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.

General and recent aspects of the chemistry and structure-activity relationships of taxoids.

The antimitotic agents of the Taxoid series are important substances as anticancer drugs. The efficacy of paclitaxel (Taxol) and docetaxel (Taxotere) has been well demonstrated in the treatment of breast, ovarian and lung cancers. Although these drugs have brought benefits in cancer chemotherapy, they unfortunately possess some disadvantages due to their inefficacy on certain resistant cancers, and due to their toxic side effects. For these reasons, the synthesis of new taxoids with improved biological activity is still an important research area. This review while covering general aspects of taxoid chemistry focuses on recent developments in this area especially those contributing to the improved availability of antimitotic taxoids. Studies of structure-activity relationships are also described.

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.

New synthesis of benzo-delta-carbolines, cryptolepines, and their salts: in vitro cytotoxic, antiplasmodial, and antitrypanosomal activities of delta-carbolines, benzo-delta-carbolines, and cryptolepines.

The paper describes, in its first part, a new synthesis of benzo-delta-carbolines, cryptolepines, and their salts. The strategy is based on the association between halogen-dance and hetero-ring cross-coupling. It is fully convergent and regioselective with interesting overall yields from 27% to 70%. A halogen-dance mechanism in quinoline series is also proposed. The formal synthesis of potential antimalarial compounds and the first total synthesis of 11-isopropylcryptolepine are also described. In the second part, cytotoxic activity against mammalian cells and activities against Plasmodium falciparum and Trypanosoma cruzi of benzo-delta-carbolines and delta-carbolines were evaluated in vitro to study the structure-activity relationships. For benzo-delta-carbolines, methylation at N-5 increases the cytotoxic and antiparasitic activities. A further alkylation on C-11 generally increases the cytotoxic activity but not the antiparasitic activity, cryptolepine and 11-methylcryptolepine being the most active on both parasites. Taking advantage of the fluorescence of the indoloquinoline chromophore, cryptolepine was localized by fluorescence microscopy in parasite DNA-containing structures suggesting that these compounds act through interaction with parasite DNA as proposed for cryptolepine on melanoma cells. For delta-carbolines, methylation at N-1 is essential for the antimalarial activity. 1-Methyl-delta-carboline specifically accumulates in the intracellular parasite. It has weak cytotoxic activity and can be considered as a potential antimalarial compound.

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.

Pyrrolidinoindoline alkaloids from Psychotria oleoides and Psychotria lyciiflora.

The chemical study of two Rubiaceae from New Caledonia, Psychotria lyciiflora and Psychotria oleoides, led to the isolation of several pyrrolidinoindoline alkaloids. Two dimers, the known meso-chimonanthine (9) and the new Nb-desmethyl-meso-chimonanthine (5), and a known trimer, hodgkinsine (1), have been isolated from P. lyciiflora. Hodgkinsine (1), quadrigemine C (2), isopsychotridine B (3), psychotridine (4), and three new alkaloids, quadrigemine I (6), oleoidine (7), and caledonine (8), have been isolated from P. oleoides. Structural assignments of the compounds were based on mass spectra analysis and 2D NMR experiments. A tentative stereochemical determination is made from 2D NMR experiments, circular dichroism study and chemical correlations. Some of these compounds are functional antagonists of somatostatine (SRIH).

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.

Comparative pharmacokinetics of antitumor Vinca alkaloids: intravenous bolus injections of navelbine and related alkaloids to cancer patients and rats.

The kinetics of distribution and elimination in rats of the antitumor drug navelbine and of two of its analogues, Na-formyl navelbine and deacetyl navelbine amide, have been studied by radioimmunoassay and compared with the kinetics obtained with vinblastine and vincristine. Fitting to two-exponential curves was used to derive pharmacokinetic parameters. Clearance was found to parallel toxicity for all drugs: it increases from 0.19 1 h-1 kg-1 for vincristine to 0.41 for Na-formyl navelbine, 1.4 for vinblastine, 2.3 for navelbine, and 2.6 for deacetyl navelbine amide. Terminal half-lives were longer for the Na-formyl-substituted alkaloids (around 13 h) than for the others (8-10 h). We have also studied navelbine kinetics in cancer patients entered in recent navelbine clinical trials and found that navelbine pharmacokinetics are characterized by fast and extensive distribution, high clearance (0.92 +/- 0.27 1 h-1 kg-1), and a relatively long terminal half-life (31.2 +/- 4.4 h). Relationships between chemical structure, pharmacokinetic properties, and toxicity or therapeutic efficiency within the Vinca alkaloid series are discussed, together with the relevance of animal models such as the rat in the screening of new antitumor drugs.