Anti-Cancer Effect of Gingerol in Cancer Prevention and Treatment.

Cancer is one of the most lethal diseases in the world. Because of the high death rate associated with cancer and the side effects of chemotherapy and radiation therapy, patients require alternative strategies for its treatment. Ginger (Zingiber officinale) has enormous medicinal properties and health benefits. In this review, we discuss the basic mechanism by which gingerol (an active component of ginger) modulates a variety of cell signaling pathways linked to cancer, including Nuclear Factors (NF-κB), Signal Transducer and Activator of Transcription 3 (STAT3), Activator Protein-1 (AP-1), ß-catenin, Growth Factors Receptors (EGFR, VEGFR); Mitogen-Activated Protein Kinases (MAPK) and pro-inflammatory mediators (TNF-α and COX-2). Both in vitro and in vivo studies support the role of gingerol in cancer. The efficacy of gingerol by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against various kinds of cancer. An effort has been made through this comprehensive review to highlight the recent developments and milestones achieved in cancer therapies via studies based on different cell lines using gingerol.

Synthesis, docking, cytotoxicity, and LTA4H inhibitory activity of new gingerol derivatives as potential colorectal cancer therapy.

Leukotriene A4 hydrolase (LTA4H) is a proinflammatory enzyme that generates the inflammatory mediator leukotriene which may play an important role in chronic inflammation associated carcinogenesis. [6]-gingerol, the major bioactive compound of Zingiber officinale, is a potential inhibitor of LTA4H, a highly expressed enzyme in colorectal carcinoma. Eighteen compounds; seven of natural origin (including [4]-, [6]-, [8]-, and [10]-gingerol), five new and six known semi-synthesized [6]-gingerol derivatives were examined using docking, in vitro cytotoxicity against human colon cancer cells (HCT-116) and LTA4H aminopeptidase and epoxide hydrolase inhibitory studies. Methyl shogoal (D8) showed to be the most potent compound against HCT-116 cells (IC50; 1.54µM). Remarkably, D8 proved to be non-cytotoxic to normal cells; (TIG-1) and (HF-19) with high selective index (SI; 52.3). Furthermore [6]-gingerol derivatives showed potent LTA4H inhibitory activities in comparison to the universal positive controls (bestatin and 4BSA). Among the natural gingerols, [10]-gingerol (N3) exhibited the highest LTA4H aminopeptidase and epoxide hydrolase inhibitory activities with IC50; 21.59 and 15.24µM, respectively. Meanwhile, methyl shogoal (D8) and 4'-O-prenyl-[6]-gingerol (D10) retained the highest inhibition with IC50; 4.92 and 3.01µM, for aminopeptidase, and 11.27 and 7.25µM for epoxide hydrolase activities, respectively.

Synthesis of analogues of gingerol and shogaol, the active pungent principles from the rhizomes of Zingiber officinale and evaluation of their anti-platelet aggregation effects.

The present study was aimed at discovering novel biologically active compounds based on the skeletons of gingerol and shogaol, the pungent principles from the rhizomes of Zingiber officinale. Therefore, eight groups of analogues were synthesized and examined for their inhibitory activities of platelet aggregation induced by arachidonic acid, collagen, platelet activating factor, and thrombin. Among the tested compounds, [6]-paradol (5b) exhibited the most significant anti-platelet aggregation activity. It was the most potent candidate, which could be used in further investigation to explore new drug leads.

Synthesis and in vitro evaluation of analogues of avocado-produced toxin (+)-(R)-persin in human breast cancer cells.

A structure-activity study of several new synthetic analogues of the avocado-produced toxin persin has been conducted, with compounds being evaluated for their cytostatic and pro-apoptotic effects in human breast cancer cells. A 4-pyridinyl derivative demonstrated activity comparable to that of the natural product, suggesting future directions for exploration of structure-activity relationships.

Preparation and evaluation of 5, 9-dimethyl-2-cyclopropyl-2-decanol as a penetration enhancer for drugs through rat skin.

In the present study a new alcohol derivative of tetrahydrogeraniol (THG), an acyclic monoterpene, has been prepared by using Grignard reagent and methyl cyclopropyl ketone. Penetration enhancing effects of THG and the synthesized derivative 5,9-dimethyl-2-cyclopropyl-2-decanol (DICNOL) on the transdermal penetration of 5-fluorouracil (5-FU) and tramadol hydrochloride (tramadol HCl) across the excised rat skin were studied by an in vitro permeation technique using Franz diffusion cells. Azone was used as standard enhancer for comparison. DICNOL and THG significantly enhanced 5-FU and tramadol HCl penetration through rat skin compared with the control. DICNOL enhanced the permeability of 5-FU and tramadol HCl across full thickness skin by about 11 and 20 fold, respectively. Increased partition coefficient and diffusion coefficient values were obtained by these enhancers. The results suggest that the amount of DICNOL in the skin, especially in the stratum corneum, may be related to its penetration enhancing effects.

Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines.

Different delivery strategies to improve the immunogenicity of peptide/protein-based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG(200)) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained; however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system.

Orchid mimics honey bee alarm pheromone in order to attract hornets for pollination.

Approximately one-third of the world's estimated 30,000 orchid species are deceptive and do not reward their pollinators with nectar or pollen. Most of these deceptive orchids imitate the scent of rewarding flowers or potential mates. In this study, we investigated the floral scent involved in pollinator attraction to the rewardless orchid Dendrobium sinense, a species endemic to the Chinese island Hainan that is pollinated by the hornet Vespa bicolor. Via chemical analyses and electrophysiological methods, we demonstrate that the flowers of D. sinense produce (Z)-11-eicosen-1-ol and that the pollinator can smell this compound. This is a major compound in the alarm pheromones of both Asian (Apis cerana) and European (Apis mellifera) honey bees and is also exploited by the European beewolf (Philanthus triangulum) to locate its prey. This is the first time that (Z)-11-eicosen-1-ol has been identified as a floral volatile. In behavioral experiments, we demonstrate that the floral scent of D. sinense and synthetic (Z)-11-eicosen-1-ol are both attractive to hornets. Because hornets frequently capture honey bees to feed to their larvae, we suggest that the flowers of D. sinense mimic the alarm pheromone of honey bees in order to attract prey-hunting hornets for pollination.

Total synthesis of (3R,9R,10R)-panaxytriol via tandem metathesis and metallotropic [1,3]-shift as a key step.

Enyne metathesis is unique for its capacity to carry out multiple bond formation in tandem fashion. Its combined use with metallotropic [1,3]-shift allowed for the development of a novel strategy for the total synthesis of a conjugated 1,3-diyne-containing natural product (3R,9R,10R)-panaxytriol.

Lipase-catalyzed transesterification of dihydrocaffeic acid with flaxseed oil for the synthesis of phenolic lipids.

Lipase-catalyzed transesterification reaction of dihydrocaffeic acid (DHCA) with flaxseed oil in organic solvent media was investigated. Using equal molar concentration of DHCA and flaxseed oil, only phenolic monoacylglycerols were obtained with a transesterification yield (TY) of 18.9%. A 1:4 DHCA to flaxseed oil ratio resulted in the production of both phenolic mono and diacylglycerols, with TY of 39.6 and 27.8%, respectively. On the other hand, when 1:8 ratio of DHCA to flaxseed oil was used, the TY of phenolic diacylglycerols (46.0%) was higher than that of the phenolic monoacylglycerols (33.3%). The TY of phenolic diacylglycerols increased from 25.1 to 55.8%, when the ratio of the hexane/2-butanone reaction medium was changed from 65:35 to 85:25 (v/v); however, the TY of phenolic monoacylglycerols decreased slightly from 34.0 to 31.8%. The relative proportion of the C(18:3)n-3 was higher in the phenolic mono and diacylglycerols, 64.9 and 59.5%, respectively, as compared to the original flaxseed oil, 53.1%. The radical scavenging ability of phenolic lipids was significant; however, it was about half than that of alpha-tocopherol.

Effect of hexacosanol on the characteristics of novel sustained-release allopurinol solid lipospheres (SLS): factorial design application and product evaluation.

This investigation involved the evaluation of the effect of hexacosanol (HC, ceryl alcohol), a new hydrophobic wax modifier (WM) in comparison with conventional modifiers, on the development of sustained-release allopurinol (AP) solid lipospheres (SLS) intended for use in a suspension formulation and other oral dosage forms. Various beeswax (BW)/WM blends (composition ratio 1:1) were thus used to prepare SLS by a modified oil-in-water emulsion meltable disperse-phase (MDP) encapsulation method without using organic solvents and the influence of these blends on the drug encapsulation efficiency (EE), size distribution and the time for 50% of the drug to be released (t50%) was investigated. Results indicated that incorporation of HC in wall matrix of SLS provided the means to enhance the EE of AP and to modulate the rate of drug release into dissolution media (simulated gastric fluid (S.G.F.: pH 1.2) and simulated intestinal fluid (S.I.F.: pH 7.4). The effects of the process variables; HC concentration, dispersant (pluronic F-68: PF-68) concentration and drug:wax ratio were also studied on the properties of AP-loaded SLS by a 2(3) factorial design. The EE values were in the range of 80.8-92.67%. The only significant parameter affecting (P<0.01) the size and size distribution of the SLS formulations was the amount of the PF-68, whereas the factor with the biggest influence (P<0.05) on the drug EE was the initial loading of AP (in terms of the drug:wax ratio). The amount of HC blended with wax and the initial drug loading significantly (P<0.01) affected the t50% values of all of the formulations. The release of AP was more extended (t50% values (S.I.F.; pH 7.4)=9.91-25.36 h, depending on the drug:wax ratio) and surface morphology of SLS was improved with higher HC content (15%, w/w) formulations. The release patterns fitted the Baker-Lonsdale dissolution kinetics for spherical matrices. A significant decrease of plasma uric acid levels (P<0.05) and hepatic impairment in male rats was observed after oral administration of a SLS (mean size: 120 microm) suspensions of the optimum formulation, compared to suspensions of pure AP.

Straightforward synthesis of panaxytriol: an active component of Red Ginseng.

A total synthesis of (3R,9R,10R)-panaxytriol (1) was accomplished enantioselectively (40% overall yield; 30% for the longest sequence). A key step was a Cadiot-Chodkiewicz cross-coupling reaction on two fragments containing, in the aggregate, three unprotected hydroxyl groups. One fragment was synthesized by a highly enantioselective reduction of an enynone. The other arose from a highly enantioselective dihydroxylation of an allylic alcohol.

Chemoenzymatic asymmetric total syntheses of antitumor agents (3R,9R,10R)- and (3S,9R,10R)-Panaxytriol and (R)- and (S)-Falcarinol from Panax ginseng using an enantioconvergent enzyme-triggered cascade reaction.

Total asymmetric synthesis of two components of Panax ginseng showing antitumor activity, i.e., (3R,9R,10R)- and (3S,9R,10R)-Panaxytriol and of both enantiomers of Falcarinol was accomplished. Due to the fact that the synthetic strategy was based on enantioconvergent biotransformations, the occurrence of any undesired stereoisomer was entirely avoided. The absolute configuration of naturally occurring Panaxytriol was confirmed to be (3R,9R,10R) on the basis of optical rotation values. It was shown that enzyme-triggered cascade reactions represent a valuable tool for the synthesis of natural products.

The stability of gingerol and shogaol in aqueous solutions.

Gingerols, pungent principles of ginger (the rhizome of Zingiber officinale), are biologically active components that may make a significant contribution towards medicinal applications of ginger and some products derived from ginger. Gingerols, however, are thermally labile due to the presence of a beta-hydroxy keto group in the structure, and undergo dehydration readily to form the corresponding shogaols. This study investigated the stability of [6]-gingerol [5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one] at temperatures ranging from 37 to 100 degrees C in aqueous solutions, at pH 1, 4, and 7. Quantitative measurements of [6]-gingerol and its major degradation product [6]-shogaol [1-(4-hydroxy-3-methoxyphenyl)decan-4-ene-3-one] were performed by HPLC. Kinetics of [6]-gingerol degradation was characterized by least square fitting of a rate equation. It was found that gingerol exhibited novel reversible kinetics, in which it undergoes dehydration-hydration transformations with shogaol, the major degradation product. Degradation rates were found to be pH dependent with greatest stability observed at pH 4. The reversible degradation of [6]-gingerol at 100 degrees C and pH 1 was relatively fast and reached equilibrium within 2 h. Activation energies for the forward and reverse reactions for [6]-gingerol were calculated from the Arrhenius equation using reaction rates obtained at temperatures ranging from 37 to 100 degrees C.

Synthesis and cytotoxic activity of a series of diacetylenic compounds related to falcarindiol.

The synthesis of a series of diacetylenic compounds related to the natural product falcarindiol has been carried out. Unsymmetrical diacetylenes were prepared by a modification of the Cadiot-Chodkiewicz coupling reaction, while a Glaser coupling was used to prepare symmetrical diacetylenes. These compounds have been tested for in vitro cytotoxic activity against Hep-G2, and H-4-II-E cell lines. Diacetylenes with additional unsaturation at C-1, 2, appended with hydroxyl groups at C-3 and C-8, or with long hydrophobic chains, exhibited IC50 values in the micromolar range.