Biocompatible metal-assisted C-C cross-coupling combined with biocatalytic chiral reductions in a concurrent tandem cascade.

In this study, we present a concurrent chemo/biocatalytic one pot reaction cascade by combining a metal (Pd/Cu) assisted Liebeskind-Srogl (L-S) coupling with an enantioselective enzymatic reduction for the production of chiral amines and alcohols. The latter transformation was realized by applying enantiocomplementary alcohol dehydrogenases from Lactobacillus kefir (R-selective) and Rhodococcus ruber (S-selective). Compatibility issues were solved by investigating first the L-S-coupling protocol in water at room temperature. Subsequently, we investigated two different biphasic systems and applied a biomimicking approach to separate enzyme-deactivating components. By using a lipophilic membrane in a smart reactor design, we were able to perform concurrent catalytic cascades with overall concentrations up to 100 mM substrate and to produce 1-phenylethylamine and several chiral alcohols in high yields (up to 81% over 2 steps) and enantiomeric purity ((+) and (-)-enantiomers both with 99% ee).

Small molecule cardiogenol C upregulates cardiac markers and induces cardiac functional properties in lineage-committed progenitor cells.

BACKGROUND/AIMS: Cell transplantation into the heart is a new therapy after myocardial infarction. Its success, however, is impeded by poor donor cell survival and by limited transdifferentiation of the transplanted cells into functional cardiomyocytes. A promising strategy to overcome these problems is the induction of cardiomyogenic properties in donor cells by small molecules. METHODS: Here we studied cardiomyogenic effects of the small molecule compound cardiogenol C (CgC), and structural derivatives thereof, on lineage-committed progenitor cells by various molecular biological, biochemical, and functional assays. RESULTS: Treatment with CgC up-regulated cardiac marker expression in skeletal myoblasts. Importantly, the compound also induced cardiac functional properties: first, cardiac-like sodium currents in skeletal myoblasts, and secondly, spontaneous contractions in cardiovascular progenitor cell-derived cardiac bodies. CONCLUSION: CgC induces cardiomyogenic function in lineage-committed progenitor cells, and can thus be considered a promising tool to improve cardiac repair by cell therapy.

VUT-MK142 : a new cardiomyogenic small molecule promoting the differentiation of pre-cardiac mesoderm into cardiomyocytes.

Intra-cardiac cell transplantation is a new therapy after myocardial infarction. Its success, however, is impeded by the limited capacity of donor cells to differentiate into functional cardiomyocytes in the heart. A strategy to overcome this problem is the induction of cardiomyogenic function in cells prior to transplantation. Among other approaches, recently, synthetic small molecules were identified, which promote differentiation of stem cells of various origins into cardiac-like cells or cardiomyocytes. The aim of this study was to develop and characterise new promising cardiomyogenic synthetic low-molecular weight compounds. Therefore, the structure of the known cardiomyogenic molecule cardiogenol C was selectively modified, and the effects of the resulting compounds were tested on various cell types. From this study, VUT-MK142 was identified as the most promising candidate with respect to cardiomyogenic activity. Treatment using this novel agent induced the strongest up-regulation of expression of the cardiac marker ANF in both P19 embryonic carcinoma cells and C2C12 skeletal myoblasts. The activity of VUT-MK142 on this marker superseded CgC; moreover, the novel compound significantly up-regulated the expression of other cardiac markers, and promoted the development of beating cardiomyocytes from cardiovascular progenitor cells. We conclude that VUT-MK142 is a potent new cardiomyogenic synthetic agent promoting the differentiation of pre-cardiac mesoderm into cardiomyocytes, which may be useful to differentiate stem cells into cardiomyocytes for cardiac repair. Additionally, an efficient synthesis of VUT-MK142 is reported taking advantage of continuous flow techniques superior to classical batch reactions both in yield and reaction time.

Palladium(II)-Catalyzed Regioselective Ortho Arylation of sp(2) C-H Bonds of N-Aryl-2-amino Pyridine Derivatives.

The direct arylation of N-(2-pyridyl) substituted anilines is described. Arylation takes place in ortho position to the amine functionality and is directed by the pyridine N-substituent. Remarkably, N-arylation was never observed as a competing process even though conditions also suitable for Buchwald-Hartwig reactions were applied. The scope of the reaction was investigated in terms of aryl donors as well as the electronic nature of the substrate. Good yields were obtained for most examples through an operationally simple procedure, which did not require inert conditions or even glove box techniques. Pd(OAc)(2) was applied as a cheap catalyst and boronic acids as readily available aryl donors. To obtain full conversion, 1,4-benzoquinone and a silver salt (e.g., Ag(2)O) were required as additives and reacted at relatively mild temperatures (e.g., 80 °C). Additionally, the pyridine-directing group was cleaved after the reaction to give ortho-arylated aniline derivatives.

Tris(acetonitrile-κN){2,6-bis-[(diphenyl-phosphan-yl)amino]-4-eth-oxy-1,3,5-triazine-κP,N,P'}iron(II) bis-(tetra-fluorido-borate) acetonitrile disolvate.

In the title compound, [Fe(CH(3)CN)(3)(C(29)H(27)N(5)OP(2))](BF(4))(2)·2CH(3)CN, the Fe(II) ion is octa-hedrally coordinated by a meridionally chelating tridentate pincer-type PNP ligand derived from 2,6-diamino-4-eth-oxy-1,3,5-triazine and by three acetonitrile mol-ecules. The four Fe-N bond lengths range from 1.9142 (12) to 1.9579 (11) Å, while the Fe-P bonds are 2.2452 (4) and 2.2506 (4) Š[P-Fe-P = 165.523 (14)°], consistent with Fe(II) in a low-spin state. Unlike related Fe PNP complexes based on 2,6-diamino-pyridine, the BF(4) anions are not hydrogen bonded to the two NH groups of the pincer ligand but show instead anion-π inter-actions with the triazine ring and acetonitrile mol-ecules in addition to ten C-H⋯F inter-actions. Most remarkable among these is an anion-π(triazine) inter-action with a short distance of 2.788 (2) Šbetween one F and the centroid of the π-acidic triazine ring. The corresponding shortest distance between this F atom and a triazine carbon atom is 2.750 (2) Å. The two NH groups of the pincer ligand donate N-H⋯N hydrogen bonds to the triazine N atom of a neighbouring complex and to an uncoordinated acetonitrile mol-ecule. This last mol-ecule is in a side-on head-to-tail association with the second uncoordinated acetonitrile at C⋯N distances of 3.467 (2) and 3.569 (2) Å. In contrast to several related compounds with diamino-pyridine- instead of diamino-triazine-based PNP ligands, the title crystal structure is remarkably well ordered. This suggests that the diamino-triazine moiety exerts notable crystal structure stabilizing effects.

Probing mixed valence in a new tppz-bridged diruthenium(III,II) complex {(mu-tppz)[Ru(bik)Cl]2}3+ (tppz=2,3,5,6-tetrakis(2-pyridyl)pyrazine, bik=2,2'-bis(1-methylimidazolyl)ketone): EPR silence, intervalence absorption, and nu(CO) line broadening.

The complex dication of the diruthenium(II) compound {(mu-tppz)[Ru(bik)Cl]2}(ClO4)2 can be oxidized and reduced in two one-electron steps each. In CH3CN/0.1 M Bu4NPF6, the odd-electron intermediates{(mu-tppz)[Ru(bik)Cl]2}n+, n=1 and 3, have comproportionation constants of 7x10(8) and 1x10(5), respectively. Both exhibit near-infrared absorptions, in the case of n=3 the 1640 nm band (epsilon=1200 M-1 cm-1, Deltanu1/2=1560 cm-1) is attributed to an intervalence charge-transfer transition. While the mixed-valent intermediate (n=3) is EPR silent even at 4 K, the n=1 form shows g(parallel) 2.005 and g( perpendicular) 1.994 at that temperature, signifying a diruthenium(II) complex of the tppz*- radical anion. The variation of energy and intensity of nuCO and of the ring vibration band around 1590 cm-1 has been monitored not only for {(mu-tppz)[Ru(bik)Cl]2}n+, n=0-4, but also for the mononuclear {(tppz)Ru(bik)Cl}n+, n=0-2. In the dinuclear complex the carbonyl stretching bands of the spectator ligand bik are shifted by about 15 cm-1 on each one-electron-transfer step, increasing with the positive charge. The mixed-valent {(mu-tppz)[Ru(bik)Cl]2}3+ shows a perceptibly broader nuCO band, suggesting incomplete valence averaging (partial localization).