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The use of bis(pinacolato)diboron as the terminal reductant allows the efficient Ni-catalyzed coupling of unactivated secondary and primary alkyl halides, generating the C(sp 3 )-C(sp 3 ) coupling products in good yields. The mild catalytic conditions display excellent functional group tolerance, and good chemoselectivities which require only 1.5 equiv. of primary bromides for the coupling with secondary bromides. Preliminary mechanistic studies suggest that an in situ organoborane/Suzuki process is not likely. It was identified that the base and ligand have more profound impact on selecting this reductive coupling pathway. The good chemoselectivity appears to be evoked by the formation of Ni-Bpin catalytic intermediates, which demands matched sizes and reactivities of the alkyl halide coupling partners for optimal coupling efficiency.Scheme 1 Coupling of ((3-bromopropoxy)methyl)benzene and 4-bromo-1tosylpiperidine.

Inspired by the concept of knowledge-based scoring functions, a new quantitative structure-activity relationship (QSAR) approach is introduced for scoring protein-ligand interactions. This approach considers that the strength of ligand binding is correlated with the nature of specific ligand/binding site atom pairs in a distance-dependent manner. In this technique, atom pair occurrence and distance-dependent atom pair features are used to generate an interaction score. Scoring and pattern recognition results obtained using Kernel PLS (partial least squares) modeling and a genetic algorithm-based feature selection method are discussed.

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A host:guest-derived gene delivery vector has been developed, based on the self-assembly of cationic β-CD derivatives with a poly(vinyl alcohol)MW27kD (PVA) main chain polymer bearing poly(ethylene glycol)MW750 (PEG) or MW2000 PEG and acid-labile adamantane-modified (Ad) grafts through an acid-sensitive benzylidene acetal linkage. These components were investigated for their ability to promote supramolecular complex formation with pDNA using two different assembly schemes, involving either pre-complexation of the pendant Ad-PVA-PEG polymer with the cationic β-CD derivatives before pDNA condensation (Method A) or pDNA condensation with the cationic β-CD derivatives prior to addition of Ad-PVA-PEG to engage host:guest complexation (Method B). The pendant polymers were observed to degrade under acidic conditions, while remaining intact for more than 5 d at pH 7. HeLa cell culture data shows that these materials have 103-fold lower cytotoxicities than 25 kD bPEI, while maintaining transfection efficiencies that are superior to those observed for this benchmark cationic polymer transfection reagent when the Method A assembly scheme is employed. These findings suggest that degradable cationic polymer constructs employing multivalent host:guest interactions may be an effective and low-toxicity vehicle for delivering nucleic acid cargo to target cells.

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