Femtosecond time-resolved infrared spectroscopy was used to study the formation of cyclobutane dimers in the all-thymine oligodeoxynucleotide (dT)18 by ultraviolet light at 272 nanometers. The appearance of marker bands in the time-resolved spectra indicates that the dimers are fully formed approximately 1 picosecond after ultraviolet excitation. The ultrafast appearance of this mutagenic photolesion points to an excited-state reaction that is approximately barrierless for bases that are properly oriented at the instant of light absorption. The low quantum yield of this photoreaction is proposed to result from infrequent conformational states in the unexcited polymer, revealing a strong link between conformation before light absorption and photodamage.

The vibrational cooling of azobenzene after photoisomerization is investigated by time resolved IR spectroscopy with femtosecond time resolution. Transient difference spectra were obtained in a frequency range where phenyl ring modes and the central N=N-stretching mode absorbs. The experimental data are discussed in terms of a simple theoretical model which was derived in order to account for the off-diagonal anharmonicity between the investigated high-frequency modes and the bath of the remaining low-frequency modes in a polyatomic molecule. It is shown that these off-diagonal anharmonic constants dominate the observed transient absorbance changes while the anharmonicity of the high-frequency modes themselves (diagonal anharmonicity) causes only minor effects. Based on the transient IR spectra, the energy flow in the azobenzene molecule can be described as follows: After an initial ultrafast intramolecular energy redistribution process, the decay of the related intramolecular temperature occurs via intermolecular energy transfer to the solvent on a time scale of ca. 20 ps.

In neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood–brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1114-9) contains supplementary material, which is available to authorized users.

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