A Walk in Nature: Sesquiterpene Lactones as Multi-Target Agents Involved in Inflammatory Pathways.

Inflammatory states are among the most common and most treated medical conditions. Inflammation comes along with swelling, pain and uneasiness in using the affected area. Inflammation is not always a simple symptom; more often is part of a defensive response of the body to an external threat or is a sign that the damaged tissue has not healed yet and needs to rest. The management of the pain associated with an inflammatory state could be a tricky task. In fact, most remedies simply quench the pain, leaving the inflammatory state unaltered. This review focuses on sesquiterpene lactones, a class of natural compounds, that represents a future promise in the treatment of inflammation. Sesquiterpene lactones are efficient inhibitors of multiple targets of the inflammatory process. Their natural sources are often ancient remedies with relevant traditional uses in folk medicines. This work also aims to elucidate how these compounds may represent the starting material for the development of new anti-inflammatory drugs.

Heteromeles Arbutifolia, a Traditional Treatment for Alzheimer's Disease, Phytochemistry and Safety.

Background: This study examined the chemistry and safety of Heteromeles arbutifolia, also called toyon or California holly, which is a traditional California Indian food and treatment for Alzheimer's disease. Methods: Plant extracts were examined by HPLC/MS, NMR and other techniques to identify compounds. Volunteers were recruited to examine the acute safety of the plant medicine using a standard short-term memory test. Results: The plant was found to contain icariside E4, dihydroxyoleanenoic acid, maslinic acid, betulin, trihydroxyoxo-seco-ursdienoic acid, catechin, vicenin-2, farrerol, kaempferide and tetrahydroxyoleanenoic acid. These compounds are anti-inflammatory agents that may protect the blood-brain barrier and prevent inflammatory cell infiltration into the brain. The dried berries were ingested by six volunteers to demonstrate the safety of the medicine. Conclusion: The plant medicine was found to contain several compounds that may be of interest in the treatment of Alzheimer's disease. The plant medicine was found to be safe.

A comparison of chinese and american Indian (chumash) medicine.

Chinese and Chumash traditional medical approaches are similar in terms of disease causation, use of acupuncture or healing touch, plants, spiritual and philosophical approaches. This article provides a brief comparison and discussion of Chinese and Chumash traditional medical practices. A table of 66 plants is presented along with Chinese and Chumash uses of each plant. These uses are compared and contrasted.

Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay.

Ribonucleotide reductase (RR) is an important therapeutic target for anticancer drugs. The structure of human RR features a 1:1 complex of two homodimeric subunits, hRRM1 and hRRM2. p53R2 is a newly identified homologue of hRRM2. We have devised a holoenzyme-based in vitro assay for the determination of the potency and subunit-selectivity of small-molecule inhibitors of RR. The assay was implemented using two forms of recombinant RR (hRRM2/hRRM1 and p53R2/hRRM1) and based on their [(3)H]CDP reduction activity. Hydroxyurea was used to standardize the assay. We found that the activities of hRRM2/hRRM1 and p53R2/hRRM1 were decreased by hydroxyurea in a dose-dependent manner. The -NH-OH segment of hydroxyurea was shown to be essential for inhibition. In the presence of Fe(III) and reductants, less inhibition of enzymatic activity by hydroxyurea was observed, especially for p53R2/hRRM1. The potency of four hydroxyurea analogues (Schiff bases of hydroxysemicarbazide, SB-HSC) decreased in the order SB-HSC 21 > SB-HSC 24 > SB-HSC 2 > hydroxyurea (HU) > SB-HSC 29. SB-HSC 2 and SB-HSC 24 inhibited p53R2/hRRM1 significantly more than hRRM2/hRRM1, whereas SB-HSC 21 and SB-HSC 29 showed low subunit-selectivity. Electron paramagnetic resonance (EPR) measurements showed that inhibition of RR was accompanied by reduction of its tyrosyl radical. The method was validated by comparison with data obtained using cell-based assays. We suggest that this novel recombinant-holoenzyme-based in vitro assay is a useful tool for the discovery of more potent and subunit-selective inhibitors of RR.

Anticancer agents: tumor cell growth inhibitory activity and binary QSAR analysis.

The tumor cell growth inhibitory activities (log 1/GI(50)) of 166 anticancer agents studied at the National Cancer Institute (NCI) in vitro anticancer screening program have allowed us to analyze the relative importance of physicochemical parameters in influencing the inhibitory activities. Increased molecular weight, as measured by the logarithm of molecular weight (log MW), is found to be an important contributor to the tumor cell growth inhibitory activities. The tumor cell growth inhibitory activities in different subpanels of the tumor cells are highly inter-correlated with each other. A simple binary quantitative structure-activity relationship (QSAR) model was derived from the 166 anticancer drugs, based on the tumor cell growth inhibitory activities transformed into a binary (active or inactive) data format. The model obtained can be tested with additional new data, and may be useful to identify active compounds from a large compound library to be included in high throughput screening.

Chemical and pharmacological investigations of Epimedium species: a survey.

More than 130 different compounds have been identified from over 16 species of the Epimedium genus of the Berberidaceae family. Eight of these species have been used in the Traditional Chinese Medicines (TCM) over centuries to treate a wide range of diseases. From in vitro and in vivo experimental data, and preliminary structure-activity relationship (SAR) analysis of the androgenic/anti-estrogenic and anti-oxidant activities of the icariin series of flavonoids and glycosides, the results appear to be consistent with those of known anti-estrogenic flavonoids, such as luteolin. Further QSAR analysis of the different active ingredients is now in progress and will be reported elsewhere. Our survey suggests the possibility of multiple targets and multiple mechanisms of action by Epimedium preparations and their purified compounds. These may serve as leads for further new drug development.

Synthesis, biological evaluation, and quantitative structure-activity relationship analysis of new Schiff bases of hydroxysemicarbazide as potential antitumor agents.

Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC(50) values were found to be in a range from 2.7 x 10(-6) to 9.4 x 10(-4) M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC(50) values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC(50) = 8.2 x 10(-5) M). The partition coefficient (log P) and ionization constants (pK(a)) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch-Fujita pi constant of -CH=NNHCONHOH. On the basis of the newly derived pi and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of pi values. Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity (SlogP), molecular size/polarizability (calculated molar refractivity), and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities. In conclusion, the results obtained in this study show that several Schiff bases of hydroxysemicarbazide are potent inhibitors of tumor cells and warrant further investigation as cancer chemotherapeutic agents.