Paclitaxel

Resistance to paclitaxel has been described in cultured cells, and it appears in several forms. In one, resistance is associated with altered expression or mutation in a- and (3-tubulins [148,149], whereas in another, paclitaxel resistance is associated with overexpression of Pgp and the MDR phenotype [150]. 

Biological target Paclitaxel is a natural polysubstituted macrocycUc compound isolated from the bark of the Pacific yew tree (Taxus brevifolid). It binds to p-tubulin, causing polymerisation of the tubulin, thereby disrupting normal microtubule dynamics requited for cell divisimi. 

Therapeutic profile Paclitaxel Taxol is an anticancer agent with a broad spectrum of activity against tumours that are often refractive to other drugs. 

Synthetic highlights The partial synthesis of paclitaxel was necessary to enhance the availability of the drug substance and avoid unsustainable use of yew trees. Many different synthetic routes have been reported and three inventive pathways for the enantioselective or site-selective approaches to various segments of the paclitaxel molecule are described. These are aU promoted by organometal catalytic complexes. Reactions presented include use of the intramolecular Heck reaction in the synthetic pathway to baccatine III the Sharpless reaction and the introduction of a trifunctional catalyst for biomimetic synthesis of chiral diols synthesis of the paclitaxel side-chain and use of a Zr-complex catalyst in the reductive N-deacylation of taxanes to primary amine, the key precursor of paclitaxel. 

Paclitaxel (1, (2a,4ot,5p,7p,10p,13a)-4,10-bis(acetyloxy)-13- [(2R,35)-3-(benzoy-lamino)-2-hydroxy-3-phenylpropanoyl]oxy -1,7-dihydroxy-9-oxo-5,20-epoxytax-ll-en-2-yl benzoate, Taxol ) is a natural compound that disrupts the cell division and growth of many malignant tumors. 

Because of the limited natural availability of the compound, as discussed in Sect. 14.3, and despite the complexity of the molecule, huge synthetic efforts have been made to achieve the total synthesis of pachtaxel. These endeavours have resulted in many elegant partial or total synthetic approaches [1-3], and these have been reviewed repeatedly [4, 5]. Numerically, by 2010, there were 156 citations in SciFinder related to the synthesis of taxol and 7,875 citations related to the general terms, taxol and synthesis. In addition to total chemical synthesis, the strategy of site-selective transformation of the complex mixture in the natural taxanes, together with enantio- and diastereo-selective transformation of paclitaxel molecular fragments, complete the pallette of selective transformations that have been studied. 

Molecular formula C47H5,N0i4 Molecular weight 853.9 CAS Registry No. 33069-62-4 

Sample preparation 1 mL Plasma -i- 300 ng N-nitrosodiphenylamine (Caution N-Nitro-sodiphenylamine is a carcinogen ) -I- 400 xL 500 mM Na2HP04, vortex for 5 s, add 5 mL ethyl acetate, mix for 1 min, centrifuge at 3000 rpm for 10 min. Remove the organic layer and evaporate it to dryness under a stream of nitrogen at room temperature, reconstitute the residue in 200 xL mobile phase, vortex for 30 s, sonicate for 30 s, inject a 100 aL aliquot. 

Mobile phase MeCN buffer 45.5 55.5 (Buffer was 1 mM Na2HP04 adjusted to pH 5 with phosphoric acid.) 

Simultaneous carmustine, 5-fluorouracil, hydrocortisone, teniposide, thiotepa Noninterfering acetaminophen, aspirin, bleomycin, busulfan, carboplatin, cyclophosphamide, cytarabine, dacarbazine, hydroi airea, ifosfamide, methotrexate, mitomycin, mi-toxantrone, procarbazine 

Sample preparation Condition a 1 mL cyano Bond Elut SPE cartridge with 2 mL MeOH and 2 mL 10 mM pH 5.0 ammonium acetate buffer. 1 mL Plasma + 1 mL 200 mM ammonium acetate, mix, add a 1 mL aliquot to the SPE cartridge, wash with 2 mL 10 mM pH 5.0 ammonium acetate, wash with 1 mL MeOH 10 mM pH 5.0 ammonium acetate 20 80, wash with 1 mL hexane, dry under vacuum for 1 min, elute with 2 mL MeCN triethylamine 100 0.1, evaporate the eluate to dryness under a stream of nitrogen at 30°, reconstitute with 200 xL mobile phase, vortex for 30 s, inject a 50 p.L aliquot. 

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Synthesis of paclitaxel and resiniferatoxin analogs, diterpenoids with oxetane fragments 97G461. 

A higher than expected incidence of CHF is also observed in patients treated with DOX and other cytotoxics (e.g., the taxane paclitaxel) or new generation targeted agents (e.g., the humanized anti-ErbB-2/neu monoclonal antibody trastuzumab) [3]. The cardiotoxic synergism of DOX with taxanes or... 

Taxanes (paclitaxel, docetaxel) are derivatives of yew tree bark (Taxus brevifolia). They stabilize microtubules in the polymerized state leading to nonfunctional microtubular bundles in the cell. Inhibition occurs during G2- and M-phases. Taxanes are also radiosensitizers. Unwanted effects include bone marrow suppression and cumulative neurotoxicity. 

Ranganathan S, Benetatos CA, Colamsso PJ et al (1998) Altered beta-tubulin isotype expression in paclitaxel-resistant human prostate carcinoma cells. Br J Cancer 77 562-566... 

Mitotic inhibitors (antimitotics) interfere with or stop cell division. Examples of mitotic inhibitors include paclitaxel (Taxol) and vincristine (Oncovin). 

F.14 Paclitaxel, which is extracted from the Pacific yew tree Taxus brevifolia, has antitumor activity for ovarian and breast cancer. It is sold under the trade name Taxol. On analysis, its mass percentage composition is 66.11% C, 6.02% H, and 1.64% N, with the balance being oxygen. What is the empirical formula of paclitaxel ... 

High pressure cycloaddition of cytraconic anhydride (140) with 2-substituted furans 142 afforded, cxo-diastereoselectively but unregioselectively, bicyclic cycloadducts 143 and 144 that have been used in straightforward routes to CD-ring fragment of paclitaxel [55] (Scheme 5.22). The cycloadducts were then... 

C2H3BrO 506-96-7) see Paclitaxel N-acetyl-2 -bromo-2 -deoxycytidine 3, S -diacetate (C 5HigBrN307 126430-12-4) see Zalcitabine A -acetyl-3 -bromo-3 -deoxycytidine 2, 5 -diacetate (C 5H gBrN307 126430-11-3) see Zalcitabine 2-acetyl-4-butyramidophenol (C 2H,5N03 40188-45-2) see Acebutolol... 

C2H3CIO 75-36-5) see Acebutolol Acetiamine Acetylcholine chloride L-Alanine Benfurodil hemisuccinate . Chlorprothixene Flumetasone Ibuprofen lotalamic acid loxitalamic acid Levodopa Methestrol dipropionate Midecamycin acetate Naproxen Nimesulide Paclitaxel Paramethasone Phensuximide Retinol Rocuronium bromide Rofecoxib Ropinirole Tazarotene Thiopropazate Tiracizine Vecuronium bromide... 

C7H )N2 1122-58-3) see Paclitaxel Zafiilukast 4-dimethylamino-3-(4-pyridyl)-3-bulen-2-one (CHH14N2O 7 504 61-7) see Milrinone 2-dimethylaminosulfunylphenothiazine... 

ChH, N20 1659-31-0) see Paclitaxel l-(2 (i-dipyrrolidino-4-pyrimidinyl)pipera7jne (C f,H2(iN(5 111641-17-9) see Tirilazad mesilate S)-l, 4-dithia-7-azaspiro[4.4)nonane-S carboxylic acid hydrobromide... 

C4H,0, 623-50-7) see Paclitaxel 13-ethylgona-5(10),15-diene-3,17-dione cyclic 3-(2,2-di-methyl-l,3-propanediyl acetal)... 

C5H9NO 10431-98-8) see Nefazodone hydrochloride ( )-ethyl 2-oxo-3-benzoylamino-3-phenylpropionate (C H,7N04 153433-79-5) see Paclitaxel ethyl 3-oxocaproatc... 

C20H2JNO3 3608-67-/) see Propiverine (-)-(lS,2S)-/V-(2-hydroxy-l-phenyl-3-butenyl)benzamide (C17H17NO2 136693-02-2) see Paclitaxel [hydroxy(4-phenylbutyl)phosphinyl]acetic acid phenylmc-thyl ester... 

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