Alvaradoins E-N, antitumor and cytotoxic anthracenone C-glycosides from the leaves of Alvaradoa haitiensis.

Bioactivity-directed fractionation of an extract of the leaves of Alvaradoa haitiensis, using the KB (human oral epidermoid carcinoma) cell line, led to the isolation and identification of 10 new anthracenone C-glycosides, alvaradoins E-N (1-10), along with the known compound chrysophanol (11). The cytotoxicity of all compounds was evaluated, and preliminary structure-activity relationships are suggested. The most potent compounds in the in vitro assays (1 and 2) were evaluated in vivo versus the P388 (murine lymphocytic leukemia) model, and alvaradoin E (1) showed antileukemic activity (125% T/C) at a dose of 0.

Novel fluoro-substituted camptothecins: in vivo antitumor activity, reduced gastrointestinal toxicity and pharmacokinetic characterization.

Purpose: The novel fluoro-substituted camptothecin analog, BMS-286309, and its prodrug, BMS-422461, were evaluated for their pharmacologic, toxicologic, metabolic and pharmacokinetic developmental potential.

Methods: In vitro and in vivo assays were used to assess the compounds for topoisomerase I activity, antitumor activity, gastrointestinal (GI) toxicity, and pharmacokinetic parameters.

Results: BMS-286309-induced topoisomerase I-mediated DNA breaks in vitro and was similar in potency to camptothecin.

Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells.

Extracts from the seeds of milk thistle, Silybum marianum, are known commonly as silibinin and silymarin and possess anticancer actions on human prostate carcinoma in vitro and in vivo. Seven distinct flavonolignan compounds and a flavonoid have been isolated from commercial silymarin extracts. Most notably, two pairs of diastereomers, silybin A and silybin B and isosilybin A and isosilybin B, are among these compounds.

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.

Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids.

Objectives: To determine the relative quantities of two hepatotoxic pyrrolizidine alkaloids, symphytine and echimidine, in teas prepared from comfrey leaves (Symphytum officinale), and to determine the potential contribution of the N-oxide forms of these alkaloids to levels of the parent alkaloids.

Design: Comfrey leaves were purchased from three commercial sources and used to prepare tea in a manner consistent with the methods used by consumers. An extraction scheme was devised for extraction of the alkaloids, and a gas chromatographic method was developed to quantify the two major alkaloids, symphytine and echimidine.

Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction.

By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones.

Hydrophilic camptothecin analogs that form extremely stable cleavable complexes with DNA and topoisomerase I.

Camptothecin (CPT) analogs that form more stable ternary complexes with DNA and topoisomerase I (termed cleavable complexes) show greater activity in their ability to inhibit tumor cell line growth in preclinical studies. Based on our earlier work, we hypothesized that analogs bearing hydrogen bonding moieties at the 7- through 10-position of CPT would result in more stable cleavable complexes. Consequently, we synthesized analogs with 7-mono-, 7-di-, and 7-trihydroxymethylaminomethyl groups.

Topoisomerase I-DNA complex stability induced by camptothecins and its role in drug activity.

The mechanism of cytotoxicity of the camptothecin family of antitumor drugs is thought to be the consequence of a collision between moving replication forks and camptothecin-stabilized cleavable DNA-topoisomerase I complexes. One property of camptothecin analogs relevant to their potent antitumor activity is the slow reversal of the cleavable complexes formed with these drugs. The persistence of cleavable complexes with time may be an essential property for increasing the likelihood of a collision between the replication fork and a cleavable complex, giving rise to lethal DNA lesions.

Cytotoxic and antimicrobial constituents of the bark of Diospyros maritima collected in two geographical locations in Indonesia.

Bioactivity-directed fractionation of extracts of two Diospyros maritima bark samples from Indonesia,one collected at sea level in a beach forest in Java and the other collected at a slight elevation away from the sea shore on the island of Lombok, yielded a diverse set of secondary metabolites. The naphthoquinone plumbagin (1), although found in extracts of both specimens, constituted a much larger percentage of the former sample, which also yielded a series of plumbagin dimers, maritinone (2), chitranone (3), and zeylanone (4). The latter sample yielded a new naphthoquinone derivative, (4S)-shinanolone (5), and a new natural product coumarin, 7,8-dimethoxy-6-hydroxycoumarin (6), along with three other analogues of plumbagin, 2-methoxy-7-methyljuglone (7), 3-methoxy-7-methyljuglone (8), and 7-methyljuglone (9).

Complete isolation and characterization of silybins and isosilybins from milk thistle (Silybum marianum).

Complete separation, isolation, and structural characterization of four diastereoisomeric flavonolignans, silybins A (1) and B (2), and isosilybins A (3) and B (4) from the seeds of milk thistle (Silybum marianum) were achieved for the first time using a preparative reversed-phase HPLC method. In addition, three other flavonolignans, silychristin (5) isosilychristin (6) and silydianin (7), and a flavonoid, taxifolin (8) were isolated. Structures, including absolute stereochemistries of 1-4, were confirmed using 2D NMR and CD spectroscopy.

Synergistic antimicrobial activity of metabolites produced by a nonobligate bacterial predator.

A naturally occurring, gram-negative, nonobligate predator bacterial strain 679-2, exhibits broad-spectrum antimicrobial activity that is due, in part, to the production of three extracellular compounds. Antimicrobial-activity-directed fractionation of a culture of strain 679-2 against a panel of microorganisms has led to the isolation of three compounds: pyrrolnitrin, maculosin, and a new compound, which we have named banegasine. Although pyrrolnitrin is well known in the literature, it has not been found in cells with the herbicide maculosin.

The activity of camptothecin analogues is enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH.

Background: Most solid human tumors exist in an acidic microenvironment, due in part to inefficient vasculature and a higher intrinsic rate of glycolysis. This leads to a tumor-selective pH gradient, which can be exploited therapeutically with antitumor agents such as the camptothecins (CPTs). Previous work in this laboratory has shown that camptothecin activity is enhanced 40- to 60-fold in monolayer cell culture by reducing the extracellular pH to 6.

Camptothecin analogs in malignant gliomas: comparative analysis and characterization.

Object: The authors compared and characterized several new classes of camptothecin (CPT) analogs (a total of 22 drugs) directed against human and murine glioma cell lines in vitro, trying to identify CPT analogs that can be used for local therapy in future clinical trials. Camptothecin is a naturally occurring alkaloid that inhibits the DNA-replicating enzyme topoisomerase I. Moreover, CPT and its analogs have shown promising antitumor activity against both systemic and intracranial neoplasms.

Bioactive prenylated flavonoids from the stem bark of Artocarpus kemando.

Four known prenylated flavonoids, artonins E (1) and O (2), artobiloxanthone (3), and cycloartobiloxanthone (4), were isolated from the stem bark of Artocarpus kemando by bioassay-guided fractionation using the DNA strand-scission and the KB cytotoxicity assays as monitors. Compounds 1 and 3 exhibited strong DNA strand-scission activity, and all four compounds were found to be cytotoxic.

Cytotoxic prenylated xanthones and the unusual compounds anthraquinobenzophenones from Cratoxylum sumatranum.

Six new xanthones, cratoxyarborenones A-F (1-6), were isolated from the leaves, twigs, and/or stem bark of Cratoxylum sumatranum along with the known compound, vismione B (9), as active constituents by bioassay-directed fractionation using the KB human cancer cell line cytotoxicity assay. In addition, two novel anthraquinobenzophenones, cratoxyarborequinones A (7) and B (8), and two known compounds, 2,4,6-trihydroxybenzophenone 4-O-geranyl ether and delta-tocotrienol, were obtained as inactive constituents.

Novel bioactive clerodane diterpenoids from the leaves and twigs of Casearia sylvestris.

Fractionation of a methanol extract of the leaves and twigs of Casearia sylvestris, as directed by activity against KB cell cytotoxicity, led to the isolation of three novel clerodane diterpenoids, casearvestrins A-C (1-3). The structures of 1-3 were deduced from one- and two-dimensional NMR experiments, including relative stereochemical assignments based on ROESY correlations and COSY coupling constants. All three compounds displayed promising bioactivity, both in cytotoxicity assays against a panel of tumor cell lines and in antifungal assays via the growth inhibition of Aspergillus niger in a disk diffusion assay.