Leonurine-cysteine analog conjugates as a new class of multifunctional anti-myocardial ischemia agent.

Department of Pharmacology, School of Pharmacy and Institute of Biomedical Sciences, Fudan University, Shanghai 201203, China.
European journal of medicinal chemistry (Impact Factor: 3.27). 06/2011; 46(9):3996-4009. DOI:10.1016/j.ejmech.2011.05.073
Source: PubMed

ABSTRACT 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.

0 0
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Hydrogen sulfide, H(2)S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H(2)S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H(2)S and have summarized the chemistry and biological activity of some natural and synthetic H(2)S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H(2)S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H(2)S has also been discussed.
    Biochemical pharmacology 10/2012; · 4.25 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Multifunction compounds (MFCs), designed as hybrid/conjugated or chimeric drugs have emerged as magic bullets in treatment of multifactorial diseases such as atherosclerosis, Alzheimer's diseases, osteoarthritis, diabetic complications and malaria.
    European journal of medicinal chemistry 01/2014; 76:31–42. · 3.27 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Leonurine possesses cardioprotective effects in myocardial ischemia due to its anti-apoptotic proterties. However, the process to isolate and purify leonurine is difficult, because its low content in the Herb Leonuri and its impurity. Moreover, the high dosage used indicates low potency of leonurine. To overcome these defects, we had synthesized a novel twin drug of leonurine, 3,5-dimethoxy-4-(3-(2- carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (compound 2). In this paper, we focused on investigating the cardioprotective effect and underlying mechanisms of compound 2. Our data showed that cell viability was significantly increased in a dose-dependent manner and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were also significantly attenuated in the compound 2-treated group. In addition, we observed the cardioprotective effects by Hoechst 33258 nucleus staining, JC-1 staining, Annexin V-FITC/PI staining and transmission electron microscopy. Compound 2 inhibited apoptosis by reducing the ratio of Bcl-2/Bax, decreasing cleaved-caspase-3 expression and enhancing the phosphorylation of Akt. Furthermore, the phosphorylation effect of compound 2 was reversed by LY294002 the phosphatidylinositol-3-kinase (PI3K) inhibitor from happening. We concluded that compound 2 played a cardioprotective role in hypoxia-induced primary cardiac myocytes apoptosis partly via modulating the PI3K/Akt pathway at a 10-fold lower concentration than leonurine.
    European journal of pharmacology 01/2013; · 2.59 Impact Factor