Rho/SRF Inhibitor Modulates Mitochondrial Functions.

CCG-1423 is a Rho A pathway inhibitor that has been reported to inhibit Rho/SRF-mediated transcriptional regulation. Serum response factor and its cofactors, which include ternary complex factors and myocardin-related transcription factors, regulate various cellular functions. In this study, we observed that CCG-1423 modulates the mitochondrial functions. The effect of this small molecule drug was determined by measuring mitochondrial function using an XFe96 Analyzer and an Oxygraph 2k (O2k) high-resolution respirometer. CCG-1423 treatment significantly reduced oxidative phosphorylation in a dose-dependent manner. However, CCG-1423 increased the glycolytic rate. We also observed that histone 4 at lysine-16 underwent hyperacetylation with the treatment of this drug. Immunolabeling with F-actin and MitoTracker revealed the alteration in the actin cytoskeleton and mitochondria. Taken together, our findings highlight a critical role of CCG-1423 in inhibiting the transcription of SRF/p49 and PGC-1α, ß, resulting in the downregulation of mitochondrial genes, leading to the repression of mitochondrial oxidative phosphorylation and overall ATP reduction. This study provides a better understanding of the effects of CCG-1423 on mitochondria, which may be useful for the assessment of the potential clinical application of CCG-1423 and its derivatives.

Synthesis, characterization, and photoluminescent studies of three-coordinate Cu(i)-NHC complexes bearing unsymmetrically-substituted dipyridylamine ligands.

A series of heteroleptic three-coordinate Cu(i) complexes bearing monodentate N-heterocyclic carbene (NHC) ligands of the type 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) and 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene (SIPr), and bidentate N-donor ligands of the type unsymmetrically-substituted dimethyl dipyridylamine (Me2Hdpa) and bis(mesityl)biazanaphthenequinone (mesBIAN) have been synthesized. The complexes [Cu(IPr)(3,4'-Me2Hdpa)]PF6, 1; [Cu(IPr)(3,5'-Me2Hdpa)]PF6, 2; [Cu(IPr)(3,6'-Me2Hdpa)]PF6, 3; [Cu(IPr)(mesBIAN)]PF6, 6; [Cu(SIPr)(3,4'-Me2Hdpa)]PF6, 7; [Cu(SIPr)(3,5'-Me2Hdpa)]PF6, 8; and [Cu(SIPr)(3,3'-Me2Hdpa)]PF6, 11 have been characterized by 1H and 13C NMR spectroscopies, elemental analysis, cyclic voltammetry, and photophysical studies in solid and solution phase. Single crystal X-ray structures were obtained for all complexes except 11. The crystallographic data reveal a mononuclear structure for all complexes with the copper atom ligated by one C and two N atoms. The UV-Vis absorption spectra of all dipyridylamine complexes in CH2Cl2 show a strong ligand-centered absorption band around 250 nm and a strong metal-to-ligand charge transfer (MLCT) band around 300 nm. When irradiated with UV light, the complexes exhibit strong emission maxima at 453-482 nm with photoluminescence quantum yields (PLQY) ranging from 0.21 to 0.87 in solid state. While the PLQY values are comparable to those of the symmetrical [Cu(IPr)(Me2Hdpa)]PF6 complexes, a stabilizing CH-π interaction has been reduced in the current systems. In particular, complex 3 lacks any strong CH-π interaction, but emits more efficiently than 1 and 2 wherein the interactions exist. Structural data analysis was performed to clarify the role of ligands' plane angle and the NH/CH⋯F interactions to the observed light interaction of unsymmetrical [Cu(NHC)(Me2Hdpa)]PF6 complexes. DFT calculations were performed to assist in the assignment of the electronic structure and excited state behavior of the complexes.