lignans and steganacin

Axial chirality is a key feature of many important organic molecules, such as biologically active compounds, stereogenic ligands and optically pure materials. Significant efforts in the field of the atropisomeric synthesis of biaryls have hence been undertaken over the past decade. Several major improvements of the already known methods to build up such chiral backbones (e.g. oxidative couplings and stereoselective Suzuki-Miyaura arylations) have been achieved and, in parallel, novel concepts have emerged enabling unprecedented synthetic routes toward molecules of this kind. These outstanding steps further unlocked the door to the preparation of previously difficult-to-access precursors of privileged ligands like BINOL, BINAM, QUINAP and many other molecules of interest.

Topics: 4-Butyrolactone; Gossypol; Lignans; Models, Molecular; Organic Chemicals; Stereoisomerism; Vancomycin

A large number of antimicrotubule agents are known that bind to tubulin in vitro and disrupt microtubule assembly in vitro and in vivo. Many of these agents bind to the same site on the tubulin molecule, as does colchicine. Of these, the natural products podophyllotoxin, steganacin and combretastatin are the subjects of this review. For each of these, the chemistry and biochemistry are described. Particular attention is given to stereochemical considerations. Biosynthetic pathways for podophyllotoxin and congeners are surveyed. The binding to tubulin and the effects on microtubule assembly and disassembly are described and compared. In addition, structural features important to binding are examined using available analogs. Several features significant for tubulin interaction are common to these compounds and to colchicine. These are described and the implications for tubulin structure are discussed. The manifold results of applying these agents to biological systems are reviewed. These actions include effects that are clearly microtubule mediated and others in which the microtubule role is less obvious. Activity of some of these compounds due to inhibition of DNA topoisomerase is discussed. The range of species in which these compounds occur is examined and in the case of podophyllotoxin is found to be quite broad. In addition, the range of species that are sensitive to the effects of these compounds is discussed.

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents, Phytogenic; Bibenzyls; Binding Sites; Cell Division; Lignans; Podophyllotoxin; Polymers; Stilbenes; Structure-Activity Relationship; Tubulin

Topics: 4-Butyrolactone; Alkaloids; Antineoplastic Agents, Phytogenic; Chemical Phenomena; Chemistry; Dioxoles; Furans; Galantamine; Lactones; Lignans; Methods; Molecular Conformation; Optical Rotation; Podophyllotoxin

A novel microwave-assisted, highly efficient protocol for the synthesis of hitherto unknown aza-analogues of (-)-Steganacin, a naturally occurring bisbenzocyclooctadiene lignan lactone with potent antileukemic and tubulin polymerization inhibitory activity, has been developed. Focused microwave irradiation is demonstrated to be highly beneficial in promoting the three crucial steps of the sequence to effect the final ring closure: the Suzuki-Miyaura reaction, Cu-mediated A3-coupling, as well as the intramolecular Huisgen 1,3-dipolar cycloaddition.

Topics: 4-Butyrolactone; Antineoplastic Agents; Aza Compounds; Lactones; Lignans; Microwaves; Tubulin Modulators

Steganacin and podophyllotoxin are two naturally occurring lignans first isolated from plant sources, which share the capability to disrupt tubulin assembly. Although not strictly essential for its activity, the lactone ring on both structures represents Achilles' heel, as it is a potential site of metabolic degradation and epimerization on its C2 carbon brings about a significant loss in potency. In the present manuscript, we have used the ruthenium-catalyzed [3+2] azide-alkyne cycloaddition, a click-chemistry reaction, to replace the lactone ring with a 1,5-disubstituted triazole in few synthetic steps. The compounds were cytotoxic, although to a lesser degree compared to podophyllotoxin, while retaining antitubulin activity. The present structures might therefore represent a good platform for the fast generation of metabolically stable compounds with few stereogenic centers that might be of value from a medicinal chemistry point of view.

Topics: 4-Butyrolactone; Antineoplastic Agents; Catalysis; Cell Line, Tumor; Humans; Lactones; Lignans; Molecular Conformation; Podophyllotoxin; Ruthenium; Triazoles; Tubulin

[reaction: see text]. A novel, microwave-enhanced, highly efficient protocol for the synthesis of hitherto unknown (-)-steganacin and (-)-steganone 7-aza analogues containing a 1,2,3-triazole ring has been presented. Microwave irradiation was found to be highly beneficial in promoting the Suzuki reaction and the 1,3-dipolar cycloaddition reaction to generate the highly strained medium-sized ring system of the title molecules.

Topics: 4-Butyrolactone; Aza Compounds; Cyclization; Lignans; Microwaves; Molecular Structure; Stereoisomerism; Triazoles

Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site.

Topics: 2-Methoxyestradiol; 4-Butyrolactone; Aminophenols; Binding Sites; Chalcone; Colchicine; Cyclopropanes; Estradiol; Indans; Lignans; Models, Molecular; Molecular Structure; Nocodazole; Podophyllotoxin; Protein Binding; Stilbenes; Structure-Activity Relationship; Sulfonamides; Thiazoles; Tubulin; Tubulin Modulators

The cytotoxic activities of optically pure and racemic steganacin congeners and analogues against KB cells in culture and the inhibitor activity of cilia regeneration in Tetrahymena were studied with regard to absolute and relative configurations. The stereochemical requirements of dibenzocyclooctadiene lignan lactones for activity were clarified.

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Cell Division; Humans; Indicators and Reagents; KB Cells; Lignans; Models, Molecular; Molecular Conformation; Molecular Structure; Structure-Activity Relationship

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Furans; Lactones; Lignans; Molecular Conformation; Stereoisomerism; X-Ray Diffraction

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Furans; Lactones; Lignans; Oxidation-Reduction; Plant Extracts; Stereoisomerism

Toxicities of various microtubule inhibitors, namely, colchicine, podophyllotoxin, maytansine, vinblastine, nocodazole, griseofulvin, and steganacine, toward numerous independently established cell lines from three different species, namely, human, mouse, and Chinese hamster, were examined. Some of these inhibitors (namely, colchicine, vinblastine, taxol, and maytansine) were found to exhibit large (between tenfold and fiftyfold) differences in their toxic and antimitotic concentrations toward various cell lines and these differences appeared to be species related inasmuch as all cell lines from a particular species showed similar sensitivities toward these inhibitors. Of the three species examined, cells of human origin exhibited maximum sensitivity toward these inhibitors while Chinese hamster cells were found to be most resistant. The reduced cellular transport of [3H]colchicine and [3H]vinblastine in Chinese hamster cells as compared to the cellular transport in human cells and the equivalent binding of [3H]colchicine and [3H]vinblastine to microtubule proteins in cell extracts from both these lines provided strong evidence that the observed differences in toxicity to these inhibitors were most likely caused by differences in the cellular transport of these drugs. In contrast to the toxicities of the above compounds, the toxicities of other microtubule inhibitors such as podophyllotoxin, steganacine, griseofulvin, and nocodazole were found to be very similar for cells from all three species, indicating that the cellular transport of these 2 groups of microtubule inhibitors differed in some important respect. Some implications of the observed species-specific differences in drug toxicity to clinical studies are discussed.

Topics: 4-Butyrolactone; Animals; Benzimidazoles; Biological Transport; Cells, Cultured; Colchicine; Cricetinae; Cricetulus; Griseofulvin; HeLa Cells; Humans; Lignans; Maytansine; Mice; Mitosis; Nocodazole; Podophyllotoxin; Species Specificity; Vinblastine

Taxol, a potent inhibitor of human HeLa and mouse fibroblast cell replication, blocked cells in the G2 and M phase of the cell cycle and stabilized cytoplasmic microtubules. The cytoplasmic microtubules of taxol-treated cells were visualized by transmission electron microscopy and indirect immunofluorescence microscopy. More than 90% of the cells treated with 10 micro M taxol for 22 hr at 37 degrees C displayed bundles of microtubules that appeared to radiate from a common site (or sites), in addition to their cytoplasmic microtubules. Untreated cells that were kept in the cold (4 degrees C) for 16 hr lost their microtubules, whereas cells that were pretreated with taxol for 22 hr at 37 degrees C continued to display their microtubules and bundles of microtubules in the cold. Taxol inhibited the migration behavior of fibroblast cells, but these cells did not lose their ability to produce mobile surface projections such as lamellipodia and filopodia.

Topics: 4-Butyrolactone; Animals; Cell Movement; DNA Replication; Fibroblasts; Fluorescent Antibody Technique; HeLa Cells; Humans; Lactones; Lignans; Mice; Microtubules; Paclitaxel; Terpenes; Tubulin

Topics: 4-Butyrolactone; Antineoplastic Agents, Phytogenic; Cell Division; Colchicine; Cycloparaffins; HeLa Cells; Lactones; Lignans; Microtubules; Mitotic Index; Protein Binding; Structure-Activity Relationship; Tubulin

Steganacin, a newly isolated tumor inhibitor, completely inhibits cleavage in sea urchin eggs at 3 X 10(-7) M by preventing the formation of the mitotic apparatus. Steganacin inhibits the polymerization of tubulin in vitro and also causes a slow depolymerization of preformed microtubules. Optical ultracentrifuge studies of steganacin-treated tubulin show a small reduction in 20 S and 30 S peaks at 0 degree. In electron microscope studies the ring structure of tubulin is seen at 0 degree but disappears if the temperature of tubulin incubated with steganacin is raised to 37 degrees. Steganacin inhibits the binding of colchicine to tubulin and thus resembles podophyllotoxin, which also competitively inhibits colchicine binding. Steganacin had a trimethoxybenzene ring and probably interacts with that portion of the colchicine-binding site that recognizes the trimethoxybenzene ring of colchicine.

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Binding, Competitive; Cell Division; Colchicine; Cycloparaffins; Female; Glycoproteins; Lactones; Lignans; Microtubules; Mitosis; Ovum; Podophyllotoxin; Sea Urchins; Tubulin; Tubulin Modulators; Ultracentrifugation

Topics: 4-Butyrolactone; Antineoplastic Agents; Cycloparaffins; Lactones; Lignans; Methods

Topics: 4-Butyrolactone; Animals; Antineoplastic Agents; Diterpenes; Lactones; Leukemia, Experimental; Lignans; Mice; Plant Extracts