Light as energy source in chemical reaction. New synthesis of valuable dithienylacetylenes
Photochromism (from Greek φωζ photo “light” and χρωμα chroma “colour”) is determined as reversible transformation between two chemical species, induced by action of light [1]. Herewith, initial form and photoinduced isomer have different physical and chemical properties. The phenomenon is attractive for the design of hi-tech materials, including optical memory elements and molecular switches. Diarylethenes is the most promising class of organic photochromic compounds due to outstanding thermal stability of both isomers and high photostability [2]. The size of so-called ethene bridge significantly affects the photochromic reaction. The photochromic diarylethenes with 4-, 5-, and 6-membered cyclic ethene bridge are known, but there is no example with 3-membered bridge. In this study we report a new approach towards dithienylacetylenes 3 that include the synthesis of diarylcyclopropenones 2 via Friedel-Crafts alkylation of heterocyclic compounds 1 with tetrachlorocyclopropene and following UV-irradiation. It was found that the diarylethenes 2 do not display photochromic properties, but they undergo quantitative photoelimination of carbon monoxide upon UV-irradiation resulting in dithienylacetylene 3. Thus, we have proposed a new synthetic two-step approach to dithienylacetylenes 3 [3], which could be useful synthons in synthesis of photochromic diarylethenes with various ethene bridges.
探討抗憂鬱症藥物phenelzine對於發生在小鼠巨噬細胞中的細胞凋亡所產生的保護作用及機制
之前有研究指出，使用一些單胺氧化酶(monoamine oxidase, MAO)的抑制劑如pargyline和clorgyline，皆可以保護serum starvation所導致的細胞凋亡，表示MAO可能在細胞凋亡的路徑中扮演重要的角色。 本研究著重於一個臨床上被拿來當抗憂鬱症藥物的MAO抑制劑苯乙肼(phenelzine, PZE)對於沿著腫瘤壞死因子-α (tumor necrosis factor-α, TNF-α)途徑而產生細胞凋亡的小鼠骨髓巨噬細胞(bone marrow-derived macrophages, BMDM)所產生的保護作用。 本研究的結果顯示PZE的確可以保護循TNF-α途徑死亡的細胞，同時使活性氧化物質(reactive oxygen species, ROS)的量下降。我們推論造成此現象的原因是PZE藉由抑制MAO，使得ROS的量下降，進而保護細胞。
An investigation of the inhibitory potential of Dronedarone on CYP2J2 mediated astemizole metabolism
Dronedarone is an anti-arrhythmic drug approved in 2009 for paroxysmal and persistent atrial fibrillation. It is less toxic than its predecessor Amiodarone as it does not cause systemic toxicity but has the same pharmacological activity. However the administration of dronedarone to permanent AF and heart failure patients leads to increased risk of stroke and cardiac death. The exact mechanism of the toxicity is currently unknown. Extrahepatic Cytochrome P450 enzymes play a dominant role in organ-specific drug metabolism and toxicity. Cytochrome P450 2J2 (CYP2J2) enzyme, a predominant enzyme found in human cardiac myocytes, metabolizes endogenous arachidonic acid (AA) into epoxyeicosatrienoic acids (EETs) which play an important role in maintaining normal cardiac physiology. Inhibition of CYP2J2 and perturbation of AA metabolic pathway could result in exacerbation of cardiac failure. This research aims to find out whether dronedarone inhibits CYP2J2 in a suitable cell model (H9C2) using astemizole as a probe substrate. Our in-house studies using recombinant CYP2J2 enzyme have shown that dronedarone potently inhibits CYP2J2. Rat myoblast cells (H9C2) will be seeded in 12-well plate and differentiated for 4 days. The cells will be then treated with different concentrations of astemizole and incubated for 24 h. The cells will then be harvested, lysed, and the cell lysate will be analyzed using liquid chromatography-mass spectrometry (LCMS). Using multi-reaction monitoring (MRM) on the LCMS, astemizole concentration as well as its CYP2J2-specific metabolite O-desmethylastemizole concentrations will be measured. The presence of O-desmethylastemizole confirms the metabolism of astemizole by CYP2J2 in H9C2 cells. By plotting a Michaelis-Menten kinetics curve, we will be able to determine the Michaelis constant (KM) and maximum rate of reaction (Vmax). H9C2 cells will be then treated with fixed concentration of astemizole while varying the dronedarone concentration. A decrease in metabolite O-desmethylastemizole conce ntration, indicates inhibition of CYP2J2 metabolism by dronedarone. Using this data, Lineweaver-Burke graph will be plotted, to determine the mode and potency of the inhibition. Our preliminary studies showed that the KM value was 2.7μM. This study will be useful in understanding if dronedarone inhibits CYP2J2 which may lead to clinically significant drug-drug interactions, one of the dangers of polypharmacy. Finally this study will shed a new light on the mechanisms for dronedarone mediated cardiac failure exacerbation.