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-[(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.