<i>N,N</i>-bis-(dimethylfluorosilylmethyl)amides of <i>N</i>-organosulfonylproline and sarcosine: synthesis, structure, stereodynamic behaviour and <i>in silico</i> studies

(O→Si)-Chelate difluorides R3R2NCH(R1)C(O)N(CH2SiMe2F)2 (9a–c, R1R2 = (CH2)3, R3 = Ms (a), Ts (b); R1 = H, R2 = Me, R3 = Ms (c)), containing one penta- and one tetracoordinate silicon atoms were synthesized by silylmethylation of amides R3R2NCH(R1)C(O)NH2, subsequent hydrolysis of unstable intermediates R3R2NCH(R1)C(O)N(CH2SiMe2Cl)2 (7a–c) into 4-acyl-2,6-disilamorpholines R3R2NCH(R1)C(O)N(CH2SiMe2O)2 (8a–c) and the reaction of the latter compounds with BF3·Et2O. The structures of disilamorpholines 8a,c and difluoride 9a were confirmed by an X-ray diffraction study. According to the IR and NMR data, the O→Si coordination in solutions of these compounds was weaker than that in the solid state due to effective solvation of the Si–F bond. A permutational isomerisation involving an exchange of equatorial Me groups at the pentacoordinate Si atom in complexes 9a–c was detected, and its activational parameters were determined by 1H DNMR. In silico estimation of possible pharmacological effects and acute rat toxicity by PASS Online and GUSAR Online services showed a potential for their further pharmacological study

Pentacoordinated chlorosilanes with <i>C,O-</i>chelate ligands derived from <i>N-</i>methyl<i>-N'-</i>organosulfonyl-prolinamides

The reaction of amides RSO2-Pro-NHMe with ClCH2SiMe2Cl in the presence of (Me3Si)2NH gave pentacoordinated chlorosilanes RSO2-Pro-N(Me)CH2SiMe2Cl with an organosulfonyl group (R = Me, Ph, 4-ClC6H4, 4-BrC6H4, 4-MeC6H4, and 4-O2NC6H4) attached to the proline nitrogen atom. An alternative method for the preparation of these compounds comprises the cyclosilylmethylation of proline methylamide by dimethylchloromethylchlorosilane to give the previously unreported heterocyclic 2-sila-5-piperazinone system in the first step. The bicyclic silacyclane synthesized is 2-sila5-piperazinone condensed with a proline residue. The action of sulfonyl chlorides RSO2Cl leads to cleavage of the sila ring Si-N bond to give the desired chlorosilanes. The hydrolysis of these products, depending on the reaction conditions, gives either silyloxonium chlorides [RSO2-ProN(Me)CH2SiMe2OH2]Cl or disiloxanes [RSO2-Pro-N(Me)CH2SiMe2]2O. X-ray diffraction structural analysis showed that the silicon atom in the chlorides and silyloxonium chlorides is pentacoordinated due to an intramolecular O→Si bond and has distorted trigonal-bipyrimidal configuration. Si-29 NMR spectroscopy showed that the disiloxanes and bicyclic sila-5-piperazinone have a tetracoordinated silicon atom

AN ANTISENSE OLIGONUCLEOTIDE DERIVATIVE TO THE MRNA OF THE NAV1.5 SODIUM CHANNEL GENE (SCN5A) DECREASES THE HEART RATE

Objective: To assess the potential of a new approach to altering the heart rate by expression inhibition of the SCN5A gene, encoding a classical sodium channel, Nav1.5, with an antisense oligonucleotide derivative in the case study of the mouse. Material and methods: C57BL/6J male mice; oligonucleotide derivative with a length of 15 nucleotides protected from nucleases by the presence of internucleotide phosphorothioate bonds and LNA (locked nucleic acids) blocks at the 5ʹ and 3ʹ ends (ASO); standard injection of ASO in physiological saline solution into the mouse caudal vein; standard technique for determination of the heart rate and blood pressure in mice with a CODA Surgical Monitor (Kent Scientific, United States); and standard quantification of apoB apolipoprotein and lipoproteins HDL-C, LDL-C, total cholesterol, TG, and ALT in the blood serum. Results: ASO decreases the heart rate in mice by 12 % over 10 days and further uniformly accelerates the heart rate to almost initial level by day 16 as well as gently decreases the mean values of systolic and diastolic pressures with their subsequent increase and gradual redistribution of “excess” pressure in the control and experimental animal groups. The level of lipid metabolism in experimental animals is decreased. Conclusions: The new approach to alter the heart rate by inhibition of the SCN5A gene expression with an antisense oligonucleotide derivative is shown to be feasible. The impact is accompanied by minor changes in the systolic and diastolic pressures and a decrease in the level of lipid metabolism. The preparation is promising in terms of the influence on the heart rate taking into account the further insight into its effect at different concentrations and possible insignificant side effects

Synthesis, structures, and stereodynamic behavior of novel pentacoordinate fluorosilanes: fluorosilyl derivatives of proline

The (O→Si)-chelate N'-(dimethylfluorosilylmethyl))-N'-methyl-N-(organosulfonyl)prolinamides RSO2-Pro-N(Me)CH2SiMe2F (2a-f, R = Me (a), Ph (b), 4-MeC6H4 (c), 4-ClC6H4 (d), 4-BrC6H4 (e), 4-NO2C6H4 (f)) were synthesized from the corresponding disiloxanes 1a-f using Et2O•BF3. According to the NMR and IR data, the extent of dimerization of fluorosilanes 2a-f in solution is negligible, while the O→Si coordination in solution is weaker than that in the solid state. Comparative CP/MAS NMR and X-ray diffraction studies revealed that in solution the coordination Si-O bond length varies in a narrow range (2.22-2.24 angstrom) that is 0.02-0.11 angstrom longer than in the crystalline state. Dynamic NMR (DNMR) studies of the fluorides revealed a fine structure of the 19F signals in the 0-20°C temperature range, which was related to the structural features of the coordination set in these complexes. The temperature dependence of the SiMe2 signals in the 1H DNMR spectra was attributed to a permutational isomerization process involving a positional exchange of equatorial ligands. The narrow range of activational barriers of the process (23-24 kcal mol-1 and more) and high negative values of the entropy of activation are similar to those observed earlier for Si-substituted N-(dimethylsilylmethyl) and N-(methylphenylsilylmethyl) amides and lactams, which suggests similar permutational processes in all cases. Gas-phase quantum chemical studies demonstrate that the solvation of F- reduces the activation barrier

Synthesis and structure of (O → Si)-chelate fluorosilane, a novel complex of pentacoordinate silicon with N-acetylvaline

A novel organosilicon complex of N-acetylvaline was synthesized by the reaction of the relative disiloxane derivative with BF3 etherate. According to X-ray and NMR data, the silicon atom of the final product is pentacoordinated in both the solid state and solution. The coordination state of silicon was correctly predicted by quantum-chemical calculations