No abstract

Astrogliosis has a very dynamic response during the progression of spinal cord injury, with beneficial or detrimental effects on recovery. It is therefore important to develop strategies to target activated astrocytes and their harmful molecular mechanisms so as to promote a protective environment to counteract the progression of the secondary injury. The challenge is to formulate an effective therapy with maximum protective effects, but reduced side effects. In this study a functionalized nanogel-based nanovector was selectively internalized in activated mouse or human astrocytes. Rolipram, an anti-inflammatory drug, when administered by these nanovectors limited the inflammatory response in A1 astrocytes, reducing iNOS and Lcn2, which in turn reverses the toxic effect of proinflammatory astrocytes on motor neurons in vitro, showing advantages over conventionally administered anti-inflammatory therapy. When tested acutely in a spinal cord injury mouse model it improved motor performance, but only in the early stage after injury, reducing the astrocytosis and preserving neuronal cells.

The coupling of the enantioselective reduction catalyzed by Old Yellow Enzymes (OYEs), together with the in situ substrate feeding product removal (SFPR) concept, significantly improved the productivity of the g-scale preparation of ethyl (S)-2-ethoxy-3-(p-methoxyphenyl)propanoate (EEHP), an important precursor of several PPAR-α/γ agonists, such as Tesaglitazar. The OYEs and the glucose dehydrogenase for cofactor regeneration were cloned, overexpressed in Escherichia coli, and purified. The synthetic sequence was completed by a NaClO2 oxidation employing cheap and environmentally friendly conditions. The product was obtained in 94% yield and with an ee of 98% over the two steps.

A dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives based on the disulfide bond exchange reaction is described. The influence of a biological target on the composition of the reaction mixture has been demonstrated. Use of high-resolution ESI mass spectrometry to evaluate the composition of the mixture shows promise for the design of new large libraries. The biological evaluation demonstrates that formation of a divalent compound affords a new chemical entity whose biological activity is not merely the sum of the single ligands activities, thus reflecting a different interaction with the biological target.

[reaction: see text] The first total enantiosynthesis of the biologically active alkaloid (-)-cytisine is reported, featuring a ruthenium-catalyzed RCM reaction as the key step. The approach relies on readily available cis-piperidine-3,5-dimethanol monoacetate as the chiral building block, and it is suited for achieving the target compound in both enantiomeric forms.