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Paclitaxel, semi-synthetic - LKT Labs

4 Thus, several syntheses of chemically modified paclitaxel derivatives have been reported.

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The biosynthetic pathway to paclitaxel has been investigated andconsists of approximately 20 enzymatic steps. The complete schemeis still unavailable. The segments that are known are verydifferent from the synthetic pathways tried thus far (Scheme1). The starting compound is geranylgeranyl 2 whichis a dimer of 1. This compound already contains all the required20 carbon atoms for the paclitaxel skeleton. More ring closingthrough intermediate 3 leads to taxusin4. The two main reasons why this type of synthesisis not feasible in the laboratory is that nature does a much betterjob controlling and a much better jobactivating a hydrocarbon skeleton with oxygen substituents forwhich is responsible in some of the oxygenations. Intermediate5 is called 10-deacetylbaccatin III.

Synthesis of Paclitaxel-Conjugated β-Cyclodextrin Polyrotaxane and Its ..

The paclitaxel drug development process took over 40 years. Theanti-tumor activity of a bark extract of the Pacific yew tree wasdiscovered in 1963 as a follow up of a government plant screening programalready in existence 20 years before that. The active substanceresponsible for the anti-tumor activity was discovered in 1969 andstructure elucidation was completed in 1971. Robert A Holton of succeeded in the total synthesis of paclitaxel in 1994, a projectthat he had started in 1982. In 1989 Holton had also developed asemisynthetic route to paclitaxel starting from . This compound is abiosynthetic precursor and is found in larger quantities thanpaclitaxel itself in (the European Yew). In1990 bought alicence to the patent for this process which in the years to followearned Florida State University and Holton (with a 40% take) over200 million .

Synthesis, Characterization, and Paclitaxel Release …

A convergent synthesis of the ABC ring of antitumor natural product paclitaxel (Taxol) is described

Resolution of Racemic Chemicals: The anticancer drug Taxol® (paclitaxel) is an antimitotic agent that inhibits the depolymerization process of microtubulin during mitosis. This drug is used in the treatment of ovarian cancer and metastatic breast cancer. Taxol® generates annually about US $1 billion in sales. Paclitaxel was originally extracted and purified from the bark of the yew Taxusbrevifolia in a very low yield. Paclitaxel was also be obtained by a semisynthetic process by coupling baccatin III (paclitaxel without the C-13 side chain) or 10-deacetylbaccatin II ([10-DAB], paclitaxel without the C-13 side chain and the C-10 acetate) to C-13 paclitaxel side chains.

Target-specific drug delivery has become an important strategy to improve the selectivity of cytotoxic drugs against targeted cells and reduce toxicity against normal cells. The general method couples a drug carrier and the drug to form a prodrug, which can be released in the target cells. Then, the drug is transformed from an inactive to an active form that performs the cell-killing function. Cancer chemotherapy is one of the important approaches to treating cancer patients, although the non-selectivity of many antitumor agents can cause serious side effects. Paclitaxel is a mitotic inhibitor that stabilizes microtubules, thereby interfering with the normal dissociation of microtubules during cell division. The compound is widely used to treat patients with lung, ovarian, breast, head and neck cancer and advanced forms of Kaposi’s sarcoma., However, serious drawbacks hamper PTX’s clinical usefulness. For instance, paclitaxel lacks selective cytotoxicity between cancer cells and normal cells, which frequently leads to serious unwanted side effects. The poor water solubility of paclitaxel is another problem that significantly reduces its wider clinical application. Different strategies have been explored to circumvent these side effects. One of the most attractive tactics is the selective targeting of tumor cells over normal cells exemplified by employing suitable monoclonal antibodies.,, A number of antigens that are preferentially expressed on tumor cells have been identified, and monoclonal antibodies have been developed to specifically bind to these tumor associated substances. Hyaluronan, a linear polysaccharide whose receptors are over-expressed in some tumors, has also been used to target paclitaxel to tumor cells. Additionally, Zhao et. al. have demonstrated the targeting of tumor cells using tripeptide modified liposomes that home on integrin receptors overexpressed on tumor cells. Cancer cells are also known to overexpress GLUT, a family of membrane proteins, to improve glucose uptake. Chen et. al. have synthesized four glycan-based paclitaxel prodrugs to specifically target GLUT over-expressing cancer cells. Inorganic nanoparticles have also been widely used for imaging, targeting and drug delivery. Gold nanomaterials represent one approach in which the ability to control the size and shape of the particles and their surface conjugation with antibodies allows for both selective imaging and photothermal killing of cancer cells by using long-wavelength light for tissue penetration.,, Angiogenesis is a crucial process for tumor progression and metastasis. An emerging strategy in cancer treatment is to target tumor-associated vascular endothelial cells (VECs) aimed at impeding the growth and survival of solid tumors by eliminating tumor blood supply. Tissue factor (TF) is aberrantly over-expressed on tumor VECs and on cancer cells in many malignant tumors, but not on normal VECs, which makes it a favorable target for cancer therapy. Several laboratories have reported promising results by targeting TF in tumor cells and VECs and thereby suppressing tumor growth in animal models.,, Tissue Factor is a transmembrane receptor for an endogenous ligand coagulation factor VIIa (fVIIa). Upon binding to fVIIa, TF forms a high-affinity and specific complex with fVIIa, and the complex subsequently initiates the blood clotting sequence. Several tripeptide chloromethyl ketones have been demonstrated to inactivate fVIIa by binding histidine in the serine protease core and render it a competitive inhibitor of fVIIa. Banner and coworkers have reported the crystal structure of D-Phe-L-Phe-L-Arg-mk-fVIIa-TF. The fVIIa component adopts an extended conformation that wraps around TF with the catalytic domain of the serine protease distal to the cell membrane. Cancer patients are generally in a hypercoagulable state since cancer cells express tissue factor, which is the cognate receptor of fVIIa. FFRck binds and inactivates fVIIa to make it a competitive inhibitor, but retains the same binding affinity as fVIIa. This is expected to prevent potential patients from thrombotic complications when PTX-FFRmk-fVIIa is administered. It requires coupling of a tripeptide chloromethyl ketone (e.g. FFRck) to the protein. The active site inactivated fVIIa retains the same binding affinity to its receptor protein, TF. Based on these evidence, we have chosen FFRmk-fVIIa as a drug carrier with two purposes. First, we intend drugs for targeted drug delivery to tumor angiogenesis and the tumor itself, since TF is induced to aberrantly express in cancer VEC by vascular endothelial growth factor (VEGF) and cancers express TF. Second, this should also prevent or minimize an increased tendency of blood clotting in cancer patients.

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Synthesis of Paclitaxel

The synthesis of C2′-PTX-FFRck is based on the observation that paclitaxel can be esterified at C2′ without protection of other functional groups. The preparation began with the global deprotection of tripeptide 1 to furnish the tripeptide chloromethylketone 2. The C2′ succinic acid derivative of PTX, namely compound 3, was treated with EEDQ and then coupled with 2 to afford the desired C2′-PTX-FFRck, 4 as a TFA salt. ()

The use of peptide chloromethyl ketones as the coupling reagent to generate irreversible inhibitors of serine proteases was pioneered by Shaw and co-workers. Our group has previously demonstrated the utility of using fVIIa as a selective anticancer drug carrier. To validate the concept, the cytotoxic agent EF24 was conjugated to fVIIa through a tripeptide-chloromethyl ketone linker. The experiment successfully demonstrated that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in rabbit cornea and Matrigel models in athymic nude mice. The potential of this particular delivery method can be maximized by inserting highly potent, but highly toxic anti-cancer drugs, for instance, paclitaxel, into the tumor cells specifically to reduce toxic side effects. In this paper, we describe the synthesis of PTX-FFRck and its conjugation to fVIIa to give PTX-FFRmk-fVIIa. We expected the latter to exhibit behavior similar to EF24-FFRmk-fVIIa, namely specific targeting of cancer cells, but with significantly greater potency.

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  • A REVIEW ON ACTINOMYCETES AND THEIR …

    Synthesis of alkynyl-substituted camphor derivatives and their use in the preparation of paclitaxel-related compounds

  • Polymeric Systems for Controlled Drug Release - …

    22.09.2011 · Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to ..

  • Uhrich was born in Aberdeen, SD, in 1965

    Paclitaxel/chemical synthesis*

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International Journal of Nanomedicine - Dove Press

Paclitaxel total synthesis in is a major ongoing research effort in the of (Taxol). This is an important in the treatment of but also expensive because the compoundis harvested from a scarce resource, namely the (Taxus brevifolia). Not only is the synthetic reproduction of thecompound itself of great commercial and scientific importance, butit also opens the way to paclitaxel derivatives not found in naturebut with greater potential.

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