Cytotoxic constituents of Glycosmis ovoidea collected in Vietnam.

Compounds derived from natural sources have been major contributors to the area of cancer chemotherapy for decades. As part of an ongoing effort to discover anticancer drug leads from tropical plants, a large-scale collection of Glycosmis ovoidea Pierre (Rutaceae), was made at Nui Chua National Park, Vietnam. Activity-guided fractionation of the chloroform-soluble fractions led to the isolation of nine coumarins, including the new compound, 1-(7-methoxy-2-oxo-2H-chromen-8-yl)-3-methyl-1-oxobut-2-en-2-yl (S)-2-methylbutanoate (1). An close analogue of 1, namely, kincuongin (2), was deemed as non-cytotoxic (IC50 > 10 µM) against five different cancer cell lines. However, co-administration of kimcuongin (2) showed an approximately 100 times potentiation of the MCF-7 breast cancer cell cytotoxicity of the previously reported flavonoid, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (10). To provide a mechanistic basis for the cancer cell line inhibition enhancement observed, an initial in silico study on compound 10 indicated that it interacts with isoforms of the NF-κB complex. In a confirmatory western blot experiment conducted, kimcuongin (2) was found to potentiate the effects of flavone 10 in inhibiting both NF-κB and PARP-1. In vivo investigations using a zebrafish (Danio rerio) model showed that compounds 2, 3, 5, and 6 did not exhibit any discernible toxicity at concentrations up to 50 µM.

Bioactive small-molecule constituents of Lao plants.

Laos has a rich plant diversity, and medicinal plants are used extensively in Lao traditional medicine for the treatment of a variety of human diseases. However, only a relatively small number of these plants have been investigated for their major components with potential antitumor, anti-infective, and other types of bioactivities. These species include Asparagus cochinchinensis, Diospyros quaesita, Gongronema napalense, Marsypopetalum modestum, Nauclea orientalis, Rourea minor, Stemona pierrei, and Stemona tuberosa. Thus far, the bioactive compounds isolated from these Lao plants include alkaloids, glycerol esters, phenolic compounds such as lignans and stilbenoids, steroids, and triterpenoids. Of these, the norlignan, nyasol (1b), the triterpenes, pyracrenic acid [3ß-O-trans-caffeoylbetulinic acid (3)] and betulinic acid (3b), and the dimeric thiopyridine, dipyrithione (5), were found to show both cancer cell cytotoxicity and anti-infective activity. The present review focuses on examples of promising lead compounds isolated from Lao plants, with their possible development as potential therapeutic agents being discussed. It is hoped that this contribution will provide useful information on higher plants growing in Laos to help stimulate future discoveries of potential agents for the treatment of cancer, infections, and other diseases.

A pentamethoxylated flavone from Glycosmis ovoidea promotes apoptosis through the intrinsic pathway and inhibits migration of MCF-7 breast cancer cells.

The rare flavone 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF) has been isolated from several plant species, and its cytotoxic activity has been reported against many types of cancer cells. In this study, PMF was purified from Glycomis ovoidea collected in Vietnam, and its antiproliferative effects and underlying mechanism of action were investigated against MCF-7 cells. PMF inhibited growth in MCF-7 > MCF-10A > MDA-MB-231 cells after 72 hr treatment, with IC50 values of 1.5, 1.9, and 8.6 µg/ml, respectively. Further experiments conducted with this compound in MCF-7 cells, showed the loss of mitochondrial membrane potential, reactive oxygen species overproduction, upregulation of BAX, cytochrome c, caspase-3 and PARP-1 and down-regulation of BCL-2 proteins as well as an increase in caspase-3/-7 activity, suggesting induction of the apoptotic intrinsic pathway. Furthermore, PMF increased cell cycle arrest in the G1 phase, which correlated with increments in the p53 and p21 levels. Additionally, MCF-7 cell migration was inhibited, which could be related to NF-κB p65 downregulation. Finally, PMF did not show toxicity in vivo in a zebrafish (Danio rerio) model. In conclusion, PMF induces cell death in MCF-7 cells through regulation of the BCL-2 protein family and may be proposed as a lead as a potential alternative for breast cancer therapy.

Cytotoxic and non-cytotoxic cardiac glycosides isolated from the combined flowers, leaves, and twigs of Streblus asper.

A new non-cytotoxic [(+)-17ß-hydroxystrebloside (1)] and two known cytotoxic [(+)-3'-de-O-methylkamaloside (2) and (+)-strebloside (3)] cardiac glycosides were isolated and identified from the combined flowers, leaves, and twigs of Streblus asper collected in Vietnam, with the absolute configuration of 1 established from analysis of its ECD and NMR spectroscopic data and confirmed by computational ECD calculations. A new 14,21-epoxycardanolide (3a) was synthesized from 3 that was treated with base. A preliminary structure-activity relationship study indicated that the C-14 hydroxy group and the C-17 lactone unit and the established conformation are important for the mediation of the cytotoxicity of 3. Molecular docking profiles showed that the cytotoxic 3 and its non-cytotoxic analogue 1 bind differentially to Na+/K+-ATPase. Compound 3 docks deeply in the Na+/K+-ATPase pocket with a sole pose, and its C-10 formyl and C-5, C-14, and C-4' hydroxy groups may form hydrogen bonds with the side-chains of Glu111, Glu117, Thr797, and Arg880 of Na+/K+-ATPase, respectively. However, 1 fits the cation binding sites with at least three different poses, which all depotentiate the binding between 1 and Na+/K+-ATPase. Thus, 3 was found to inhibit Na+/K+-ATPase, but 1 did not. In addition, the cytotoxic and Na+/K+-ATPase inhibitory 3 did not affect glucose uptake in human lung cancer cells, against which it showed potent activity, indicating that this cardiac glycoside mediates its cytotoxicity by targeting Na+/K+-ATPase but not by interacting with glucose transporters.

Plant-derived glucose transport inhibitors with potential antitumor activity.

Glucose, a key nutrient utilized by human cells to provide cellular energy and a carbon source for biomass synthesis, is internalized in cells via glucose transporters that regulate glucose homeostasis throughout the human body. Glucose transporters have been used as important targets for the discovery of new drugs to treat cancer, diabetes, and heart disease, owing to their abnormal expression during these disease conditions. Thus far, several glucose transport inhibitors have been used in clinical trials, and increasing numbers of natural products have been characterized as potential anticancer agents targeting glucose transport. The present review focuses on natural product glucose transport inhibitors of plant origin, including alkaloids, flavonoids and other phenolic compounds, and isoprenoids, with their potential antitumor properties also discussed.

Natural Product Triterpenoids and Their Semi-Synthetic Derivatives with Potential Anticancer Activity.

Triterpenoids are distributed widely in higher plants and are of interest because of their structural diversity and broad range of bioactivities. In particular, there is a very large literature on the propensity of a variety of triterpenoids to act as potential anticancer agents. In the present review, the anticancer potential is summarized for naturally occurring triterpenoids and their semi-synthetic derivatives, including examples of lupane-, oleanane-, ursane-, and cucurbitane-type pentacyclic triterpenoids, along with dammarane-type tetracyclic triterpenes including ginsenosides and their sapogenins and dichapetalins, which have been characterized as antitumor leads from higher plants. Preliminary structure-activity relationships and reported mechanisms of the antineoplastic-related activity are included. Prior studies for triterpenoids of plant origin are supportive of additional work being conducted on the more detailed biological and mechanistic evaluation for the progression of this type of natural products as possible cancer chemotherapeutic agents.

Cytotoxic and NF-κB and mitochondrial transmembrane potential inhibitory pentacyclic triterpenoids from Syzygium corticosum and their semi-synthetic derivatives.

Syzygium is a large genus of flowering plants, with several species, including the clove tree, used as important resources in the food and pharmaceutical industries. In our continuing search for anticancer agents from higher plants, a chloroform extract of the leaves and twigs of Syzygium corticosum collected in Vietnam was found to be active toward the HT-29 human colon cancer cell line. Separation of this extract guided by HT-29 cells and nuclear factor-kappa B (NF-κB) inhibition yielded 19 known natural products, including seven triterpenoids, three ellagic acid derivatives, two methylated flavonoids, a cyclohexanone, four megastigmanes, a small lactone, and an aromatic aldehyde. The full stereochemistry of (+)-fouquierol (2) was defined for the first time. Biological investigations showed that (+)-ursolic acid (1) is the major cytotoxic component of S. corticosum, which exhibited also potent activities in the NF-κB and mitochondrial transmembrane potential (MTP) inhibition assays conducted, with IC50 values of 31 nM and 3.5 µM, respectively. Several analogues of (+)-ursolic acid (1) were synthesized, and a preliminary structure-activity relationship (SAR) study indicated that the C-3 hydroxy and C-28 carboxylic acid groups and 19,20-dimethyl substitution are all essential in the mediation of the bioactivities observed for this triterpenoid.

An Intramolecular CAr-H•••O=C Hydrogen Bond and the Configuration of Rotenoids.

Over the past half a century, the structure and configuration of the rotenoids, a group of natural products showing multiple promising bioactivities, have been established by interpretation of their NMR and electronic circular dichroism spectra and confirmed by analysis of single-crystal X-ray diffraction data. The chemical shift of the H-6' 1H NMR resonance has been found to be an indicator of either a cis or trans C/D ring system. In the present study, four structures representing the central rings of a cis-, a trans-, a dehydro-, and an oxadehydro-rotenoid have been plotted using the Mercury program based on X-ray crystal structures reported previously, with the conformations of the C/D ring system, the local bond lengths or interatomic distances, hydrogen bond angles, and the H-6' chemical shift of these compounds presented. It is shown for the first time that a trans-fused C/D ring system of rotenoids is preferred for the formation of a potential intramolecular C6'-H6'•••O=C4 H-bond, and that such H-bonding results in the 1H NMR resonance for H-6' being shifted downfield.

Cardiac Glycoside Constituents of Streblus asper with Potential Antineoplastic Activity.

Three new (1-3) and two known (4 and 5) cytotoxic cardiac glycosides were isolated and characterized from a medicinal plant, Streblus asper Lour. (Moraceae), collected in Vietnam, with six new analogues and one known derivative (5a-g) synthesized from (+)-strebloside (5). A preliminary structure-activity relationship study indicated that the C-10 formyl and C-5 and C-14 hydroxy groups and C-3 sugar unit play important roles in the mediation of the cytotoxicity of (+)-strebloside (5) against HT-29 human colon cancer cells. When evaluated in NCr nu/nu mice implanted intraperitoneally with hollow fibers facilitated with either MDA-MB-231 human breast or OVCAR3 human ovarian cancer cells, (+)-strebloside (5) showed significant cell growth inhibitory activity in both cases, in the dose range 5-30 mg/kg.

Isolation of Bioactive Rotenoids and Isoflavonoids from the Fruits of Millettia caerulea.

Three new rotenoids (1-3), two new isoflavonoids (4 and 5), and six known analogues (6-11) were isolated from an n-hexane partition of a methanol extract of the fruits of Millettia caerulea, with the structures of the new compounds elucidated by analysis of their spectroscopic data. The relative configurations of the rotenoids were determined by interpretation of their NMR spectroscopic data, and their absolute configurations were established using electronic circular dichroism spectra and specific rotation values. All compounds isolated were evaluated for their cell growth inhibitory activity against the HT-29 human colon cancer cell line, and the known compounds, (-)-3-hydroxyrotenone (6) and (-)-rotenone (7), were found to be potently active. When tested in an NF-κB inhibition assay, compound 6 showed activity. This compound, along with the new compound, (-)-caeruleanone D (1), and the known compound, ichthynone (8), exhibited K-Ras inhibitory potency. Further bioactivity studies showed that the new compounds, (-)-3-deoxycaeruleanone D (2) and (-)-3-hydroxycaeruleanone A (3), and the known compounds 8 and 11 induced quinone reductase in murine Hepa 1c1c7 cells.

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones.

Sesquiterpene lactones are of considerable interest due to their potent bioactivities, including cancer cell cytotoxicity and antineoplastic efficacy in in vivo studies. Among these compounds, artesunate, dimethylaminoparthenolide, and L12ADT peptide prodrug, a derivative of thapsigargin, are being evaluated in the current cancer clinical or preclinical trials. Based on the structures of several antitumor sesquiterpene lactones, a number of analogues showing greater potency have been either isolated as natural products or partially synthesized, and some potential anticancer agents that have emerged from this group of lead compounds have been investigated extensively. The present review focuses on artemisinin, parthenolide, thapsigargin, and their naturally occurring or synthetic analogues showing potential anticancer activity. This provides an overview of the advances in the development of these types of sesquiterpene lactones as potential anticancer agents, including their structural characterization, synthesis and synthetic modification, and antitumor potential, with the mechanism of action and structure-activity relationships also discussed. It is hoped that this will be helpful in stimulating the further interest in developing sesquiterpene lactones and their derivatives as new anticancer agents.

Assay development for the discovery of semaphorin 3B inducing agents from natural product sources.

Semaphorins are a class of membrane-bound and secreted proteins. They have been found to regulate basic cell functions such as axonal growth cone guidance and recent studies have focused on their effect on tumor progression. Semaphorin 3B (Sema3B) particularly is a secreted protein that has been known to modulate proliferation and apoptosis, processes that are critical for tumor progression and development. In spite of its importance, there is yet no high-throughput screening assay available to detect or quantify the expression of Sema3B for natural product anticancer drug discovery purposes. Therefore, the development of a new high-throughput bioassay for the discovery of Sema3B inducing agents from natural product sources is described herein. A wide variety of pure compounds and extracts from plants and microorganisms has been found suitable for screening using this Sema3B assay to detect and quantify the effect of Sema3B inducing agents and thereby identify new selective bioactive Sema3B lead compounds for anticancer drug discovery and development. Also, this new bioassay procedure is based on a high-throughput platform using an enzyme-linked immunosorbent assay that involves the optimization of sensitivity and selectivity levels as well as accuracy, reproducibility, robustness, and cost effectiveness.

Biological and biomedical functions of Penta-O-galloyl-D-glucose and its derivatives.

Penta-O-galloyl-D-glucose (PGG) is a simple hydrolysable tannin in plants. PGG exists in two anomeric forms, α-PGG and ß-PGG. While ß-PGG can be found in a wide variety of plants, α-PGG is rather rare in nature. Numerous studies with ß-PGG revealed a wide variety of biological activities, such as anti-microbial and anti-cancer functions. Until recently, studies with α-PGG were limited by the lack of its availability. Since the development of an efficient chemical synthesis of the compound, several investigations have revealed its anti-diabetic, anti-cancer, and anti-platelet-coagulation functions. Based on structure-activity-relationship (SAR) studies with α-PGG, a variety of α-PGG-related novel compounds were synthesized and some of them have been shown to possess promising therapeutic activities. In this review, the authors will survey and evaluate the biological functions of PGG with a focus on α-PGG and its derivatives.

[Study on extraction of coumarins in Cnidium monieri by supercritical CO2 and separation of compositions analysis].

OBJECTIVE: To analyze the chemical constituents of supercritical carbon dioxide extraction products from Cnidium monieri. METHOD: Four-factor and three-level orthogonal experimental design was used to optimize the SFE conditions as guided by the content of total coumarins in the extract. The chemical constituents were separated and identified by recrystalization. RESULT: Optimum extraction process was established: 25 MPa as extraction pressure, 50 degrees C as extraction temperature, 6.5 MPa as separation pressure and 60 degrees C as separation temperature. CONCLUSION: Changes in extraction pressure, temperature, time, pulverized degree and separation pressure affect the extracting results remarkably. The two kinds of chemical constituents were separated by recrystallization from C. monieri and identified by the methods of UV, IR, MS, NMR.

[Studies on the chemistry of two new compounds of Hemistepta lyrata].

AIM: To study the chemical constituents of Hemistepta lyrata. METHODS: To separate compounds with various chromatography technology and to elucidate their structures by chemical and spectral analysis. RESULTS: Two compounds were isolated from Hemistepta lyrata and their structures were determined as hemiceramide (I), hemisterpene ether (II). CONCLUSION: Compounds I and II are new compounds.