gniditrin and daphnetoxin

Despite the existence of an extended armamentarium of effective synthetic drugs to treat HIV, there is a continuing need for new potent and affordable drugs. Given the successful history of natural product based drug discovery, a library of close to one thousand plant and fungal extracts was screened for antiretroviral activity. A dichloromethane extract of the aerial parts of Daphne gnidium exhibited strong antiretroviral activity and absence of cytotoxicity. With the aid of HPLC-based activity profiling, the antiviral activity could be tracked to four daphnane derivatives, namely, daphnetoxin (1), gnidicin (2), gniditrin (3), and excoecariatoxin (4). Detailed anti-HIV profiling revealed that the pure compounds were active against multidrug-resistant viruses irrespective of their cellular tropism. Mode of action studies that narrowed the site of activity to viral entry events suggested a direct interference with the expression of the two main HIV co-receptors, CCR5 and CXCR4, at the cell surface by daphnetoxin (1).

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Daphne; Diterpenes; Heterocyclic Compounds, 4 or More Rings; Mediterranean Region; Molecular Structure; Receptors, CXCR4

Low-density lipoprotein receptor (LDLR) plays a pivotal role in the control of plasma LDL-cholesterol level. This occurs predominantly at the transcriptional level through two gene regulation elements, named SRE: sterol-responsive element and SIRE: sterol-independent responsive element. We have developed a high-throughput screening using LDLR promoter activation-based assay to search for cholesterol-lowering compounds from a Chinese herb-based natural compound library. With this approach, we identified two compounds, named Daphnetoxin and Gniditrin, from Chinese herb Daphne giraldii Nitsche, which could activate LDLR promoter. Characterization of these compounds showed that they increased the level of LDLR mRNA and consequently up-regulate LDLR expression. The structures of these compounds are different from well-known LDLR promoter activating compounds such as GW707. The results suggested that these herbal compounds could represent good candidates for development of new classes of cholesterol-lowering drugs.

Topics: Anticholesteremic Agents; Diterpenes; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Heterocyclic Compounds, 4 or More Rings; Promoter Regions, Genetic; Receptors, LDL; RNA, Messenger; Up-Regulation

To study the constituents with the pain-relieving activity from the stem rind of Daphne giraldii.. The partition of the ethanol extract and chromatographic separation of the fractions were carried out by the monitoring of anelgesic pharmacological activity. The structures of the isolated compounds were determined by MS and NMR.. Four compounds were isolated from the pain-relieving fraction. Three of them were identified as diterpenes, gniditrin (1), gnidicin (2) and daphnetoxin (3). Compound 4 was determined as Z-octadecyl caffeate.. Compounds 1, 2 and 4 were isolated from the plant for the first time.

Topics: Analgesics; Caffeic Acids; Daphne; Diterpenes; Heterocyclic Compounds, 4 or More Rings; Molecular Structure; Plant Stems; Plants, Medicinal