Chemie und Biologie von Taxol
TL;DR: Taxus brevifolia, e.g., polyoxygeniertes Diterpen aus der Pazifischen Eibe, wurde in den spaten sechziger Jahren bei einer umfassenden Untersuchung pflanzlicher Stoffe auf antineoplastische Wirkstoffe entdeckt, an which es scheint, das die Medien aufmerksam geworden sind and jede neue Entwicklung gespannt er
Abstract: Die Pflanzen konnten als Quelle von Verbindungen betrachtet werden, aus denen sich der Chemiker solche mit besonderen Eigenschaften heraussuchen kann. Taxol, ein komplexes, polyoxygeniertes Diterpen aus der Pazifischen Eibe, Taxus brevifolia, wurde in den spaten sechziger Jahren bei einer umfassenden Untersuchung pflanzlicher Stoffe auf antineoplastische Wirkstoffe entdeckt. In den vergangenen zwei Jahrzehnten sind das Interesse an Taxol und die damit verbundenen Forschungsarbeiten langsam an dem Punkt angelangt, an dem es scheint, das die Medien aufmerksam geworden sind und jede neue Entwicklung gespannt erwarten. Das, was einstmals eine weitgehend unbekannte Verbindung war, an der nur die masochistischsten unter den Synthesechemikern und eine ebenso kleine Zahl von Zellbiologen Interesse zeigten, ist heute eine der wenigen organischen Substanzen, die — wie etwa Benzol oder Aspirin — auch dem Durchschnittsburger, dem Namen nach bekannt sind. Die wissenschaftlichen Untersuchungen von Taxol haben sich in dieser Zeit enorm ausgeweitet: Arzte erforschen zur Zeit seine Wirkung auf nahezu jedes bekannte Neoplasma; Biologen untersuchen die Wechselwirkungen zwischen Taxol und Zellskelettsystemen, um auf diese Weise die Mechanismen zu ergrunden, nach denen Zellen funktionieren; Synthesechemiker, die von der einzigartigen und empfindlichen Struktur sowie von der Funktionalitat des Taxols gefesselt sind, arbeiten intensiv daran, einen synthetischen Zugang zu ihm zu finden. Die Nachfrage nach Taxol ist in der Tat in den letzten funf Jahren so stark gestiegen, das intensiv nach Quellen alternativ zur Extraktion von T. brevifolia gesucht wird. Da bei den vielfaltigen Arbeiten uber Taxol der Wissensumfang schnell zunimmt, mag es fur den in diesem Gebiet Interessierten schwierig sein, sich ein angemessenes Grundwissen anzueignen. Wir wollen in diesem Beitrag daher erstmalig versuchen, einen Uberblick sowohl uber die Chemie als auch uber die Biochemie dieser einzigartigen Verbindung zu geben.
Citations
More filters
TL;DR: The scope of this novel method for the preparation of polycyclic arenes is illustrated by thetotal synthesis of a series of polyoxygenated phenanthrenes that are close relatives of the anticancer agent combretastatin A-4, as well as by the total synthesis of the aporphine alkaloid O-methyl-dehydroisopiline and its naturally occurring symmetrical dimer.
Abstract: Readily available biphenyl derivatives containing an alkyne unit at one of their ortho-positions are converted into substituted phenanthrenes on exposure to catalytic amounts of either PtCl2, AuCl, AuCl3, GaCl3 or InCl3 in toluene. This 6-endo-dig cyclization likely proceeds through initial pi-complexation of the alkyne unit followed by interception of the resulting eta2-metal species by the adjacent arene ring. The reaction is inherently modular, allowing for substantial structural variations and for the incorporation of substituents at any site of the phenanthrene product. Moreover, it is readily extended to the heterocyclic series as exemplified by the preparation of benzoindoles, benzocarbazoles, naphthothiophenes, as well as bridgehead nitrogen heterocycles such as pyrrolo[1,2-a]quinolines. Depending on the chosen catalyst, biaryls bearing halo-alkyne units can either be converted into the corresponding 10-halo-phenanthrenes or into the isomeric 9-halo-phenanthrenes; in the latter case, the concomitant 1,2-halide shift is best explained by assuming a metal vinylidene species as the reactive intermediate. The scope of this novel method for the preparation of polycyclic arenes is illustrated by the total synthesis of a series of polyoxygenated phenanthrenes that are close relatives of the anticancer agent combretastatin A-4, as well as by the total synthesis of the aporphine alkaloid O-methyl-dehydroisopiline and its naturally occurring symmetrical dimer.
521 citations
TL;DR: A series of 36 linear and cyclic beta- and gamma-peptides consisting of as few as two, and as many as 15 residues, was offered as substrates to 15 commercially available proteases of bacterial, fungal, and eukaryotic origin, including a beta-lactamase and amidases, as well as most vigorous, nonspecific proteases, such as the 20S proteasome from human erythrocytes as mentioned in this paper.
Abstract: A series of 36 linear and cyclic beta- and gamma-peptides consisting of as few as two, and as many as 15 residues, was offered as substrates to 15 commercially available proteases of bacterial, fungal, and eukaryotic origin, including a beta-lactamase and amidases, as well as most vigorous, nonspecific proteases, such as the 20S proteasome from human erythrocytes. For comparison, an alpha-eicosapeptide and standard substrates of the proteolytic enzymes were included in the investigation. Under conditions of complete cleavage of the alpha-peptide within 15 min the beta- and gamma-peptides were stable for at least 48 h. Inhibition studies with seven beta- and gamma-peptides and alpha-chymotrypsin show that the residual enzyme activity toward succinyl-Ala-Ala-Pro-Phe-p-nitroanilide is unchanged within experimental error after incubation for 15 min with the peptide analogues. Thus, beta- and gamma-peptides with proteinogenic side chains, that is, consisting of the singly or doubly homologated natural alpha-amino acids (one or two CH(2) groups inserted in the backbone of each residue), are completely stable to common proteases, without inhibiting their normal activity (as demonstrated for alpha-chymotrypsin). This proteolytic stability of peptides built of homologated amino acids is a prerequisite for their potential use as drugs.
377 citations
TL;DR: A series of activatable ("turn-on") tetrazine-conjugated fluorescent probes was developed, which react rapidly in an inverse-electron-demand cycloaddition with strained dienophiles such as trans-cyclooctene, thereby strongly increasing the fluorescence intensity.
Abstract: Glowing tags: a series of activatable ("turn-on") tetrazine-conjugated fluorescent probes was developed, which react rapidly in an inverse-electron-demand [4+2] cycloaddition with strained dienophiles such as trans-cyclooctene, thereby strongly increasing the fluorescence intensity. The novel turn-on probes were applied for intracellular live-cell imaging of a microtubuli-binding trans-cyclooctene modified taxol.
365 citations
TL;DR: This review reflects on changes in technology, new molecules of substantial interest, changing ethical principles for organism collection and heightened awareness of the chemical and biological potential of the tropical rain forests.
172 citations
TL;DR: Approaches to improve and accelerate the joint drug discovery and development process are expected to arise mainly from innovation in drug target elucidation and lead finding.
Abstract: About 30% of the worldwide sales of drugs are based on natural products. Though recombinant proteins and peptides account for increasing sales rates, the superiority of low-molecular mass compounds in human diseases therapy remains undisputed mainly due to more favorable compliance and bioavailability properties. In the past, new therapeutic approaches often derived from natural products. Numerous examples from medicine impressively demonstrate the innovative potential of natural compounds and their impact on progress in drug discovery and development. However, natural products are currently undergoing a phase of reduced attention in drug discovery because of the enormous effort which is necessary to isolate the active principles and to elucidate their structures. To meet the demand of several hundred thousands of test samples that have to be submitted to high-throughput screening (HTS) new strategies in natural product chemistry are necessary in order to compete successfully with combinatorial chemistry. Today, pharmaceutical companies have to spend approximately US $350 million to develop a new drug. Currently, approaches to improve and accelerate the joint drug discovery and development process are expected to arise mainly from innovation in drug target elucidation and lead finding. Breakthroughs in molecular biology, cell biology, and genetic engineering in the 1980 s gave access to understanding diseases on the molecular or on the gene level. Subsequently, constructing novel target directed screening assay systems of promising therapeutic significance, automation, and miniaturization resulted in HTS approaches changing the industrial drug discovery process drastically. Furthermore, elucidation of the human genome will provide access to a dramatically increased number of new potential drug targets that have to be evaluated for drug discovery. HTS enables the testing of an increasing number of samples. Therefore, new concepts to generate large compound collections with improved structural diversity are desirable.
156 citations
References
More filters
3,761 citations
TL;DR: It is reported here that taxol acts as a promoter of calf brain microtubule assembly in vitro, in contrast to plant products such as colchicine and podophyllotoxin, which inhibit assembly.
Abstract: TAXOL (Fig. 1) was isolated from the plant Taxus brevifolia (western yew) by Wani et al., who reported that the molecule has antitumour activity in several experimental systems1. In our laboratory we have found that taxol, a low molecular weight neutral compound, completely inhibits division of exponentially growing HeLa cells at low concentrations of drug (0.25 µM) that have no significant effects on DNA, RNA or protein synthesis during a 4-h incubation with the cells. HeLa cells incubated with taxol for 20 h are blocked in late G2 and/or M (ref. 2). We report here that taxol acts as a promoter of calf brain microtubule assembly in vitro, in contrast to plant products such as colchicine and podophyllotoxin, which inhibit assembly. Taxol decreases the lag time for microtubule assembly and shifts the equilibrium for assembly in favour of the microtubule, thereby decreasing the critical concentration of tubulin required for assembly. Microtubules polymerised in the presence of taxol are resistant to depolymerisation by cold (4 °C) and CaCl2 (4 mM).
3,430 citations
TL;DR: It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.
Abstract: The events of the cell cycle of most organisms are ordered into dependent pathways in which the initiation of late events is dependent on the completion of early events. In eukaryotes, for example, mitosis is dependent on the completion of DNA synthesis. Some dependencies can be relieved by mutation (mitosis may then occur before completion of DNA synthesis), suggesting that the dependency is due to a control mechanism and not an intrinsic feature of the events themselves. Control mechanisms enforcing dependency in the cell cycle are here called checkpoints. Elimination of checkpoints may result in cell death, infidelity in the distribution of chromosomes or other organelles, or increased susceptibility to environmental perturbations such as DNA damaging agents. It appears that some checkpoints are eliminated during the early embryonic development of some organisms; this fact may pose special problems for the fidelity of embryonic cell division.
3,048 citations
TL;DR: This work has shown that switches in and out of G1 are the main determinants of post-embryonic cell proliferation rate and are defectively controlled in cancer cells.
Abstract: Cells prepare for S phase during the G1 phase of the cell cycle. Cell biological methods have provided knowledge of cycle kinetics and of substages of G1 that are determined by extracellular signals. Through the use of biochemical and molecular biological techniques to study effects of growth factors, oncogenes, and inhibitors, intracellular events during G1 that lead to DNA synthesis are rapidly being discovered. Many cells in vivo are in a quiescent state (G0), with unduplicated DNA. Cells can be activated to reenter the cycle during G1. Similarly, cells in culture can be shifted between G0 and G1. These switches in and out of G1 are the main determinants of post-embryonic cell proliferation rate and are defectively controlled in cancer cells.
2,235 citations
TL;DR: 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.
Abstract: 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.
1,910 citations