Mechanisms of action and medicinal applications of abscisic Acid.

Since its discovery in the early 1960's, abscisic acid (ABA) has received considerable attention as an important phytohormone, and more recently, as a candidate medicinal in humans. In plants it has been shown to regulate important physiological processes such as response to drought stress, and dormancy. The discovery of ABA synthesis in animal cells has generated interest in the possible parallels between its role in plant and animal systems. The importance of this molecule has prompted the development of several methods for the chemical synthesis of ABA, which differ significantly from the biosynthesis of ABA in plants through the mevalonic acid pathway. ABA recognition in plants has been shown to occur at both the intra- and extracellularly but little is known about the perception of ABA by animal cells. A few ABA molecular targets have been identified in vitro (e.g., calcium signaling, G protein-coupled receptors) in both plant and animal systems. A unique finding in mammalian systems, however, is that the peroxisome proliferator-activated receptor, PPAR gamma, is upregulated by ABA in both in vitro and in vivo studies. Comparison of the human PPAR gamma gene network with Arabidopsis ABA-related genes reveal important orthologs between these groups. Also, ABA can ameliorate the symptoms of type II diabetes, targeting PPAR gamma in a similar manner as the thiazolidinediones class of anti-diabetic drugs. The use of ABA in the treatment of type II diabetes, offers encouragement for further studies concerning the biomedical applications of ABA.

The first naturally occurring Tie2 kinase inhibitor.

[structure: see text] Bioassay-guided fractionation of the plant Acacia aulacocarpa, guided by a bioassay for Tie2 tyrosine kinase activity, yielded the novel triterpene 3,21-dioxo-olean-18-en-oic acid (1) as the first naturally occurring non-protein inhibitor of Tie2 kinase. The structure of 1 was assigned by analysis of spectral data. In addition to its activity as an inhibitor of Tie2 kinase, compound 1 also shows modest activity against a variety of cultured mammalian cells.

Proposed active constituents of Dipladenia martiana.

3Beta-O-beta-D-glucopyranosylsitosterol, pomolic acid, ursolic acid, epicatechin, kaempferol, kaempferol-3-O-beta-D-glucopyranoside (astragalin), quercetin-7-O-beta-D-glucopyranoside, quercetin-7-O-beta-D-galactopyranoside and quebrachitol were isolated by chromatographic fractionation of the methanol extract from the aerial parts of Dipladenia martiana (Apocynaceae). The hexane extract yielded lupeol and sitostenone. These compounds are likely to be responsible for the therapeutic effects.

A bioactive spirolactone iridoid and triterpenoids from Himatanthus sucuuba.

Himatanthus sucuuba is an Amazonian tree with abundant, yet conflicting ethnobotanical information. Investigation of the polar and non-polar constituents led to the isolation of plumericin, a bioactive spirolactone iridoid, and four known pentacylic triterpenes: lupeol acetate, lupeol cinnamate, lupeol beta-phenyl propionate, and alpha-amyrin cinnamate.

Synthesis and biological evaluation of novel macrocyclic paclitaxel analogues.

[reaction: see text] This work describes the synthesis of two novel macrocyclic taxoid constructs by ring-closing olefin metathesis (RCM) and their biological evaluation. Computational studies examine conformational profiles of 1 and 2 for their fit to the beta-tubulin binding site determined by electron crystallography. The results support the hypothesis that paclitaxel binds to microtubules in a "T" conformation.

Synthesis and microtubule binding of fluorescent paclitaxel derivatives.

The preparation of two new fluorescent derivatives of paclitaxel in which the fluorophore is bonded to paclitaxel at the C-10 position is reported. Both analogues, 10-deacetyl-10-(m-aminobenzoyl)paclitaxel (1, BTax) and 10-deacetyl-10-[7-(diethylamino) coumarin-3-carbonyl]paclitaxel (2, CTax) retain good activity as promoters of in vitro tubulin assembly. Microtubule binding enhances the emission intensity of both probes.

Two bioactive saponins from Albizia subdimidiata from the Suriname rainforest.

Bioassay-guided fractionation of a methanol extract of Albizia subdimidiata using the engineered yeast strains 1138, 1140, 1353, and Sc7 of Saccharomyces cerevisiae as the bioassay tool resulted in the isolation of the two active saponins 1 and 2; one of these, albiziatrioside A (1), is described for the first time. The structures of 1 and 2 were established on the basis of HRMS, 1D and 2D NMR spectral data, and GC--MS analysis of the sugar units. Both isolated compounds showed significant cytotoxicity against the A2780 cell line.

Synthesis and bioactivity of 2,4-diacyl analogues of paclitaxel.

The 2,4-diacyl paclitaxel analogues 8a-8r were prepared from paclitaxel by acylation of 4-deacetyl-2-debenzoylpaclitaxel 1,2-carbonate (3) followed either by hydrolysis of the carbonate and acylation or by direct treatment of the carbonate with an aryllithium. Some of the resulting derivatives showed significantly improved tubulin assembly activity and cytotoxicity as compared with paclitaxel; in some cases this improvement was especially significant for paclitaxel-resistant cell lines.

Isolation, synthesis, and structure-activity relationships of bioactive benzoquinones from Miconia lepidota from the Suriname rainforest.

Bioactivity-directed fractionation of an EtOAc extract from the leaves of Miconia lepidota afforded the two benzoquinones 2-methoxy-6-heptyl-1,4-benzoquinone (1) and 2-methoxy-6-pentyl-1,4-benzoquinone (primin) (2). This is the first reported isolation of 1. Both quinones 1 and 2 exhibited activity toward mutant yeast strains based on Saccharomyces cerevisiae, indicative of their cytotoxicity and potential anticancer activity. A number of previously synthesized and new analogues were prepared and tested in the same strains. Compounds 1, 2, 2-methoxy-6-butyl-1,4-benzoquinone (5), and 2-methoxy-6-decyl-1,4-benzoquinone (6) were tested in two cytotoxicity assays. In the M109 tumor cell lines, quinones 1, 2, and 6 had an IC(50) value of 10 microg/mL. In the A2780 cell line, compounds 1, 2 and 5 had IC(50) values of 7.9, 2.9, and 3.2 microg/mL, respectively.