15 min at 0 °C) yielding [Pt2(μ-S){μ-(p-SC5F4N)}(dppp)2]F, which implies the C–F activation in the paraposition with respect the pyridine nitrogen. The mechanism of both reactions has been studied computationally and the geometries of the transition states are consistent with an SNAr mechanism where a sulfido bridging ligand replaces the fluoride anion. The energy barriers corresponding to the first and the second fluoride substitution are 131.7 and 137.1 kJ mol−1for perfluorobenzene and 85.9 and 142.7 kJ mol−1for perfluoropyridine, respectively. The different energy barrier of the first substitution explains the different experimental conditions required and the various products obtained for these reactions. [ABSTRACT FROM AUTHOR]

Combining X-ray data on thioflavin-T and theoretical calculations on its binding to a peptide model for Aβ1–42fibrils gives evidence of main stabilizing interactions, which influence the dihedral angle between the two moieties of thioflavin-T and thereby its fluorescence properties; these results shed new light on possible strategies for the design of dyes to bind amyloid fibrils more specifically. [ABSTRACT FROM AUTHOR]

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 (Ml), 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)-1 H-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 β-amyloid (Aβ) peptide. This was confirmed by Aβ 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 Aβ deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics. [ABSTRACT FROM AUTHOR]

Traumatic injury to the brain is one of the leading causes of injury-related death or disability, but current therapies are limited. Previously it has been shown that the antioxidant proteins metallothioneins (MTs) are potent neuroprotective factors in animal models of brain injury. The exogenous administration of MTs causes effects consistent with the roles proposed from studies in knock-out mice. We herewith report the results comparing full mouse MT-1 with the independent alpha and beta domains, alone or together, in a cryoinjury model. The lesion of the cortex caused the mice to perform worse in the horizontal ladder beam and the rota-rod tests; all the proteins showed a modest effect in the former test, while only full MT-1 improved the performance of animals in the rota-rod, and the alpha domain showed a rather detrimental effect. Gene expression analysis by RNA protection assay demonstrated that all proteins may alter the expression of host-response genes such as GFAP, Mac1 and ICAM, in some cases being the beta domain more effective than the alpha domain or even the full MT-1. A MT-1-to-MT-3 mutation blunted some but not all the effects caused by the normal MT-1, and in some cases increased its potency. Thus, splitting the two MT-1 domains do not seem to eliminate all MT functions but certainly modifies them, and different motifs seem to be present in the protein underlying such functions.

The high nucleophilicity of the sulfur atoms in [Pt(2)(dppp)(2)(micro-S)(2)] triggers a C-F activation process in 1,3-difluoro-2-propanol that leads to the [Pt(2)(dppp)(2)(micro-S)(micro-SCH(2)CH(OH)CH(2)F]F product through a S(N)2 mechanism, where the O-HF hydrogen bond established from the alcohol group of the organic substrate is essential for assisting the departure of the fluoride anion.