Moumita Koley

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., Ag2O) 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.

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.

Tris(acetonitrile-κN){2,6-bis­[(diphenyl­phosphan­yl)amino]-4-eth­oxy-1,3,5-triazine-κ3P,N1,P′}iron(II) bis­(tetra­fluorido­borate) acetonitrile disolvate

In the title compound, [Fe(CH3CN)3(C29H27N5OP2)](BF4)2·2CH3CN, the FeII ion is octahedrally coordinated by a meridionally chelating tridentate pincer-type PNP ligand derived from 2,6-diamino-4-ethoxy-1,3,5-triazine and by three acetonitrile molecules. 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) Å [P—Fe—P = 165.523 (14)°], consistent with FeII in a low-spin state. Unlike related Fe PNP complexes based on 2,6-diaminopyridine, the BF4 anions are not hydrogen bonded to the two NH groups of the pincer ligand but show instead anion–π interactions with the triazine ring and acetonitrile molecules in addition to ten C—H⋯F interactions. Most remarkable among these is an anion–π(triazine) interaction with a short distance of 2.788 (2) Å between 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 molecule. This last molecule 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 diaminopyridine- instead of diaminotriazine-based PNP ligands, the title crystal structure is remarkably well ordered. This suggests that the diaminotriazine moiety exerts notable crystal structure stabilizing effects.

Efforts to induce cardiac electrophysiological properties in skeletal myoblasts in vitro

Background When the myocardium is injured by an acute infarction, a fibrous, non-contractile scar develops, because mature cardiac tissue cannot effectively regenerate. In patients this often results in congestive heart failure, one of the major health problems in the developed world. Although multipotent cardiac stem cells, which could support myocardial regeneration, were recently identified, their limited availability prevents therapeutic applications. More readily available stem cell populations derived from other tissues, such as undifferentiated skeletal myocytes (myoblasts) or bone marrow-derived adult stem cells, have been shown to be capable of repairing cardiac damage in animal models. These cell types, however, have a very limited capacity to transdifferentiate into functional cardiomyocytes after transplantation into the heart. This fact certainly hampers their beneficial therapeutic effects. A strategy to overcome this problem would be the induction of cardiomyogenic function in stem cells prior to transplantation. Here, we tried two different in vitro strategies to achieve this goal in skeletal myoblasts.

Metal-Catalyzed Cross-Coupling Reactions in the Decoration of Pyridines

Cross-coupling reactions involving pyridine derivatives are discussed for both approaches involving pyridine as organometal or as (pseudo)halide species. All types of cross-coupling methods are included, and mainly literature from the past decade is covered. Older landmark contributions are included as well whenever it is necessary to communicate key concepts. This chapter is organized according to the coupling type and the role of the pyridine derivative, either as (pseudo)halide or as organometal species.