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: 3.45). 06/2011; 46(9):3996-4009. DOI: 10.1016/j.ejmech.2011.05.073
Source: PubMed


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.

9 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: 1. Herba Leonuri, a traditional Chinese medicine, has a long history of development and application in China. In particular, Herba Leonuri has been widely used in the treatment of gynaecological and obstetric disorders for thousands of years. Recent studies have shown that Herba Leonuri has many different effects. 2. Herba Leonuri contains several active components, including alkaloids, flavonoids, diterpenes compounds and fatty acids. Recent studies have shown that these molecules exert beneficial effects in coronary artery disease and cerebral ischaemia. Thus, these molecules may become novel candidates for drug discovery and development. 3. The present review provides an overview of the chemical composition, with a focus on biological activity, of Herba Leonuri to stimulate new studies on traditional Chinese medicine.
    Clinical and Experimental Pharmacology and Physiology 03/2012; 39(3):274-82. DOI:10.1111/j.1440-1681.2011.05630.x · 2.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of novel amide and thioester conjugates between Danshensu and cysteine derivatives have been designed and synthesized based on the strategy of "medicinal chemical hybridization". Pharmacological evaluation indicated that the amide conjugates 3a/4a/17a and thioester conjugates 6a-d exhibited obvious protective effects on H(2)O(2)-induced human umbilical vein endothelial cells (HUVECs). Pretreated with these conjugates could increase glutathione (GSH) activity and decrease malondialdehyde (MDA) level. Further study on mechanism of compound 4a revealed that it was related to its mitochondrial-protective effect and regulation of apoptosis-related proteins expression (Bax, p53, PARP, caspase-3, caspase-9 and Bcl-2). These results indicate that these Danshensu-cysteine analog conjugates possess significant cardiovascular-protective effects and merit further investigation.
    European Journal of Medicinal Chemistry 07/2012; 55:176-87. DOI:10.1016/j.ejmech.2012.07.016 · 3.45 Impact Factor
  • 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; 85(5). DOI:10.1016/j.bcp.2012.10.019 · 5.01 Impact Factor
Show more