Potential of cyclopenta[b]benzofurans from Aglaia species in cancer chemotherapy.

During the past few years, a group of cyclopenta[b]benzofurans from the plant genus Aglaia has received broad scientific attention as interesting natural product lead compounds with potential anticancer and insecticidal activities. Since the first cyclopenta[b]benzofuran derivative, rocaglamide, from Aglaia elliptifolia, was found to exhibit antileukemic activity in a murine in vivo model, the genus Aglaia has been subjected to further investigation. Over 40 cyclopenta[b]benzofurans have been tested against different human cancer cell lines, and the cumulative results provide some important clues as to how to improve their activity through modification of their chemical structures.

Drug discovery from natural sources.

Organic compounds from terrestrial and marine organisms have extensive past and present use in the treatment of many diseases and serve as compounds of interest both in their natural form and as templates for synthetic modification. Over 20 new drugs launched on the market between 2000 and 2005, originating from terrestrial plants, terrestrial microorganisms, marine organisms, and terrestrial vertebrates and invertebrates, are described. These approved substances, representative of very wide chemical diversity, together with several other natural products or their analogs undergoing clinical trials, continue to demonstrate the importance of compounds from natural sources in modern drug discovery efforts.

Cytotoxic clerodane diterpenoids from the leaves of Premna tomentosa.

Three clerodane diterpenoids, premnones A-C (1-3), were isolated from a chloroform-soluble fraction of Premna tomentosa along with four known flavonoids and three known triterpenoids. Among these isolates, premnones A-C exhibited cytotoxic activity when evaluated against a small panel of tumor cell lines. However, premnone A was found to be inactive when evaluated in a follow-up in vivo hollow fiber assay at the highest dose tested (50mg/kg), using LNCaP, Lu1, and MCF-7 cells.

Interference by naturally occurring fatty acids in a noncellular enzyme-based aromatase bioassay.

Natural product drug discovery efforts frequently utilize noncellular screening assays. Fatty acids are commonly found in natural product extracts, and some have been shown to interfere with noncellular assays. Several pure fatty acids were tested using a noncellular aromatase assay, with the unsaturated analogues showing strong inhibitory activity, while the saturated analogues were inactive.

Tropane aromatic ester alkaloids from a large-scale re-collection of Erythroxylum pervillei stem bark obtained in Madagascar.

Fractionation by pH zone-refining countercurrent chromatography of an extract of the stem bark of Erythroxylum pervillei, obtained on a kilogram scale in southern Madagascar, led to the isolation and characterization of four tropane aromatic ester alkaloids as minor constituents, namely, pervilleines G (5) and H (6) and cis-pervilleines B (7) and F (8). Their structures were determined by spectroscopic data interpretation.

Cytotoxic constituents from the stem bark of Dichapetalum gelonioides collected in the Philippines.

Fractionation of an ethyl acetate-soluble extract of the stem bark of Dichapetalum gelonioides, collected in the Philippines, using the LNCaP (hormone-dependent human prostate) cell line as a monitor, led to the purification of three dichapetalin-type triterpenoids [dichapetalins A (1), I (2), and J (3)], along with two dolabrane norditerpenoids (6, 7), and the additional triterpenoids zeylanol (8), 28-hydroxyzeylanol (9), and betulinic acid. Since compounds 1-3 exhibited promising selectivity against the SW626 (human ovarian cancer) cell line, a re-collection of the plant material was carried out, to obtain more of these compounds for additional biological testing. Two further phenylpyranotriterpenoids [dichapetalins K (4) and L (5)] were isolated from the re-collected plant material.

The role of pharmacognosy in modern medicine and pharmacy.

This review details the contribution to modern medicine and pharmacy made by natural products and drugs derived from natural products, with an emphasis on essential medicines and new introductions to the market. Areas covered include recent advances in the development of drugs derived from marine organisms, microbes, terrestrial animals, and vascular plants, and current issues regarding botanical medicines. The role of natural products in drug discovery and development is evaluated, particularly with regard to their value as sources of drug leads with "drug-like" properties.

Beccaridiol, an unusual 28-nortriterpenoid from the leaves of Diplectria beccariana.

A C29-triterpene, beccaridiol (1), a dihydrochalcone natural product, 2',4'-dihydroxy-3-(4-methoxyphenyl)-propiophenone (2), as well as three known compounds, 4'-hydroxy-1',2'-dihydro-beta-ionone, 4'-O-methyldavidigenin (3), and ursolic acid, have been isolated from an EtOAc-soluble extract of the leaves of Diplectria beccariana. Beccaridiol (1) was characterized as an ursane-type 28-nortriterpene possessing an unusual aromatic E-ring by spectroscopic data interpretation. The relative configuration of this unusual isolate was established by analyzing the observed NOESY NMR correlations, and the absolute stereochemistry of 1 was then determined based on the circular dichroism (CD) spectrum of its 2,3-di-p-bromobenzoate (1b) derivative.

Cytotoxic lignans from the stems of Helicteres hirsuta collected in Indonesia.

Cytotoxicity-guided fractionation of the stems of Helicteres hirsuta, of Indonesian origin, led to the isolation and identification of six lignans, namely, (+/-)-pinoresinol, (+/-)-medioresinol, (+/-)-syringaresinol, (-)-boehmenan, (-)-boehmenan H and (+/-)-trans-dihydrodiconiferyl alcohol. Of these isolates, (+/-)-pinoresinol exhibited potent cytotoxic effects when evaluated against a small panel of cancer cell lines.

An anthraquinone with potent quinone reductase-inducing activity and other constituents of the fruits of Morinda citrifolia (noni).

Morinda citrifolia, commonly known as noni, has a long history of utilization throughout much of tropical Polynesia and is considered to be the second most important medicinal plant in the Hawaiian Islands. Recently, the use of noni as a dietary supplement in the United States has greatly increased. Bioassay-guided fractionation of a dichloromethane-soluble partition of a MeOH extract of noni fruits has led to the isolation of an extremely potent quinone reductase inducer, 2-methoxy-1,3,6-trihydroxyanthraquinone (1).

A hexacyclic ent-trachylobane diterpenoid possessing an oxetane ring from Mitrephora glabra.

[chemical reaction: see text]. Three new ent-trachylobane diterpenoids (1-3) were isolated and structures elucidated from Mitrephora glabra Scheff. (Annonaceae).

Activity-guided isolation of cytotoxic constituents from the bark of Aglaia crassinervia collected in Indonesia.

Activity-guided fractionation of a CHCl(3)-soluble partition of the MeOH extract of the bark of Aglaia crassinervia collected in Indonesia led to the isolation of three new glabretal-type triterpenoids, aglaiaglabretols A-C (1-3), as well as nine known compounds, 3-epi-cabraleahydroxylactone (4), cabraleahydroxylactone (5), rocaglaol (6), 2beta,3beta-dihydroxy-5alpha-pregn-17(20)-(E)-16-one, scopoletin, and mixtures of cabraleadiol and epicotillol and of beta-sitosterol and stigmasterol. The structures of compounds 1-3 were determined on the basis of spectroscopic and chemical methods. The structure of aglaiaglabretol A (1) was confirmed by single-crystal X-ray analysis, and the absolute stereochemistry of this isolate was established by the Mosher ester method.

Drug discovery from medicinal plants.

Current research in drug discovery from medicinal plants involves a multifaceted approach combining botanical, phytochemical, biological, and molecular techniques. Medicinal plant drug discovery continues to provide new and important leads against various pharmacological targets including cancer, HIV/AIDS, Alzheimer's, malaria, and pain. Several natural product drugs of plant origin have either recently been introduced to the United States market, including arteether, galantamine, nitisinone, and tiotropium, or are currently involved in late-phase clinical trials.

Diterpene glycosides from Egletes viscosa.

A phytochemical investigation of the CHCl (3)-soluble extract of the entire plant of Egletes viscosa (Asteraceae), collected in Peru, afforded two new labdane glycosides, 13-hydroxy-7-oxolabda-8,14-diene 13( R)- O-alpha- L-arabinopyranoside and 13-hydroxylabda-7,14-diene 13( R)- O-alpha- L-arabinopyranoside, along with four known compounds. The structures of the new compounds were elucidated by spectroscopic and chemical methods.

Antitumour activity of 3-chlorodeoxylapachol, a naphthoquinone from Avicennia germinans collected from an experimental plot in southern Florida.

As part of an ongoing collaborative effort to discover new anticancer agents from plants, an extract obtained from the leaves and twigs of Avicennia germinans, collected in a coastal area of southern Florida, was identified as possessing cytotoxic activity in a panel of human cancer cell lines. Fractionation of the petroleum ether partition, using cytotoxicity to guide the fractionation, led to the isolation of 3-chlorodeoxylapachol. The antitumour potential of 3-chlorodeoxylapachol was demonstrated with the in-vivo hollow fibre assay, a model of antitumour activity using human cancer cell-filled fibres implanted into mice.

Limnophilaspiroketone, a highly oxygenated phenolic derivative from Limnophila geoffrayi.

A highly oxygenated phenolic spiroketone, limnophilaspiroketone (1), was isolated from the aerial parts of Limnophila geoffrayi collected in Thailand. The structure of 1 was determined based on spectroscopic data interpretation. This novel isolate, obtained as a major secondary metabolite constituent, was verified as a racemate using the Mosher ester method.

Apoptotic anticancer effect of alvaradoin E isolated from Alvaradoa haitiensis.

Two anthracenone C-glycosides, alvaradoins E and F, isolated from the leaves of Alvaradoa haitiensis Urb. (Simaroubaceae), were found to have potent inhibitory activities with cultured cancer cells. Using the in vivo hollow fiber model, these compounds demonstrated significant growth inhibition at the i.

Cytotoxic constituents of the twigs of Simarouba glauca collected from a plot in Southern Florida.

Activity-guided fractionation of a chloroform-soluble extract of Simarouba glauca twigs collected from a plot in southern Florida, and monitored with a human epidermoid (KB) tumor cell line, afforded six canthin-6-one type alkaloid derivatives, canthin-6-one (1), 2-methoxycanthin-6-one (2), 9-methoxycanthin-6-one (3), 2-hydroxycanthin-6-one (4), 4,5-dimethoxycanthin-6-one (5) and 4,5-dihydroxycanthin-6-one (6), a limonoid, melianodiol (7), an acyclic squalene-type triterpenoid, 14-deacetyleurylene (8), two coumarins, scopoletin (9) and fraxidin (10), and two triglycerides, triolein (11) and trilinolein (12). Among these isolates, compounds 1-4, 7 and 8 exhibited cytotoxic activity against several human cancer cell lines. 14-Deacetyleurylene (8) was selectively active against the Lu1 human lung cancer cell line, but was inactive in an in vivo hollow fiber assay using this same cell type.

Chemical constituents of the fruits of Morinda citrifolia (Noni) and their antioxidant activity.

Purification of a n-BuOH-soluble partition of the MeOH extract of Morinda citrifolia (Noni) fruits led to the isolation of two new iridoid glucosides, 6alpha-hydroxyadoxoside (1) and 6beta,7beta-epoxy-8-epi-splendoside (2), as well as 17 known compounds, americanin A (3), narcissoside (4), asperuloside, asperulosidic acid, borreriagenin, citrifolinin B epimer a, citrifolinin B epimer b, cytidine, deacetylasperuloside, dehydromethoxygaertneroside, epi-dihydrocornin, d-glucose, d-mannitol, methyl alpha-d-fructofuranoside, methyl beta-d-fructofuranoside, nicotifloroside, and beta-sitosterol 3-O-beta-d-glucopyranoside. The structures of the new compounds were determined by spectroscopic data interpretation. Compound 4, borreriagenin, cytidine, deacetylasperuloside, dehydromethoxygaertneroside, epi-dihydrocornin, methyl alpha-d-fructofuranoside, and methyl beta-d-fructofuranoside were isolated for the first time from M.

Constituents of the leaves and twigs of Calyptranthes pallens collected from an experimental plot in Southern Florida.

Fractionation of the chloroform-soluble extract of the leaves and twigs of Calyptranthes pallens, collected from an experimental plot in a hardwood forest of southern Florida, using a hormone-dependent human prostate carcinoma (LNCaP) tumor cell line, led to the isolation of a phloroglucinol derivative with a novel carbon skeleton, pallenic acid (1), and a new triterpenoid, 3beta-hydroxy-18alpha,19alpha-urs-20-en-28-oic acid (2). The known compound methylene-bis-aspidinol (3) was selectively active against the human oral epidermoid carcinoma (KB) cell line. Several known compounds of the ellagic acid, lignan, phloroglucinol, sterol, and triterpene types were also obtained in the present investigation.

Activity-guided fractionation of the leaves of Ormosia sumatrana using a proteasome inhibition assay.

Activity-guided fractionation of a chloroform-soluble extract of the leaves of Ormosia sumatrana, using a proteasome inhibition assay, led to the isolation of a new A-type proanthocyanidin derivative, 3'-O-cinnamoylprocyanidin A-2 (1), and a new cerebroside, sumatranoside (2). The structures of these two isolates were determined as epicatechin-(2 beta-->O-->7',4 beta-->8')-epicatechin-3'-O-cinnamate (1) and 1-O-(beta-d-glucopyranosyl)-(2S,3S,4R)-2N-[(2'R)-2'-hydroxy-tetracosanoyl]-9Z-octadecene-1,3,4-triol (2), respectively, by spectroscopic and chemical methods. Sumatranoside (2) exhibited proteasome inhibitory activity with an IC(50) value of 30 microM.

Constituents of the stems of Macrococculus pomiferus and their inhibitory activities against cyclooxygenases-1 and -2.

As part of our program directed towards the discovery of new cancer chemopreventive agents from plants, the EtOAc-soluble extract of the stems of M. pomiferus was found to inhibit the enzyme cyclooxygenase-2 (COX-2). Bioassay-directed fractionation of this extract led to the isolation of two dibenzylbutyrolactone lignans, (8R,8'R)-3'-O-demethyl-5-hydroxymatairesinol (1) and (8R,8'R)-3'-O-demethyl-5-methoxymatairesinol (2), as well as seven known compounds, (-)-5'-methoxyyatein (3), blumenol A, (-)-deoxypodophyllotoxin (anthricin), (-)-deoxypodorhizone, 2,6-dimethoxyhydroquinone, 4-hydroxybenzaldehyde, and beta-sitosterol glucoside.