An efficient semi-synthesis of 1-hydroxyl oleanolic acid analogs.

An efficient route for the semi-synthesis of either 1α- or 1ß-OH epimers of 1-hydroxy-3-deoxyolean-12-en-28-oic acid (1), 6-8 steps from oleanolic acid is reported. The synthesis involves stereoselective formation of α,ß-unsaturated epoxy ketone and subsequent Wharton reaction as key steps, offering a new access to the 1-O-substituted oleanolic acid-type pentacyclic triterpenoids.

Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods.

The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode. Among them 3b and 3d are more active than the parent compound OA. A molecular simulation study was performed to attempt to explain the structure-activity relationship (SAR) and the antagonistic action. To the best of our knowledge, this is the first report on semi-synthetic pentacyclic triterpenoids with FXR-modulatory activities.

Synthesis and Biological Evaluations of Cytotoxic and Antiangiogenic Triterpenoids-Jacaranone Conjugates.

BACKGROUND: The development of antiangiogenic agents arises as a more effective and selective therapeutic approach for the treatment of cancer. In addition to reduced acute toxicity, the efficacy of chemotherapy could be improved when administered in combination specific antiangiogenic with cytotoxic agents. The conjugation or hybridization of bifunctional molecules is one of the alternative rational design strategies for co-administration of anticancer drugs. OBJECTIVE AND METHODS: The goal of this work is to prepare the conjugates of an antiangiogenic triterpene, 3-oxo oleanolic acid, and structurally related triterpenoids with a cytotoxic semibenzoquinone, jacaranone. The cytotoxic, antiproliferative and antiangiogenic activities of segments and conjugates were determined. The possible targets of conjugates 6a-6h were predicted using Similarity Ensemble Approach (SEA). RESULTS: The results showed that these conjugates are more potent in both cytotoxic and antiangiogenic assays than their corresponding parent molecules, and are also selectively more active against melanoma cells B16 and metastatic B16BL6 than the two other cancer cell lines (A549 and MCF-7) tested. The predicted antiangiogenesis related targets could involve glycogen phosphorylase, neuraminidase, interferon gamma, and tubulin beta chain. CONCLUSION: The bifunctional conjugates could be useful as dual acting antitumor/antigiogenic agents.

A novel C,D-spirodioxene taxoid synthesized through an unexpected Pd-mediated ring cyclization.

A novel C,D-spirodioxene taxoid (6) was prepared from paclitaxel (1a), with the key steps including an unexpected Pd-mediated ring cyclization. The anti-tubulin activity of 6 was decreased relative to that of 1a and a previously reported C,D-spirolactone taxane (5). These observations could be rationalized on the basis of molecular modeling results. To the best of our knowledge, this is the first example indicating that 1,4-dioxenes can be synthesized from a mono-allyl vicinal diol through a Wacker-type cyclization. This strategy may be applicable to the synthesis of other C,D-spiro taxoids.

Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups.

To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects.

[Effects of different prevention and control measures on schistosomiasis prevalence in different limnetic regions].

OBJECTIVE: To compare the schistosomiasis control effects of the comprehensive control measures based on infectious resources control and the conventional control measures, so as to provide the evidence for improving prevention and control strategies. METHODS: In the Hanbei River basin, the comprehensive control measures based on infectious resources control (conventional measures plus grazing prohibition in the marshland, machine instead of cattle, and marshland development, and so on) were carned out, and in the Nanzhi River basin, the conventional control measures were performed. The schistosomiasis epidemic data were collected, analyzed and compared from 2004 to 2011. RESULTS: In 2004, the infection rate of the populations and cattle in Nanzhi River basin was lower than that in the Hanbei River basin. From 2004 to 2011, the Oncomelania hupensis snail frame occurrence rate and the average density of living snails in the Nanzhi River basin was lower than that in the non-ploughing marshland and preventing wave woods of the Hanbei River basin, and there were schistosome infected snails in the Nanzhi River basin. From 2008 to 2010, there were no infected snails in the non-ploughing marshland of the Hanbei River basin. From 2007, the cattle have been eliminated in the Hanbei River basin. From 2007 to 2011, there were no infected snails in the preventing wave woods of the Hanbei River, but there were schistosome infected cattle found by stool examinations every year in the Nanzhi River basin. From 2004 to 2011, the infection rates of population presented downward trends in the two river basins, but the downward trend was more significant in the Hanbei River basin than in the Nanzhi River basin. CONCLUSION: The conventional control measures and comprehensive control measures based on infectious resources control are both effective, but the latter is more effective.

Isolation, identification, semi-synthesis of aziditaxel derivatives and their biological evaluation.

Two new taxoids (5 and 6) were obtained by isolating impurities in aziditaxel, and their structures were characterized based on data analysis of (1)H NMR, (13)C NMR, HPLC-MS, and through comparison with literature. In order to test their cytotoxicities against human nonsmall lung cancer cell lines (A549), sufficient amounts of compounds 5 and 6 were obtained by semi-synthesis and both of them showed equipotent cytotoxiesty compared with taxol, docetaxel, and aziditaxel.

Pentacyclic triterpenoids and their saponins with apoptosis-inducing activity.

Pentacyclic triterpenoids exert their antitumor activity through different mechanisms, one of which is apoptosis induction. Although there are many reports on the apoptosis inducing activity of pentacyclic triterpenoids, a systematic survey and discussion on their structure-activity relationships (SARs) is still lacking. In this review, we summarized such activity of oleanane, ursane and lupane type triterpenoids, the most abundant pentacyclic triterpene prototypes in plants. Their structural characteristics responsible for the activity are also discussed, in order to unravel their SARs for the apoptotic induction and benefit further investigations on the antitumor triterpenoids.

Structural studies of taxol analogues for drug discovery.

BACKGROUND: The major mechanism of action of antitumor taxanes, including two clinically useful antitumor agents, paclitaxel and docetaxel, lies in their interactions with ß-tubulin in microtubule polymers, leading to cell cycle arrest and apoptosis. However, owing to the technical limitations, the molecular interactions of ligands with the residues in taxane binding sites of tubulin as well as the conformations adopted by taxanes on binding are still not fully understood. OBJECTIVE: This review focuses on the exploration of paclitaxel's interactions with tubulin, and the impact of such efforts on the drug discovery for new taxanes and microtubule stabilizing agents (MSAs). METHODS: Data were identified through the search of Chemical Abstracts and PubMed databases for research articles and reviews up to April 2008. CONCLUSION: Based on a collection of information gathered from crystallography, 1D and 2D NMR spectroscopy (NOESY, ROESY, REDOR), and structural-activity relationship (SAR) by chemical synthesis and pharmacological assays, 'opened' or T-shape conformations have been predicted to be the biologically active ones in recent years, and confirmed by further SAR studies. Some more potent analogues than paclitaxel or simplified compounds with similar potencies to that of paclitaxel have been discovered. Structural studies of taxol analogues will continue to make great contributions to the rational design of taxanes and novel prototype MSAs for drug discovery.