Cytotoxicity of Rhamnosylanthraquinones and Rhamnosylanthrones from Rhamnus nepalensis.

An extract of the fruits of Rhamnus nepalensis collected in Hoa Binh Province, Vietnam, was cytotoxic to KB cells. A bioassay-guided fractionation led to the isolation of a series of known anthraquinones and anthrones, one new rhamnosylanthraquinone, 3'-O-acetylfrangulin A (8), several new rhamnosylanthrones, the prinoidin-emodin bianthrones (9A-D), the prinoidin bianthrones (10A,B), and the rhamnepalins (11A-C). A structure-cytotoxic activity relationship study was performed on these isolates and some semisynthetic derivatives.

Semisynthesis of D-ring modified taxoids: novel thia derivatives of docetaxel.

Two novel 5(20)-thia analogues of docetaxel have been synthesized from 10-deacetylbaccatin III or taxine B and isotaxine B. The key step of these syntheses is the concomitant thietane ring formation and acetylation of the tertiary alcohol at C-4. Both compounds are less cytotoxic than docetaxel but have divergent activity on microtubule disassembly.

First total synthesis of phenylpyridine analogues of the antimitotic rhazinilam.

The first synthesis of phenylpyridine analogues of rhazinilam and evaluation of these new structures as inhibitors of microtubule disassembly by interaction with tubulin are described. The synthesis is based on such key steps as picolinic metalation, hetero-ring cross-coupling and reduction of an acetyl group to an ethyl group. Elaboration of a quaternary picolinic carbon is one of the challenges of the synthesis. Biological evaluation of compounds bearing a quaternary picolinic carbon showed interactions with tubulin similar to (-)-rhazinilam but at a lower level.

Neutral and basic taxoid contents in the needles of Taxus species.

The concentrations of paclitaxel, 10-deacetylbaccatin III (10-DAB III), basic taxoids (= "total alkaloids", TA), taxine B and isotaxine B (= "taxines B", TBS) in the dried needles of 127 trees belonging to 30 Taxus cultivars and species were determined by HPLC. Neutral and basic taxoid contents varied in individual trees within species as well as among varieties and species. The objective of this large analysis was to select the highest-yielding trees for each metabolite.

Effects of the hydrophobicity of taxoids on their interaction with tubulin.

Modifications of the hydrophobic character at the 7 and 10 positions of the taxoids greatly modified the effect of these drugs on the tubulin microtubule system. The presence of an alkyl chain at these positions decreased the activity while their corresponding more polar analogues restored the activity of these molecules. It appears that the recognition of taxoids by tubulin depends on the location of the most important hydrophobic area.

Structure-activity relationship of polyisoprenyl benzophenones from Garcinia pyrifera on the tubulin/microtubule system.

Microtubule disassembly inhibitory properties have been established for the known polyisoprenylated benzophenones xanthochymol (1a) and guttiferone E (1b). The compounds were isolated from the fruits of Garcinia pyrifera collected in Malaysia. A structure-activity relationship study, including natural and semisynthetic derivatives, delineated some structural features necessary for the interaction with tubulin within this compound class.

Novel allocolchicinoids with an eight membered B-ring: design, synthesis and inhibition of tubulin assembly.

Several B-ring variations of O-methyl androbiphenyline (8), newly accessible from (-)-(M,7S)-colchicine via photooxygenation and subsequent endoperoxide-transformation, were synthesized and evaluated for their inhibitory effects on tubulin assembly in vitro. The amino-allocolchicinoid (9), a key compound in this study, was transformed to the highly potent ketone 10 and by oxidation with H2O2/Na2WO4 to a mixture of syn/anti-oximes, like 11 and 12. These could easily be transformed to hitherto unknown allocolchicinoids 13 and 14 with an eight membered B-ring lactam obtained via a Beckmann rearrangement. Surprisingly both do not notably affect tubulin assembly, despite obvious structural similarities with active analogues of the thiocolchicine- and azasteganacin-series.

D-ring substituted rhazinilam analogues: semisynthesis and evaluation of antitubulin activity.

Novel (-)- and (+)-rhazinilam derivatives substituted on the D-ring (compounds 3, 4, 5 and 6) have been prepared from (+)-vincadifformine 7 and (-)-tabersonine and evaluated against the disassembly of microtubules into tubulin. Along with this study, a reproducible 'one pot' semisynthesis of (-)-rhazinilam 1 from (+)-1,2-didehydroaspidospermidine 2 was performed allowing the easy preparation of these new compounds.

Fluorescent and biotinylated analogues of docetaxel: synthesis and biological evaluation.

Six novel docetaxel analogues that possess a N-(7-nitrobenz-2-oxa-1,3-diazo-4-yl)amido-6-caproyl chain in position 7 or 3' (11 and 16a), a N-(7-nitrobenz-2-oxa-1,3-diazo-4-yl)amido-3-propanoyl group at 3' (16b) and a 5'-biotinyl amido-6-caproyl chain in position 7, 10 or 3', respectively, have been synthesized. These compounds exhibit activity against microtubule disassembly similar to that of docetaxel but show discrepant activities on living cells. Although addition of microtubules to 11, 16a and b enhance their fluorescence, no shift of the emission maxima was observed. The fluorescent docetaxel derivatives show a specific labeling of microtubules in living cells, demonstrating that the microtubule cytoskeleton constitutes their main subcellular localization.

Interactions between docetaxel (Taxotere) and Plasmodium falciparum-infected erythrocytes.

Taxotere (docetaxel) inhibits Plasmodium falciparum erythrocytic development in vitro at nanomolar concentrations, both in chloroquine-sensitive (F32/Tanzania) and chloroquine-resistant (FcB1/Colombia, FcR3/Gambia) strains. The dose-response assays performed on asynchronous cultures during 42 hr showed clear biphasic curves with a plateau from 50 microM to 10 nM and a single sigmoid curve with a concentration inhibiting 50% of growth (IC50) of 3-6 nM observed after a 72-hr incubation. Addition of Taxotere to different stages of FcB1 revealed two types of targets: one type on ring/trophozoite-infected erythrocytes (RBCs), at the micromolar level, and another type on schizont-infected RBCs with Taxotere at micromolar concentrations inhibited the merozoite invasion of erythrocytes and parasite growth. These Taxotere-RBC interactions were stable, at least for 1 day. Pulse experiments of 5 hr with Taxotere efficiently inhibit parasite development regardless of the period of the parasite's erythrocytic life cycle. However, different cellular effects were obtained depending upon periods of drug incubations. The inhibition of P. falciparum development by Taxotere should provide additional strategies to block parasite development.

[Chemical and biological studies on Taxol (Paclitaxel) and Taxotere (Docetaxel), new antineoplastic agents]. / Recherches chimique et biologique autour du Taxol (Paclitaxel) et du Taxotère (Docetaxel), nouveaux agents antitumoraux.

Since the discovery of Taxol and of its antitumor activity a number of chemical, pharmacological and clinical studies have been performed on this natural diterpene isolated from the genus Taxus. Because the extraction of Taxol from the bark is expensive, difficult and damaging to the Taxus species, alternative sources have been studied. To date, one of the most promising alternatives is the semisynthesis of Taxol from 10-deacetylbaccatin III, a renewable precursor found in the needles of the European yew tree, Taxus baccata. From this natural compound, a number of new active compounds bearing different substituents at carbons 2, 4, 5, 7, 10, 13, 2' and 3' have been prepared. Among the new substances, Taxotere (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol) was found to be one of the most potent in its interaction to the cellular target of antitumor taxoids: tubulin. The chemistry and structure-activity relationships of the antitumor taxoids are presented.

Taxoids, a new class of antitumour agents of plant origin: recent results.

The taxoids are natural products isolated from the yew tree (Taxaceae). Certain compounds of this family possess interesting antitumour properties. The discovery of one such compound, taxol and the development of an even more active derivative, Taxotere, are described. Taxotere represents a major progress in the domain of cancer chemotherapy.

[Taxotere: from yew's needles to clinical practice]. / Le taxotère: des aiguilles d'if à la clinique.

Taxotere [N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol] is a new chemical entity obtained by semisynthesis from 10-deacetylbaccatin III, a non cytotoxic precursor extracted from the needles of the European yew Taxus baccata. Taxotere retains the unique mechanism of action of taxol and inhibits the depolymerisation of microtubules into tubulin. In vitro, Taxotere is cytotoxic against murine and human tumor cells with IC50 values ranging from 4 to 35 ng/ml. Taxotere inhibits the clonogenic properties of fresh human tumor cells at clinically relevant concentrations. Taxotere is highly active in vivo against several experimental models: it is 2.7-fold more active than taxol on a log cell kill basis against B16 melanoma; ten out of the twelve models of grafted murine tumors tested respond to Taxotere; it is active with 80% complete regressions against advanced C38 colon adenocarcinoma and PO3 pancreatic ductal adenocarcinoma. Finally, Taxotere is active against several human xenografts implanted in nude mice. Safety studies were performed in dogs and mice according to NCI guidelines. Toxicological effects are observed mostly is tissues with high cell turnover (bone marrow in mice and dogs, gastrointestinal tract in dogs only) or in those where microtubules play an important role (peripheral nerves in mice only). Because of its availability, due to an efficient process using a renewable source of natural precursor, its preclinical profile (higher antitumoral activity than taxol with a comparable toxicological profile) and its unique mechanism of action, Taxotere has entered Phase I clinical trials in Europe, United States and Japan. The dose limiting toxicity is a neutropenia. Evidence of clinical activity has been noted (breast, ovarian, lung). Taxotere is now in Phase II clinical trials.

Hepatic metabolism and biliary excretion of Taxol in rats and humans.

To date there have been limited studies of the metabolism and disposition of Taxol in animals and humans. Renal disposition of unmetabolized Taxol has been documented to account for a maximum of 5% to 10% of an administered dose of Taxol in humans, but the principal processes involved in drug disposition, particularly the roles of biliary excretion and drug metabolism, have not been evaluated. Therefore, the biliary excretion of Taxol has been studied in rats and in a human patient receiving Taxol in a phase I trial. Of the total doses administered to rats and the patient, 40% and 20%, respectively, were excreted in the bile in the forms of unmetabolized Taxol and Taxol metabolites until 24 hours posttreatment. Although the biliary excretion of unmetabolized Taxol accounted for 10% and 3% of total drug disposition in the rats and in the patient, respectively, the remaining portion consisted of several metabolites. Nine metabolites were detected in rat bile, and five metabolites were detected in human bile. The chemical structures of four of the rat metabolites and three of the human metabolites have been identified thus far. With the exception of baccatin III, a minor metabolite found only in rat bile that lacks the side chain at C-13 position of the taxane ring, the other metabolites were monohydroxylated or dihydroxylated and had intact taxane rings and side chains at taxane ring positions C-2 and C-13. The taxane ring and both the C-2 and C-13 side chains were susceptible to hydroxylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure-activity relationships of Taxol and Taxotere analogues.

From Taxol, Taxotere, and 10-deacetyl baccatin III, a number of compounds have been prepared. Their biological activity was evaluated on microtubule disassembly at 0 degrees C. The conformation of these Taxol and Taxotere analogues was determined by molecular modeling experiments and nuclear magnetic resonance spectroscopy and compared with the structure of Taxotere in the crystal, obtained by an x-ray analysis. The results of these studies given information on the crucial parts of the active molecules involved in the binding to tubulin.

Alkaloids from Psychotria oleoides with activity on growth hormone release.

Bioactivity-guided purification of a crude alkaloid extract of Psychotria oleoides has afforded a new alkaloid, psycholeine [1], together with quadrigemine C [2], a tetrameric pyrrolidinoindoline compound of unknown stereochemistry. A comparison study of nmr and cd spectra of quadrigemine C and hodgkinsine [3], a trimeric pyrrolidinoindoline substance, led us to suggest the stereochemistry of quadrigemine C. The structure and configuration of psycholeine was determined by spectroscopic means and chemical correlation with quadrigemine C. Psycholeine interacts with somatostatin receptors and exhibits a somatostatin antagonistic activity on GH secretion by pituitary cells in primary culture.

[Anticancer substances of vegetable origin. Spindle poisons: vincaleukoblastine, leurocristine and navelbine; taxol and taxotere]. / Substances anticancéreuses d'origine végétale. Les poisons du fuseau: vincaleucoblastine, leurocristine et Navelbine; taxol et Taxotère.

The biological activity of spindle poisons can easily be measured using an in vitro assay based on the interaction of these substances with their cellular "receptor": tubulin. The use of this assay led us to select Navelbine and Taxotere as antimitotic substances. These compounds, as well as their natural parents: vincaleucoblastine, leurocristine and taxol respectively, have been obtained by semi-synthesis using relatively abundant natural precursors as starting materials. This paper summarizes the preparation of these important anticancer drugs.

Experimental antitumor activity of taxotere (RP 56976, NSC 628503), a taxol analogue.

Taxotere (RP 56976; NSC 628503; N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl taxol) is a new microtubule stabilizing agent. It is obtained by semisynthesis from a noncytotoxic precursor extracted from the needles of the tree, Taxus baccata L. Taxotere was evaluated for antitumor activity against a variety of transplantable tumors of mice. Taxotere had no marked schedule dependency and was found active by the i.v. and the i.p. routes. Upon i.v. administration, 9 of 11 tumor models tested responded to Taxotere. B16 melanoma was found highly sensitive to Taxotere, with a tumor growth inhibition of 0% and a 3.0 log10 tumor cell kill at the maximum tolerated dose. In the same trial, taxol produced only a 1.1 log10 tumor cell kill at the maximum tolerated dose. Taxotere cured early stage pancreatic ductal adenocarcinoma 03 (6 of 6 cures) and colon adenocarcinoma 38 (7 of 7 cures). It also effected greater than 80% complete regressions of advanced stage disease with both tumors. Taxotere was active against early and advanced stage colon adenocarcinoma 51, with 2.3 and 1.7 log10 cell kill, respectively. Four other tumors responded to a lesser extent: Lewis lung (5.5% tumor growth inhibition), Glasgow osteogenic sarcoma (27.2% tumor growth inhibition), L1210 and P388 leukemias (70 and 54% increase in life span, respectively). Because of its good preclinical activity and its unique mechanism of action, Taxotere has entered Phase I clinical trials.