Journal of Pharmacy and Pharmacology

In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplished by bis-amination of 9-chlorotetrahydroacridine and its congeners under heated conditions.

The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vitro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyllinked bis-tacrine (5b) exhibited the strongest cytotoxic profile with GI50 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08 μM against breast, colon, melanoma and non-small lung cancer cells. Congeners bearing a longer alkyl chain were on average 30- to 100-fold less cytotoxic against these cancer cells. Shorter connecting alkyl chains of bis-tacrine or its congeners dramatically decreased the cytotoxic effects.

Compound 5b has been selected for further biological evaluation of its anticancer profile.

Tranilast is an anti-allergic agent that blocks the release of chemical mediators, such as histamine and leukotrienes from mast cells, and has been reported to suppress keloid and hypertrophic scar formation. Since matrix metalloproteinases (MMPs) play an essential role in tissue remodelling, this study was undertaken to determine whether tranilast suppresses MMP production from neutrophils after lipopolysaccharide (LPS) stimulation in-vitro. Neutrophils from five healthy donors (1times105 cells/mL) were stimulated with 1.0 μg mL−1 LPS in the presence or absence of various concentrations of tranilast for 24 h. MMP-7, MMP-8, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels in the culture supernatants were assayed by ELISA. In addition, the influence of tranilast on MMP mRNA expression and transcriptional factor activation in cells cultured for 12 h and 4 h was also evaluated by reverse transcriptase—polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Tranilast inhibited MMP and TIMP-1 production from neutrophils when cells were treated with the agent at more than 5.0times10−5  m. It also suppressed MMP mRNA expression and transcriptional factor activation induced in neutrophils by LPS stimulation. The results suggest that tranilast inhibits the formation of keloid scarring through the suppression of factors such as MMPs and TIMP, which are essential for tissue remodelling, from inflammatory cells.

The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-κB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-κB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-κB activation will first be summarised, leading to the Ikk (IkB kinase) complex, that subsequently initiates phosphorylation of the NF-κB inhibitory protein (IkB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-κB inhibitors. A large number of compounds are currently known as NF-κB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.

Critical micelle concentrations (cmc) have been measured by the surface tension method for binary mixtures of dodecyltrimethyl-ammonium bromide with tetradecyltrimethylammonium bromide, binary mixtures of C14/C16 homologues, a ternary mixture of the C12/C14/C16 compounds and additionally for each component individually. The antibacterial activities of the systems against Escherichia coli were determined by a British Standard Method (B.S. 3286: 1960). Thermodynamic activities of the solutions at two survivor levels, calculated from the physical and biological measurements, were sufficiently constant to sustain the Ferguson principle for these micelle-forming antibacterial agents. A theoretical treatment of micelle formation for multi-component solutions of surfactants gave cmc’s by calculation in close agreement with the experimentally determined values. The purity and composition of the surfactants was determined by gas liquid chromatography.

Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine for the treatment of a wide range of gastrointestinal symptoms. The essential oil from its bark was investigated for acute toxicity in mice and for its ability to prevent the formation of ulceration of the gastric mucosa in different models of experimentally induced gastric ulcer in mice and rats.

When previously administered orally at a dose of 100mg kg-1, the essential oil significantly reduced (P < 0.01) the gastric injury induced by hypothermic restraint stress (48%), indomethacin (47%), ethanol (86%) and pylorus ligature models (87%) in rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 200mg kg-1 the essential oil from C. cajucara significantly reduced (P < 0.01) the formation of gastric lesions by 52% and 67%, respectively, when compared with the control group. In rats submitted to pylorus ligature, the essential oil given orally increased the volume of gastric juice when compared with the control group (P < 0.01). When the essential oil (100mg kg-1) was administered intraduodenally to mice, significant modifications were found in gastric parameters such as pH and total acid content after oil treatment. We observed significant changes (P < 0.01) in gastric juice parameters such as an increase in volume and a decrease in gastric acidity (pH and total acid content). The acute toxicologic effects of the essential oil from C. cajucara were assessed in mice. The LD50 values were 9.3g kg-1 by the oral route and 680mg kg-1 by the intraperitoneal route.

The good yield of essential oil obtained from dried C. cajucara bark (1%) as well as its anti-ulcerogenic activity and low toxicity suggest that pharmacological studies of this substance as a potential new anti-ulcerogenic drug are warranted.

Effects of an acidic polysaccharide fraction, BR-2, from the roots of Bupleurum falcatum L., on HCl-ethanol, ethanol and water immersion stress-induced gastric lesions in mice and pylorus-ligated ulcers in rats have been studied. Oral administration of BR-2 at doses of 50 to 200 mg kg−1 inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl-ethanol and ethanol, in a dose dependent manner. This protective effect was observed after oral, intraperitoneal, and subcutaneous administration of BR-2 (25–100 mg kg−1). BR-2 also inhibited the formation of gastric ulcers which were induced by water immersion stress or pylorus-ligation. Prostaglandin E2 in gastric juice from rats and in gastric mucosa from mice was not influenced by oral administration of BR-2. The protective action of BR-2 against HCl-ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin (20 mg kg−1, i.p.). The amount of alcian blue binding to mucosa also increased after administration of BR-2 (100 mg kg−1, p.o.); however, the amount of hexosamine and N-acetylneuraminic acid in mucosa did not change significantly.