Isabelle Sasaki

Two functions, one molecule: a metal-binding and a targeting moiety to combat Alzheimer's disease.

It is estimated that Alzheimer’s disease (AD) strikes 5 % of people over the age of 65. In Western countries, this number was 15 % in the mid 1990s and is estimated to exceed 20 % in 2020. The increasing number of AD victims expected in the near future will place the healthcare system under increasing pressure. To date there is no disease-modifying therapy available. This clearly underlines the need to find new and more efficient medical treatments for AD. Alzheimer’s disease is a complex multifactorial neurodegenerative disease in which many genetic and environmental factors are involved. In this respect, drugs exhibiting several therapeutic activities that intervene in different biological functions in the development of AD seem to be very attractive. A variation of this concept is to add a targeting moiety that brings and concentrates the other moiety/ ies at its/their place of action, and thus potentially increases the drug’s efficiency and reduces its side effects. Such multitarget-directed molecules are expected to have a better therapeutic profile to combat such complex diseases. What are the preferred targets in AD? As the disease is multifactorial, there are several different processes linked to AD. Two of the most prominent ones are the processes leading to the two morphological hallmarks of AD: the aggregation of the peptide amyloid-b (Ab) to form amyloid plaques and the formation of neurofibrillary tangles (NFTs) by the hyperphosphorylated tau protein. In particular, the former one has been considered to be a central process and a relatively early event in the cascade process that leads to AD. A large number of researchers consider the so-called “amyloid cascade hypothesis” (Scheme 1) to be the key event in AD etiology. This hypothesis suggests that the mismetabolism of Ab and its amyloid-precursor protein (APP) is the initiating event in AD pathogenesis, and subsequently leads to the aggregation of Ab. The formation of Ab aggregates would instigate further pathological events, including the formation of NFTs and the disruption of synaptic connections; this would lead to a reduction in neurotransmitters, the death of tangle-bearing neurons and dementia (Scheme 1). Aggregation intermediates (often called oligomers) are now considered to be more toxic than amyloid plaques; and the production of reactive oxygen spe-

Molecular materials for switchable nonlinear optics in the solid state, based on ruthenium-nitrosyl complexes

The promising class of (polypyridine-ruthenium)-nitrosyl complexes capable of high yield Ru–NO/Ru–ON isomerization is targeted as a potential molecular device for the achievement of complete NLO switches in the solid state. A computational investigation conducted at the PBE0/6-31+G** DFT level for benchmark systems of general formula [R-terpyridine-RuIICl2(NO)](PF6) (R being a substituent with various donating or withdrawing capabilities) leads to the suggestion that an isomerization could produce a convincing NLO switch (large value of the βON/βOFF ratio) for R substituents of weak donating capabilities. Four new molecules were obtained in order to test the synthetic feasibility of this class of materials with R = 4′-p-bromophenyl, 4′-p-methoxyphenyl, 4′-p-diethylaminophenyl, and 4′-p-nitrophenyl. The different cis-(Cl,Cl) and trans-(Cl,Cl) isomers can be separated by HPLC, and identified by NMR and X-ray crystallographic studies.

Synthesis of Chiral Molecules Containing Pyridine and 1,3-Pyrimidine Units: Potential Building Blocks for Helicating and Caging Ligands

Abstract A simple and efficient method for the synthesis of new chiral polyaza heterocylic structures containing pyridines and 1,3-pyrimidine units has been developed. It is based on the reaction of the appropriate enaminones with optically pure carboxamidine derived from the commercially available (R)-(−)-myrtenal.

trans- and cis-(Cl,Cl)-[RuII(FT)Cl2(NO)](PF6): promising candidates for NO release in the NIR region

cis- and trans-(Cl,Cl)-[RuII(FT)Cl2(NO)](PF6) complexes show efficient NO photodelivery upon two-photon excitation in the NIR region. Moreover, cytotoxicity and phototoxicity studies provide evidence that these complexes are promising candidates as photoactivatable molecular tools for resection of malignancies.

The effect of the conformation on the quadratic nonlinear optical response of metal carbonyl based chromophores with one-dimensional charge transfer capabilities: a computational investigation

The synthesis and the quadratic nonlinear optical (NLO) properties of (4-(4′-dimethylaminophenyl)pyridine)chromium and tungsten pentacarbonyl are reported. Experimentally, the chromophores exhibit molecular hyperpolarizabilities (β) equal to 15.5 and 21.7 × 10−30 cm5 esu−1, respectively at 1.064 μm, which arise from a charge transfer capability along the molecular C2 symmetry axis, in relation to the π-conjugated structure of the ligand. At a more fundamental level, these molecules have been investigated as possible synthetic targets to illustrate the ZINDO prediction that, in chromophores with one-dimensional charge transfer capabilities a specific set of substituents could be found to switch the β direction, on passing from a ground state geometry with co-planar aromatic rings to a conformation in which the rings are perpendicular. Due to the C2 symmetry requirement, this situation implies that β is necessarily vanishing for a specific conformation. The possibilities to observe experimentally and to use this intriguing effect in a perspective of a molecular switch are critically evaluated.

The simple production of nonsymmetric quaterpyridines through Kröhnke pyridine synthesis

Summary Quaterpyridines have been demonstrated to be useful building blocks in metallo-supramolecular chemistry; however, their synthesis requires the preparation of sensitive building blocks. We present here three examples of nonsymmetric quaterpyridines that were easily obtained in yields of 70–85% by condensation of commercially available enones with 6-acetyl-2,2’:6’,2’’-terpyridine through a Kröhnke pyridine synthesis. Easy access to 6-acetyl-2,2’:6’,2’’-terpyridine starting from 2,6-diacetylpyridine and 2-acetylpyridine is described. The X-ray analysis of a chiral quaterpyridine and its Pt(II) complex is presented.

New annelated 2,2′:6′,2′′-terpyridines and their Ru(II) complexes: synthesis and characterisation

Abstract Two annealed terpyridine ligands have been prepared in which the substituted groups are located on the 4,4′′,5,5′′ positions. The corresponding homoleptic ruthenium(II) complexes were obtained in excellent yields, one of which was analysed by X-ray crystallography.

Ruthenium bis(bipyridine) sulfoxide complexes: new catalysts for alkene epoxidation

The ruthenium bis(bipyridine) sulfoxide complexes Ru-1 and Ru-2 exhibit high catalytic activity for epoxidation of unfunctionalized olefins in the presence of [bis(acetoxy)iodo]benzene; with the chiral catalyst, Ru-2, asymmetric induction up to 94% was observed for beta-methylstyrene.

Synthesis of Dicyanopyridines

Abstract Synthesis of the title compounds in four steps using inexpensive collidine and lutidine as starting materials is described.

2,6-Bis(5,6-dicyclohexyl-1,2,4-triazin-3-yl)-pyridine-dichloromethane-wa ter (1/1/0.625)

The title compound, 2,6-bis(5,6-dicyclohexyl-1,2,4-triazin-3-yl) pyridine, C35H57N7.CH2Cl2.0.625H(2)O, crystallizes with two molecules in the asymmetric unit, along with 1.25 molecules of water and two molecules of dichloromethane. The water molecules are involved in hydrogen-bond interactions with some N atoms of the triazine rings.