The anti-proliferative effects of a frankincense extract in a window of opportunity phase ia clinical trial for patients with breast cancer.

PURPOSE: Boswellic acids, active components of frankincense, suppress tumor proliferation in vitro with a strong clinical trial safety profile in patients with inflammatory diseases. We performed a Phase Ia window of opportunity trial of Boswellia serrata (B. serrata) in patients with breast cancer to evaluate its biologic activity and safety. METHODS: Patients with invasive breast cancer were treated pre-operatively with B. Serrata (2400 mg/day PO) until the night before surgery for a median of 11 days (SD 6 days; range: 5-23 days). Paraffin-embedded sections from pretreatment diagnostic core biopsies and post-treatment surgical excisions were evaluated using a tunnel assay and immunohistochemistry staining with Ki-67 antibodies. A non-intervention retrospective control arm consisting of core and surgical tissue specimens from untreated patients was used to compare patients treated with B. Serrata. The change in proliferation and apoptosis between diagnostic core specimens and surgical specimens was compared between the control and treatment groups using a two-tailed paired t-test. RESULTS: Twenty-two patients were enrolled, of which 20 received treatment, and 18 had sufficient tissue for IHC. There was an increase in percent change in proliferation from core biopsy to surgical excision in the control group (n = 18) of 54.6 ± 21.4%. In the B. serrata-treated group there was a reduction in proliferation between core biopsy and excision (n = 18) of 13.8 ± 11.7%. This difference was statistically significant between the control and B. serrata-treated groups (p = 0.008). There was no difference in change in apoptosis. There were no serious adverse events related to the drug. CONCLUSION: Boswellia serrata inhibited breast cancer proliferation and was well-tolerated in a Phase Ia window of opportunity trial.

Lemon yellow #15 a new highly stable, water soluble food colorant from the peel of Citrus limon.

To provide stable and low-cost naturally derived yellow pigments, a variety of food byproducts were evaluated and the constituents of lemon peel have emerged yielding a highly promising natural product with applications as a food dye. Here we report a new, highly stable and water soluble food dye called yellow #15 from the ethanol extract of the zest of Citrus limon. The structure of lemon yellow #15 was carefully assigned on the basis of spectroscopic data, including 1D and 2D NMR spectroscopy, and the absolute configuration was established by comparison of the experimental CD with calculated electronic circular dichroism (ECD) spectral data. CIELAB values and Delta CIELAB were measured and revealed this new water-soluble pigment has superior light stability relative to other natural products used as food dyes.

A Chemical Investigation of the Leaves of Morus alba L.

The leaves of Morus alba L. are an important herbal medicine in Asia. The systematic isolation of the metabolites of the leaves of Morus alba L. was achieved using a combination of liquid chromatography techniques. The structures were elucidated by spectroscopic data analysis and the absolute configuration was determined based on electronic circular dichroism (ECD) spectroscopic data and hydrolysis experiments. Their biological activity was evaluated using different biological assays, such as the assessment of their capacity to inhibit the aldose reductase enzyme; the determination of their cytotoxic activity and the evaluation of their neuroprotective effects against the deprivation of serum or against the presence of nicouline. Chemical investigation of the leaves of Morus alba L. resulted in four new structures 1⁻4 and a known molecule 5. Compounds 2 and 5 inhibited aldose reductase with IC50 values of 4.33 µM and 6.0 µM compared with the potent AR inhibitor epalrestat (IC50 1.88 × 10−3 µM). Pretreatment with compound 3 decreased PC12 cell apoptosis subsequent serum deprivation condition and pretreatment with compound 5 decreased nicouline-induced PC12 cell apoptosis as compared with control cells (p < 0.001).

Assignment of Absolute Configuration of a New Hepatoprotective Schiartane-Type Nortriterpenoid Using X-Ray Diffraction.

A new schiartane-type nortriterpenoid, micrandilactone H was isolated from Kadsuralongipedunculata Finet et Gagnep. Its 2D (two dimension) structure was elucidated by NMR spectroscopic analysis, and it is similar to that of Kadnanolactones H and the absolute configuration was established through X-ray diffraction and ECD data analysis. This represents the first complete assignment of the absolute configuration of a schiartane-type nortriterpenoid by X-ray diffraction and the ECD method. Micrandilactone H showed moderate hepatoprotective activity against N-acetyl-p-aminophenol (APAP)-induced toxicity in HepG2 cells with cell survival rates of 56.84% at 10 µM.

HPLC Plasma Assay of a Novel Anti-MRSA Compound, Kaempferol-3-O-Alpha-L-(2",3"-di-p-coumaroyl)rhamnoside, from Sycamore Leaves.

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious pathogen that is resistant to current antibiotic therapy. Thus, there is an urgent need for novel antimicrobial agents that can effectively combat these new strains of drug-resistant "superbugs". Recently, fractionation of an extract from Platanus occidentalis (American sycamore) leaves produced an active kaempferol molecule, 3-O-alpha-L-(2",3"-di-p-coumaroyl)rhamnoside (KCR), in four isomeric forms; all four isomers exhibit potent anti-MRSA activity. In order to further the preclinical development of KCR as a new antibiotic class, we developed and validated a simple analytical method for assaying KCR plasma concentration. Because KCR will be developed as a new drug, although comprising four stereoisomers, the analytical method was devised to assay the total amount of all four isomers. In the present work, both a plasma processing procedure and an HPLC method have been developed and validated. Mouse plasma containing KCR was first treated with ethanol and then centrifuged. The supernatant was dried, suspended in ethanol, centrifuged, and the supernatant was injected into an HPLC system comprising a Waters C18, a mobile phase composing methanol, acetonitrile, and trifluoroacetic acid and monitored at 313 nm. The method was validated by parameters including a good linear correlation, a limit of quantification of 0.27 microg/mL, and high accuracy. In summary, this method allows a rapid analysis of KCR in the plasma samples for pharmacokinetics studies.

Evaluation of three medicinal plant extracts against Plasmodium falciparum and selected microganisms.

BACKGROUND: A great revival of scientific interests in drug discovery has been witnessed in recent years from medicinal plants for health maintenance. The aim of this work was to investigate three Nigerian medicinal plants collected in Nigeria for their in vitro antiplasmodial and antimicrobial activities. MATERIALS AND METHODS: Extracts obtained from parts of Persea americana, Jatropha podagrica and Picralima nitida and their fractions were evaluated for in vitro antiprotozoal and antimicrobial activity. RESULT: The methanol extract of P. nitida demonstrated activity against chloroquine-sensitive and chloroquine-resistant P. falciparum clones with IC50 values of 6.3 and 6.0 µg/mL, respectively. Methanol and chloroform extracts of P. americana seed showed antifungal activity against Cryptococcus neoformans IC50 less than 8 and 8.211 µg/mL respectively. Finally, the petroleum ether extract of P. americana had activity against methicillin-resistant Staphylococcus aureus (MRSA) with an IC50 value of 8.7 µg/mL. CONCLUSION: The study revealed the antibacterial and antiplasmodial activities of the plants extracts at the tested concentrations.

Isolation of antileishmanial, antimalarial and antimicrobial metabolites from Jatropha multifida.

OBJECTIVE: To investigate the antileishmanial, antimicrobial and antimalarial activities of the pure metabolites from Jatropha multifida used in African ethnomedicine. METHODS: The methanolic stem bark extract of Jatropha multifida used in Nigerian folk medicine as remedy against bacterial infections was subjected to column chromatography and HPLC analyses to obtain three known metabolites, microcyclic lathyrane diterpenoids (1-3). Structures were confirmed by comparison of 1D and 2D spectral data with literature. RESULTS: The three compounds exhibited inhibition of antileishmanial, antimalarial and antimicrobial actions against the tested organisms with compouds 2 and 3 active against Cryptococcus neoformans at IC50 of 8.2 and 8.7 µg/mL, respectively. CONCLUSIONS: The research lends support to the ethnomedicinal use of the plant in combating microbial infections, leishmaniasis and malarial infections.

Significance of endangered and threatened plant natural products in the control of human disease.

One in five of the world's plant species is threatened with extinction according to the 2010 first global analysis of extinction risk. Tilman et al. predicted a massive ecological change to terrestrial plants within the next 50-100 y, accompanied by an increase in the number of global plant species facing extinction [Tilman D, et al. (2001) Proc Natl Acad Sci USA 98(10):5433-5440]. Most of the drug-producing plant families contain endangered species never previously studied for their utility to human health, which strongly validates the need to prioritize protection and assessment of these fragile and endangered groups [Zhu F, et al. (2011) Proc Natl Acad Sci USA 108(31):12943-12948]. With little prior attention given to endangered and rare plant species, this report provides strong justification for conservation of the rare plant Diplostephium rhododendroides Hieron., as well as other potential drug-producing endangered species in this and other groups.

Natural product studies of U.S. endangered plants: volatile components of Lindera melissifolia (Lauraceae) repel mosquitoes and ticks.

The number of endangered plant species in the U.S. is significant, yet studies aimed towards utilizing these plants are limited. Ticks and mosquitoes are vectors of significant pathogenic diseases of humans. Repellents are critical means of personal protection against biting arthropods and disease transmission. The essential oil and solvent extracts from Lindera melissifolia (Walt.) Blume (Lauraceae) (pondberry) drupes were gathered and analyzed by GC and GC-MS. The essential oil obtained from this endangered plant showed a significant dose dependent repellency of ticks and a moderate mosquito repellent effect while the subsequent hexanes extract was completely ineffective. Fractional freezing enriched the tick repellent components of the essential oil. Several known tick repellent components were recognized by the GC-MS comparison of the resulting fractions and ß-caryophyllene, α-humulene, germacrene D and ß-elemene warrant evaluations for tick repellency. Identifying pondberry as a potential renewable source for a broad spectrum repellent supports efforts to conserve similar U.S. endangered or threatened plant species.

Liver X receptor and peroxisome proliferator-activated receptor agonist from Cornus alternifolia.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptors superfamily and are transcription factors activated by specific ligands. Liver X receptors (LXR) belong to the nuclear hormone receptors and have been shown to play an important role in cholesterol homeostasis. From the previous screening of several medicinal plants for potential partial PPARγ agonists, the extracts of Cornus alternifolia were found to exhibit promising bioactivity. In this paper, we report the isolation and structural elucidation of four new compounds and their potential as ligands for PPAR. METHODS: The new compounds were extracted from the leaves of C. alternifolia and fractionated by high-performance liquid chromatography. Their structures were elucidated on the basis of spectroscopic evidence and analysis of their hydrolysis products. RESULTS: Three new iridoid glycosides including an iridolactone, alternosides A-C (1-3), a new megastigmane glycoside, cornalternoside (4) and 10 known compounds, were obtained from the leaves of C. alternifolia. Kaempferol-3-O-ß-glucopyranoside (5) exhibited potent agonistic activities for PPARα, PPARγ and LXR with EC50 values of 0.62, 3.0 and 1.8 µM, respectively. CONCLUSIONS: We isolated four new and ten known compounds from C. alternifolia, and one known compound showed agonistic activities for PPARα, PPARγ and LXR. GENERAL SIGNIFICANCE: Compound 1 is the first example of a naturally occurring iridoid glycoside containing a ß-glucopyranoside moiety at C-6.

Antiproliferative effects of curcuphenol, a sesquiterpene phenol.

Curcuphenol is a sesquiterpene isolated from sponges and plants having several significant biological activities. The present study explored its effect on cell proliferation and apoptosis in Caco-2 human colon cancer cells. It was demonstrated that curcuphenol in concentrations in the range of 29-116 µg/ml inhibited cell proliferation and DNA replication and induced cell death in a dose-dependent manner. The induction of apoptosis was associated with a stimulation of the activity of caspase-3. The findings presented here suggest that curcuphenol has antiproliferative and pro-apoptotic properties.

New guaiane sesquiterpenes and furanocoumarins from Notopterygium incisum.

In addition to twenty-nine known compounds, two new guaiane sesquiterpenes and two new furanocoumarins were isolated from the chloroform extract of the rhizomes of Notopterygium incisum. The new structures were elucidated by means of spectroscopic methods including 2 D NMR techniques and mass spectrometry to be 8 beta-acetoxy-4 alpha,6 alpha-dihydroxy-1 alpha,5 alpha( H)-guai-9-ene (incisumdiol A, 1), 4 alpha,6 alpha-dihydroxy-1 alpha,5 alpha( H)-guai-9-ene (incisumdiol B, 2), 5-[(2 E,5 Z)-7-hydroxy-3,7-dimethyl-2,5-octadienoxy]psoralene ( 3) and 5-[(2,5)-epoxy-3-hydroxy-3,7-dimethyl-6-octenoxy]psoralene ( 4).

Antiviral and anticancer optimization studies of the DNA-binding marine natural product aaptamine.

Aaptamine has potent cytotoxicity that may be explained by its ability to intercalate DNA. Aaptamine was evaluated for its ability to bind to DNA to validate DNA binding as the primary mechanism of cytotoxicity. Based on UV-vis absorbance titration data, the K(obs) for aaptamine was 4.0 (+/-0.2) x 10(3) which was essentially equivalent to the known DNA intercalator N-[2-(diethylamino)ethyl]-9-aminoacridine-4-carboxamide. Semi-synthetic core modifications were performed to improve the general structural diversity of known aaptamine analogs and vary its absorption characteristics. Overall, 26 aaptamine derivatives were synthesized which consisted of a simple homologous range of mono and di-N-alkylations as well as some 9-O-sulfonylation and bis-O-isoaaptamine dimer products. Each product was evaluated for activity in a variety of whole cell and viral assays including a unique solid tumor disk diffusion assay. Details of aaptamine's DNA-binding activity and its derivatives' whole cell and viral assay results are discussed.

Identification of antidepressant drug leads through the evaluation of marine natural products with neuropsychiatric pharmacophores.

The marine environment is a valuable resource for drug discovery due to its diversity of life and associated secondary metabolites. However, there is very little published data on the potential application of marine natural products to treat neuropsychiatric disorders. Many natural products derived from chemically defended organisms in the marine environment have pharmacophores related to serotonin or clinically utilized antidepressant drugs. Therefore, in the present study, compounds selected for their structural similarity to serotonin or established antidepressants were evaluated for antidepressant-like activity using the forced swim and tail suspension tests in mice. The antidepressant positive controls, citalopram (selective serotonin reuptake inhibitor) and despiramine (tricyclic antidepressant) both dose-dependently reduced immobility time in the forced swim and tail suspension tests. Two marine natural product compounds tested, aaptamine and 5,6-dibromo-N,N-dimethyltryptamine, also produced significant antidepressant-like activity in the forced swim test. In the tail suspension test, the antidepressant-like effects of 5,6-dibromo-N,N-dimethyltryptamine were confirmed, whereas aaptamine failed to produce significant results. None of the tested compounds induced hyperlocomotion, indicating that nonspecific stimulant effects could not account for the observed antidepressant-like actions of the compounds. These studies highlight the potential to rationally select marine derived compounds for treating depression and other neuropsychiatric disorders.

Marine pharmacology in 2000: marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antituberculosis, and antiviral activities; affecting the cardiovascular, immune, and nervous systems and other miscellaneous mechanisms of action.

During 2000 research on the pharmacology of marine chemicals involved investigators from Australia, Brazil, Canada, Egypt, France, Germany, India, Indonesia, Israel, Italy, Japan, the Netherlands, New Zealand, Phillipines, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the United States. This current review, a sequel to the authors' 1998 and 1999 reviews, classifies 68 peer-reviewed articles on the basis of the reported preclinical pharmacologic properties of marine chemicals derived from a diverse group of marine animals, algae, fungi, and bacteria. Antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis, or antiviral activity was reported for 35 marine chemicals. An additional 20 marine compounds were shown to have significant effects on the cardiovascular and nervous system, and to possess anti-inflammatory or immunosuppressant properties. Finally, 23 marine compounds were reported to act on a variety of molecular targets and thus could potentially contribute to several pharmacologic classes. Thus, as in 1998 and 1999, during 2000 pharmacologic research with marine chemicals continued to contribute potentially novel chemical leads to the ongoing global search for therapeutic agents in the treatment of multiple disease categories.

Marine natural products and their potential applications as anti-infective agents.

The oceans are a unique resource that provide a diverse array of natural products, primarily from invertebrates such as sponges, tunicates, bryozoans, and molluscs, and from marine bacteria and cyanobacteria. As infectious diseases evolve and develop resistance to existing pharmaceuticals, the marine environment provides novel leads against fungal, parasitic, bacterial, and viral diseases. Many marine natural products have successfully advanced to the late stages of clinical trials, including dolastatin 10, ecteinascidin-743, kahalalide F, and aplidine, and a growing number of candidates have been selected as promising leads for extended preclinical assessment. Although many marine-product clinical trials are for cancer chemotherapy, drug resistance, emerging infectious diseases, and the threat of bioterrorism have all contributed to the interest in assessing natural ocean products in the treatment of infectious organisms. In this review, we focus on the pharmacologically tested marine leads that have shown in-vivo efficacy or potent in-vitro activity against infectious and parasitic diseases.