1.Addition Reactions of Me3 SiCN with Aldehydes Catalyzed by Aluminum Complexes Containing in their Coordination Sphere O, S, and N Ligands.
Yang Z1,2, Yi Y3, Zhong M3, De S4, Mondal T4, Koley D5, Ma X3, Zhang D3, Roesky HW6. Chemistry. 2016 Apr 8. doi: 10.1002/chem.201505162. [Epub ahead of print]
The reaction of one equivalent of LAlH2 (1; L=HC(CMeNAr)2 , Ar=2,6-iPr2 C6 H3 , β-diketiminate ligand) with two equivalents of 2-mercapto-4,6-dimethylpyrimidine hydrate resulted in LAl[(μ-S)(m-C4 N2 H)(CH2 )2 ]2 (2) in good yield. Similarly, when N-2-pyridylsalicylideneamine, N-(2,6-diisopropylphenyl)salicylaldimine, and ethyl 3-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylate were used as starting materials, the corresponding products LAl[(μ-O)(o-C6 H4 )CN(C5 NH4 )]2 (3), LAlH[(μ-O)(o-C4 H4 )CN(2,6-iPr2 C6 H3 )] (4), and LAl[(μ-NH)(o-C8 SH8 )(COOC2 H5 )]2 (5) were isolated. Compounds 2-5 were characterized by 1 H and 13 C NMR spectroscopy as well as by single-crystal X-ray structural analysis. Surprisingly, compounds 2-5 exhibit good catalytic activity in addition reactions of aldehydes with trimethylsilyl cyanide (TMSCN).
2.Mechanism of inactivation of γ-aminobutyric acid aminotransferase by (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic Lee H1, Doud EH, Wu R, Sanishvili R, Juncosa JI, Liu D, Kelleher NL, Silverman RB. J Am Chem Soc. 2015 Feb 25;137(7):2628-40. doi: 10.1021/ja512299n. Epub 2015 Feb 10.
γ-Aminobutyric acid aminotransferase (GABA-AT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, the principal inhibitory neurotransmitter in mammalian cells. When the concentration of GABA falls below a threshold level, convulsions can occur. Inhibition of GABA-AT raises GABA levels in the brain, which can terminate seizures as well as have potential therapeutic applications in treating other neurological disorders, including drug addiction. Among the analogues that we previously developed, (1S,3S)-3-amino-4-difluoromethylene-1-cyclopentanoic acid (CPP-115) showed 187 times greater potency than that of vigabatrin, a known inactivator of GABA-AT and approved drug (Sabril) for the treatment of infantile spasms and refractory adult epilepsy. Recently, CPP-115 was shown to have no adverse effects in a Phase I clinical trial. Here we report a novel inactivation mechanism for CPP-115, a mechanism-based inactivator that undergoes GABA-AT-catalyzed hydrolysis of the difluoromethylene group to a carboxylic acid with concomitant loss of two fluoride ions and coenzyme conversion to pyridoxamine 5'-phosphate (PMP).
3.Antinociceptive effects of FTY720 during trauma-induced neuropathic pain are mediated by spinal S1P receptors.
Zhang DD, Linke B, Suo J, Zivkovic A, Schreiber Y, Ferreirós N, Henke M, Geisslinger G, Stark H, Scholich K. Biol Chem. 2015 Jun;396(6-7):783-94. doi: 10.1515/hsz-2014-0276.
FTY720 (fingolimod) is, after its phosphorylation by sphingosine kinase (SPHK) 2, a potent, non-selective sphingosine-1-phosphate (S1P) receptor agonist. FTY720 has been shown to reduce the nociceptive behavior in the paclitaxel model for chemotherapy-induced neuropathic pain through downregulation of S1P receptor 1 (S1P1) in microglia of the spinal cord. Here, we investigated the mechanisms underlying the antinociceptive effects of FTY720 in a model for trauma-induced neuropathic pain. We found that intrathecal administration of phosphorylated FTY720 (FTY720-P) decreased trauma-induced pain behavior in mice, while intraplantar administered FTY720-P had no effect. FTY720-P, but not FTY720, reduced the nociceptive behavior in SPHK2-deficient mice, suggesting the involvement of S1P receptors. Fittingly, intrathecal administration of antagonists for S1P1 or S1P3, W146 and Cay10444 respectively, abolished the antinociceptive effects of systemically administered FTY720, demonstrating that activation of both receptors in the spinal cord is necessary to induce antinociceptive effects by FTY720.
4.Synthesis of fluorinated analogues of sphingosine-1-phosphate antagonists as potential radiotracers for molecular imaging using positron emission tomography.
Prasad VP1, Wagner S2, Keul P3, Hermann S4, Levkau B3, Schäfers M5, Haufe G6. Bioorg Med Chem. 2014 Oct 1;22(19):5168-81. doi: 10.1016/j.bmc.2014.08.009. Epub 2014 Aug 17.
Sphingosine-1-phosphate (S1P) receptors play major roles in cardiovascular, immunological and neurological diseases. The recent approval of the sphingolipid drug Fingolimod (Gilenya®), a sphingosine-1-phosphate agonist for relapsing multiple sclerosis, in 2010 exemplifies the potential for targeting sphingolipids for the treatment of human disorders. Moreover, non-invasive in vivo imaging of S1P receptors that are not available till now would contribute to the understanding of their role in specific pathologies and is therefore of preclinical interest. Based on fluorinated analogues of the S1P1 receptor antagonist W146 showing practically equal in vitro potency as the lead structure, the first S1P receptor antagonist [18F]-radiotracer has been synthesized and tested for in vivo imaging of the S1P1 receptor using positron emission tomography (PET). Though the tracer is serum stable, initial in vivo images show fast metabolism and subsequent accumulation of free [18F]fluoride in the bones.
