Total synthesis of cynaropicrin.

Cynaropicrin is found in artichoke (Cynara scolymus) and is the source of its bitter taste and it is a sesquiterpene lactone with a 5-7-5 tricyclic skeleton, six chiral centers, and four exo-olefins. This natural product has numerous attractive biological activities including the inhibition of NF-κB activation, antihepatitis C activity, and antitrypanosomal activity. In this study, the first total synthesis of cynaropicrin was achieved starting from (S)-α-pinene. The synthesis involved a stereoselective Favorskii rearrangement and an indium-promoted diastereoselective Barbier reaction.

The caspase-independent algorithm of programmed cell death in Leishmania induced by baicalein: the role of LdEndoG, LdFEN-1 and LdTatD as a DNA 'degradesome'.

In the post-genomic perspective, the quest of programmed cell death (PCD) mechanisms in kinetoplastid parasites lies in the identification and characterization of cell death executer proteins. Here, we show that baicalein (BLN), a potent topoisomerase IB inhibitor, generates an oxidative stress in the parasites leading to altered physiological and morphological parameters, which are characteristic of PCD. For the first time we elucidate that, caspase-independent activation of a novel effector molecule, endonuclease G (LdEndoG), mediates BLN-induced cell death. Functional characterization of LdEndoG identifies Flap endonuclease-1 (LdFEN-1) and LdTatD-like nuclease as other effector molecules. BLN treatment translocates LdEndoG from mitochondria to nucleus, where it forms separate complexes with LdFEN-1 and LdTatD to constitute a DNA 'degradesome' unique to these parasites. Conditional antisense knockdown of LdEndoG provides protection against PCD. This knowledge paves the path toward a better understanding of the PCD pathway in simpler systems, which could be exploited in anti-leishmanial chemotherapy.

Oroxylum indicum (L.) Kurz, an important Asian traditional medicine: from traditional uses to scientific data for its commercial exploitation.

ETHNOPHARMACOLOGICAL RELEVANCE: Oroxylum indicum\ (L.) Kurz has been used for centuries as a traditional medicine in Asia in ethnomedicinal systems for the prevention and treatment of several diseases, such as jaundice, arthritic and rheumatic problems, gastric ulcers, tumors, respiratory diseases, diabetes, and diarrhea and dysentery, among others. The present review provides scientific evidence supporting the therapeutic potency of the plant for ethnomedicinal uses and identifies gaps for future research to facilitate commercial exploitation. METHODS: This review is based on available information on traditional uses and phytochemical, pharmacological, clinical and toxicity data for Oroxylum indicum that was collected from electronic (SciFinder, PubMed, Science Direct, and ACS, among others) and library searches. KEY FINDING: A variety of traditional medicinal uses of Oroxylum indicum in different Southeast and South Asian countries have been reported in books describing the uses of these plants. Phytochemical investigations of the different parts of the plant resulted in identification of approximately 111 compounds, among which flavonoids, naphthalenoids and cyclohexylethanoids are the predominant groups. The crude extracts and their isolates exhibit a wide spectrum of in vitro and in vivo pharmacological activities involving antimicrobial, anti-inflammatory, anti-arthritic, anticancer, anti-ulcer, hepatoprotective, antidiabetic, antidiarrheal and antioxidant activities. Flavonoids are the major constituents of all parts of the plant. From a toxicity perspective, only aqueous and ethanolic extracts of stem bark, root bark and fruits have been assessed and found to be safe. The major flavonoids of the stem bark, such as baicalein, chrysin and oroxylin A, were reported for the first time as natural flavonoids with potent inhibitory activity against endoprotease enzymes and proprotein convertases, which play a key role in the growth of cancer and in viral and bacterial infections. Flavonoids are the active components of bioactive extracts. Several Ayurvedic medicines have been formulated either singly using this plant or along with other herbs for the treatment of different diseases. CONCLUSIONS: Pharmacological results have supported some traditional medicinal uses of Oroxylum indicum. Several extracts and their isolates have been reported to exhibit interesting pharmacological properties. These components could be useful as sources of modern medicines following future detailed studies to elucidate their underlying mechanisms, toxicity, synergistic effects and clinical trials. Attention should also be focused on pharmacological studies investigating the traditional uses of the plant, which have not been yet addressed, as well as clinical studies investigating commercial Ayurvedic medicines and other ethnomedicinal preparations in human subjects based on this plant to confirm the safety and quality of the preparations.

Inhibition of tumor cells proliferation and migration by the flavonoid furin inhibitor isolated from Oroxylum indicum.

BACKGROUND: The medicinally active plant Oroxylum indicum (OI) has drawn considerable research interest because of its many observed biological activities. Of particular interest is its antitumorigenic activity. The plant is a rich source of flavonoids and their glycosides. Recently flavonoids have been described as inhibitors of kexin-type proteases of superfamily Proprotein Convertase Subtilisin/ Kexins (PCSKs) which have been implicated in tumor growth and malignancy. These enzymes particularly furin (PCSK3) cleaves inactive precursor growth factors into their mature forms that promote tumor growth. As a result, finding furin-inhibitors became of high interest in cancer research. In this regard, the plant OI with known anticancer activities may provide an important source. OBJECTIVE: The objective of this study is to examine and compare anti-tumorigenic activity of furin inhibitory flavonoid compounds from OI. RESULTS: Studies were conducted to evaluate the effect on CT-26 cell proliferation and migration of 4 flavonoids baicalein, chrysin, oroxylin-A and its glycoside isolated from OI. Data revealed that baicalein exhibited most potent inhibitory effect on proliferation and migration on the analyzed tumor cell line. Baicalein at 10 µM completely blocked the proliferation even after 5 days. The results are consistent with the observed in vitro anti-furin activity of baicalein as measured against a fluorogenic peptide and pro-hVEGF-C as substrates. Mature VEGF-C is a strong indicator and biomarker of tumor progression and therefore the antifurin activity may explain the observed anticancer properties of baicalein. Since baicalein is the major constituent of OI, our data provided scientific rationale for the observed anticancer activity of OI and also offered a new lead molecule for future exploration as potential antitumor agents.

Proprotein convertase inhibitory activities of flavonoids isolated from Oroxylum indicum.

BACKGROUND: Proprotein Convertases (PCs) or Proprotein Convertase Subtilisin/Kexins (PCSKs) belong to a family of calcium-dependent endoproteases that are structurally related to bacterial subtilisin and yeast kexin. These enzymes play major roles in the processing of inactive precursor proteins producing their bioactive mature forms that are implicated in a wide variety of diseases including cancer, viral and bacterial infections. As a result, PCs are major targets for intervention of these diseases. OBJECTIVE: Our objective in this study is to find non-peptide inhibitors of PC-enzymes from a potential natural source. RESULTS: Herein we describe several natural flavonoid compounds as inhibitors of PC-enzymes including furin, a key member. These compounds were isolated from the medicinal plant Oroxylum indicum, fully characterized and tested in vitro for their PC-inhibitory property against the fluorogenic peptide substrate, Boc-RVRR-MCA (Boc = tert-butyloxy carbonyl, MCA = 4-methyl coumarin7-amide). The measured Ki and IC50 were found to be in low microM ranges. A comparative analysis of inhibition against furin, PC4, PC5 and PC7 suggested a partial selectivity towards PC4. These flavonoids also blocked efficiently the PC4-mediated processing of a fluorogenic peptide derived from the processing site of its substrate, pro-Insulin Growth Factor-1 (proIGF-1). This anti-protease activity may provide a rationale for the observed anticancer and anti-HIV properties of some of these flavonoid compounds. This is the first demonstration of anti-PC activity of flavonoid compounds.