Structure of a synthetic taxol precursor: N-tert-butoxycarbonyl-10-deacetyl-N-debenzoyltaxol

Guéritte-Voegelein, Françoise; Guénard, Daniel; Mangatal, L.; Potìer, Pierre; Guilhem, Jean; Césario, Michèle; Pascard, Claudine

doi:10.1107/s0108270189009376

Cited by 76 publications

(103 citation statements)

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“…This compound and another related derivative, taxotere (docetaxel) (lb) (Gu6ritte-Voegelein et al, 1990), can be obtained by hemisynthesis from a natural molecule, 10-deacetylbaccatin III, (2).…”

Section: Commentmentioning

confidence: 99%

A 10-Deacetylbaccatin III Derivative: 11,12-Dihydro-7-triethylsilyl-10-deacetylbaccatin III

Chiaroni¹,

Riche²,

Marder³

et al. 1995

Acta Crystallogr C

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Section: Commentmentioning

confidence: 99%

A 10-Deacetylbaccatin III Derivative: 11,12-Dihydro-7-triethylsilyl-10-deacetylbaccatin III

Chiaroni¹,

Riche²,

Marder³

et al. 1995

Acta Crystallogr C

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“…The recently determined 3.7-Å structure of the ␣␤-TB-PTX complex (12), obtained by electron crystallography (EC) of zinc-induced TB sheets, clearly shows the location of the binding site but lacks the resolution to completely determine the ligand conformation. Therefore, in the original report, the x-ray crystal structure of Taxotere (13) served as a PTX surrogate. More recently, the EC crystal structure of TB has been docked into a 20-Å map of the MT to provide a high-resolution model of this polymer (14).…”

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confidence: 99%

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Snyder

Nettles²,

Cornett³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

363

396

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The chemotherapeutic drug Taxol is known to interact within a specific site on ␤-tubulin. Although the general location of the site has been defined by photoaffinity labeling and electron crystallography, the original data were insufficient to make an absolute determination of the bound conformation. We have now correlated the crystallographic density with analysis of Taxol conformations and have found the unique solution to be a T-shaped Taxol structure. This T-shaped or butterfly structure is optimized within the ␤-tubulin site and exhibits functional similarity to a portion of the B9-B10 loop in the ␣-tubulin subunit. The model provides structural rationalization for a sizeable body of Taxol structureactivity relationship data, including binding affinity, photoaffinity labeling, and acquired mutation in human cancer cells.

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“…Table 1. Structural and biological properties of taxanes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and epothilones (15,16,(18)(19)(20)(21) used in this study location of paclitaxel binding site in the β subunit but lacked the resolution to exactly define the whole ligand conformation. As a consequence, not all the amino acid residues were well solved and paclitaxel was replaced by the X-ray structure of docetaxel.…”

Section: Resultsmentioning

confidence: 99%

“…As a consequence, not all the amino acid residues were well solved and paclitaxel was replaced by the X-ray structure of docetaxel. 8 In order to provide a 3D QSAR model for taxanes binding into β-tubulin, a shell of amino acids, together with a training set of taxanes (compounds 1-11, 13, and 14, Figure 1, Table 1) was submitted to the ligand equilibration protocol implemented in PrGen software.…”

Section: Resultsmentioning

confidence: 99%

A pharmacophore modeling approach to design new taxol® mimics: towards the synthesis of potential anticancer and MDR-reversing agent

Renzulli¹,

Rocheblave²,

Avramova³

et al. 2006

Arkivoc

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The remarkable therapeutic importance of taxane diterpenoids as anticancer drugs and their challenging structural complexity have stimulated worldwide enormous efforts. Our group developed a theoretic quantitative model describing the relationship between structure and biological activity of microtubules-stabilizing anticancer agents (MSAAs) aimed at gaining an insight into the specific structural features required for the ligand-receptor binding. The model was demonstrated to be able to estimate/predict the microtubule-stabilising activity for a series of taxanes and provided further details about the influence of each pharmacophore point on the ligand binding affinity. Molecular modeling studies from our group revealed that modified Taxuspines U and X could adopt a conformation similar to the bioactive conformation of paclitaxel and can be well accommodated within the pseudoreceptor model. Following the suggestions coming from the model we rationally designed and synthesized new simplified taxuspine U analogues. In particular, we developed a new methodology for the synthesis of such compounds involving a macrocyclisation reaction via RCM in presence of different functional groups.

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Structure of a synthetic taxol precursor: N-tert-butoxycarbonyl-10-deacetyl-N-debenzoyltaxol

Cited by 76 publications

References 0 publications

A 10-Deacetylbaccatin III Derivative: 11,12-Dihydro-7-triethylsilyl-10-deacetylbaccatin III

A 10-Deacetylbaccatin III Derivative: 11,12-Dihydro-7-triethylsilyl-10-deacetylbaccatin III

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

A pharmacophore modeling approach to design new taxol® mimics: towards the synthesis of potential anticancer and MDR-reversing agent

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