•An analogue of rhynchophylline (G2) and its stereoisomers (G2-a and G2-b) were synthesized.•The three compounds displayed the significant microvascular relaxation activity on rat mesenteric arteries.•G2 ameliorated diabetes-induced endothelial dysfunction in rat mesenteric arteries in vivo.•G2 could induce the recovery of endothelial function by upregulating eNOS expression.Dysfunction in vascular reactivity in the micro- and macrocirculation is well established in cardiovascular disease. However, little is known about methods that may improve vascular reactivity in patients likely to develop microvascular dysfunction. One of the racemic analogues of rhynchophylline (G2) and its stereoisomers (G2-a and G2-b) were synthesized to address this knowledge gap. The preliminary pharmaceutical studies on the relaxation of the rat thoracic aorta showed that G2 and its stereoisomers are more potent (at least 30-fold) than the natural product rhynchophylline, which encouraged us to further investigate their functions and mechanisms as treatments for microvascular dysfunction caused by diabetes. G2-a displayed the best microvascular relaxation activity on rat mesenteric arteries among the three compounds, and G2 or G2-a caused relaxation in an endothelium-dependent manner. In ex vivo tests, G2 and G2-a exhibited a weaker potency in inducing microvascular relaxation in mesenteric arteries from diabetic rats than from normal rats, most likely, due to microvascular endothelium damage caused by diabetes. However, based on the animal studies, G2 ameliorated diabetes-induced endothelial dysfunction in rat mesenteric arteries in vivo. Further investigations of the mechanism showed that G2 mainly induced the recovery of endothelial function by upregulating endothelial nitric oxide synthase (eNOS) expression and further increasing the concentration of nitric oxide (NO), which is required for vascular relaxation.Download high-res image (268KB)Download full-size image

A novel fluorescent probe for discriminating cysteine (Cys) and glutathione (GSH) has been developed inspired by chemical ligation. The probe is able to react rapidly with Cys or GSH by nucleophilic aromatic substitution. In the case of Cys, the first produced sulfur-substituted BODIPY is unstable and undergoes a subsequent intramolecular displacement affording an amino-substituted BODIPY through a five membered cyclic transition stat. This irreversible aromatic hydrocarbon transfer from sulfur to nitrogen atoms is mostly like the well-known chemical ligation process. In comparison, the bulkiness of GSH sharply hinders such an aromatic hydrocarbon transfer process. Based on these reactions, the distinct fluorescence responses to Cys and GSH were achieved, and the probe can be used for the detection of Cys over GSH in living cells.Download full-size image

The novel codrugs of Leonurine and Aspirin, compounds 545 and 503 have been synthesized and evaluated on their cardioprotective effects. Preliminary pharmacological studies showed that both compounds 545 and 503 were able to increase cell viability of hypoxia-induced H9c2 cells, and compound 545 exhibited at least ten fold potency than 503 and their parent drugs (Leonurine and Aspirin). Further mechanisms studies indicated that the cardioprotective effect of 545 due to its (1) anti-oxidative ability by increasing SOD and CAT enzymes activity and decreasing MDA content and LDH leakage rate, (2) anti-apoptosis activity by regulating apoptosis-associated proteins expression during hypoxia, (3) anti-inflammatory effect by suppression of pro-inflammatory mediators. All of these results demonstrate that compound 545 as a new class of Leonurine analogue could be a drug candidate in our further drug development studies.

In this paper, we developed a novel fluorescent probe B601 for endogenous H2S detection. In the probe B601, the fast responding and highly selective reaction site towards H2S, incorporating the membrane permeable BODIPY fluorescent dye, enables the probe to be applied for the detection of endogenous H2S via the CSE enzymatic pathway.

The design, synthesis and biological evaluation of novel Leonurine-cysteine analog conjugates 3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (1a), 3,5-dimethoxy-4-(2-animo-3-allysulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (1b) and 3,5-dimethoxy-4-(3-(2-chlorocarbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (2) were reported in this paper. We tested their effects on hypoxia-induced neonatal rat ventricular myocytes. Our data showed that all of them had cardioprotective effects. Both of 1a and 1b were able to modulate hydrogen sulfide production, and 1a possessed higher biological activity than 1b and 2, which indicated that there was positive correlation between conjugates and their precursors. Furthermore we illuminated that the cardioprotective mechanism of 1a were related to increase SOD and CAT activity, decrease MDA and ROS level, protect some cell organs and regulate apoptosis-associated genes and proteins expression (bcl-2 and bax) via the caspase-3 pathway in molecular level. These results indicated that 1a had the potential to be a new class of multifunctional anti-myocardial ischemia agent. Most importantly, these results provided us important clues for the further design and modification of this type of Leonurine-cysteine analog conjugates in future.Compound 1a was able to anti-oxidative stress and anti-apoptosis mainly by caspase-3 pathway.Highlights► We first reported detailed synthesis method of Leonurine-cysteine analogue conjugate. ► There was positive correlation between conjugates and their precursors. ► We first exactly pointed out that 1a protected some cell organs. ► We first exactly pointed out 1a prevented apoptosis via the caspase-3 pathway.

BODIPY-Le, a colorimetric and ratiometric fluorescent probe based on boron-dipyrromethene for selective detection sulfite ion, was investigated. Boron-dipyrromethene levulinyl ester (BODIPY-Le) is composed of an indole-based BODIPY dye and the levulinyl protective group, which could be easily and selectively deprotected by sulfites. As a result, the absorption and emission spectra show a dramatic red shift, and the development of a colorimetric and ratiometric fluorescent sulfite probe could be achieved. Besides, BODIPY-Le also exhibited prominent turn-on or turn-off type fluorogenic signaling toward sulfite ions once excited at 510 and 620 nm, respectively.

A boron-dipyrromethene-Cu2+ ensemble based colorimetric probe for detection of hydrogen sulfide in aqueous media is reported. Complex 1–Cu(II) is able to selectively sense hydrogen sulfide over other anions and thiols followed by the release of compound 1 to give a remarkable change of UV absorption in aqueous solution (HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) buffer, 50 mM, pH 7.4, 5% DMSO).

Most reported fluorescent probes have limitations in practical applications in living systems due to the strong autofluorescence background, construction of probes with near-infrared (NIR) fluorescence emission is an accessible approach for addressing this challenge. We here designed a NIR fluorescent probe for monitoring the endogenous production of H2S in living cells. The designed probe showed significant NIR fluorescence turn-on response to H2S with high selectivity, enabling the sensitive detection H2S. Importantly, the probe could be applied in monitoring the endogenous production of H2S in raw264.7 macrophages. This study showed that fluvastatin can promote the activity of cystathionine γ-lyase (CSE) for generation H2S.A new fluorescent probe was designed for H2S, which showed significant NIR fluorescence turn-on response to H2S with high selectivity. Importantly, the probe has been successfully applied in monitoring the endogenous production of H2S in raw264.7 macrophages upon stimulation with fluvastatin.

In this paper, we developed a novel fluorescent probe B601 for endogenous H2S detection. In the probe B601, the fast responding and highly selective reaction site towards H2S, incorporating the membrane permeable BODIPY fluorescent dye, enables the probe to be applied for the detection of endogenous H2S via the CSE enzymatic pathway.