150665-56-8Relevant articles and documents
The synthesis of novel taxoids for oral administration
Jing, Yun-Rong,Zhou, Wei,Li, Wan-Liang,Zhao, Lin-Xiang,Wang, Yong-Feng
, p. 194 - 203 (2014/01/17)
A group of novel taxoids, with modifications at C-7, C-10, C-3′ and C-14 positions of paclitaxel, was synthesized in order to improve their biological profile by decreasing their affinity with P-glycoprotein (P-gp) and increasing cellular permeability. Most of the new taxoids demonstrated the similar potent cytotoxic activities in MCF-7 human tumor cell line as paclitaxel in vitro. In the permeability assay with monolayers of Caco-2 cells, most of the compounds demonstrated an increased trans-cellular transport in A-to-B direction in comparison with paclitaxel. Among them the compounds T-13, T-15 and T-26 showed the highest permeability, and with efflux ratios better than that of ortataxel. The interaction of the compounds T-13 and T-26 with P-gp was evaluated using Madin-Darby canine kidney (MDCK)-multidrug resistance-1(MDR1) and MDCK-wild-type (WT). The results indicated that T-13 and T-26 were poor substrates for P-gp and possessed inhibiting effects of P-gp mediated efflux. It was thus clear that simultaneous modifications at the C-7, C-10 and C-3′ positions of paclitaxel significantly impaired its interactions with P-gp and interfered with P-gp mediated efflux.
A structure-based design of new C2- and C13-substituted taxanes: Tubulin binding affinities and extended quantitative structure-activity relationships using comparative binding energy (COMBINE) analysis
Coderch, Claire,Tang, Yong,Klett, Javier,Zhang, Shu-En,Ma, Yun-Tao,Shaorong, Wang,Matesanz, Ruth,Pera, Benet,Canales, Angeles,Jimenez-Barbero, Jesus,Morreale, Antonio,Diaz, J. Fernando,Fang, Wei-Shuo,Gago, Federico
, p. 3046 - 3056 (2013/07/26)
Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand-receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications. The Royal Society of Chemistry 2013.
Design, synthesis and structure-activity relationships of novel taxane-based multidrug resistance reversal agents
Ojima, Iwao,Borella, Christopher P.,Wu, Xinyuan,Bounaud, Pierre-Yves,Oderda, Cecilia Fumero,Sturm, Matthew,Miller, Michael L.,Chakravarty, Subrata,Chen, Jin,Huang, Qing,Pera, Paula,Brooks, Tracy A.,Baer, Maria R.,Bernacki, Ralph J.
, p. 2218 - 2228 (2007/10/03)
A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure - activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.
Process for the preparation of baccatin III derivatives
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Page/Page column 4-5, (2008/06/13)
A process for the preparation of 14 beta-hydroxy-1,4-carbonate-deacetylbaccatin III and intermediates useful for the preparation of novel taxan derivatives with antitumor activity are disclosed.
Structure-activity relationship study of taxoids for their ability to activate murine macrophages as well as inhibit the growth of macrophage-like cells
Ojima, Iwao,Fumero-Oderda, Cecilia L.,Kuduk, Scott D.,Ma, Zhuping,Kirikae, Fumiko,Kirikae, Teruo
, p. 2867 - 2888 (2007/10/03)
A series of new taxoids modified at the C-3′, C-3′N, C-10, C-2 and C-7 positions has been designed, synthesized and evaluated for their potency to induce NO and TNF production by peritoneal murine macrophages (Mφ) from LPS-responsive C3H/HeN and LPS-hyporesponsive C3H/HeJ strains and human blood cells, and for their ability to inhibit the growth of Mφ-like cell lines J774.1 and J7.DEF3. The SAR-study has shown that the nature of the substituents at these positions have critical effect on the induction of TNF and NO production by Mφ. Positions C-3′ and C-10 are the most flexible and an intriguing effect of the length of the substituents at the C-10 position is observed for taxoids bearing a straight chain alkanoyl moiety. An aromatic group at the C-3′N and C-2 positions is required for the activity, while only hydroxyl or acetyl substituents seem to be tolerated at the C-7 position. The natural stereochemistry in the C-13 isoserine side chain of the taxoids is an absolute requirement for macrophage activation. It has also been clearly shown that there is no correlation between the ability of the taxoids to induce TNF/NO production in C3H/HeN Mφ and the cytotoxicity against Mφ-like cells.
Synthetic studies with 13-deoxybaccatin III
Ahn, Yu Mi,Vander Velde, David G.,Georg, Gunda I.
, p. 7140 - 7143 (2007/10/03)
An efficient synthesis of 13-epi-7-O-(triethylsilyl)baccatin III from 13-deoxybaccatin III is described. Oxidation of 13-deoxy-7-O-(triethylsilyl)baccatin III with tert-butyl peroxide, followed by reduction with SmI2, produced 13-epi-7-O-(triethylsilyl)baccatin III in good overall yield. The preparation of 13-oxo-7-O-(triethylsilyl)baccatin III from 13-epi-7-O-(triethylsilyl)baccatin III using tetrapropylammonium perruthenate and N-methylmorpholine N-oxide is also reported.
Synthesis and biological evaluation of amide-linked A-norpaclitaxels
Chordia, Mahendra D.,Kingston, David G. I.
, p. 5699 - 5710 (2007/10/03)
A novel amide-linked A-norpaclitaxel 3a and two 2-aroyl analogs 3b and 3c were prepared from 10-deacetyl baccatin III. Key steps in the synthesis were the conversion of 7-(triethylsilyl)baccatin m to its 13β-chloro-A-nor derivative 6, reaction with sodium
Total synthesis of baccatin III and taxol
Danishefsky, Samuel J.,Masters, John J.,Young, Wendy B.,Link,Snyder, Lawrence B.,Magee, Thomas V.,Jung, David K.,Isaacs, Richard C. A.,Bornmann, William G.,Alaimo, Cheryl A.,Coburn, Craig A.,Di Grandi, Martin J.
, p. 2843 - 2859 (2007/10/03)
An intramolecular Heck reaction (90 → 91) serves as the key step in the total synthesis of the titled compounds. The synthetic route is based on utilizing the Wieland-Miescher ketone (5) as a matrix to provide the C and D rings of the targets and to provide functionality implements for joining this sector to an A ring precursor (6). Catalytically induced enantiotopic control and early emplacement of the oxetane are other features of the route.
Total synthesis of Taxol. 1. Retrosynthesis, degradation, and reconstitution
Nicolaou,Nantermet,Ueno,Guy,Couladouros,Sorensen
, p. 624 - 633 (2007/10/02)
A successful strategy for the enantioselective synthesis of the natural stereoisomer of Taxol (1) has been developed. This strategy utilized the convergent assembly of Taxol's central eight-membered B ring from preformed synthons for rings A (10) and C (9) followed by late introduction of the D ring and side chain. Degradative studies confirmed the viability of certain crucial manipulations including oxidation of the C13 position (35 → 3) and regioselective introduction of the C1-hydroxyl, C2-benzoyloxy moiety (29 → 31). Additionally, a convenient method for the large-scale production of 29, a derivative useful for C2 analog production, was developed.
Eine Totalsynthese von Taxol
Masters, John J.,Link, J. T.,Snyder, Lawrence B.,Young, Wendy B.,Danishefsky, Samuel J.
, p. 1886 - 1888 (2007/10/03)
Keywords: Baccatin III; Heck-Reaktionen; Taxol; Totalsynthesen
