The Conformations of Taxol in Chloroform

Snyder, James P.; Nevins, Neysa; Cicero, and Daniel O.; Jansen, Johanna M.

doi:10.1021/ja9930115

Cited by 76 publications

(110 citation statements)

References 19 publications

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“…An alternative implementation of GARP-1 decoupling using a scan-dependant decoupler offset of a limited 13C spectral region has recently been reported. The NMR data of taxol shown here generally refer to assignments that are well documented, 16,[24][25][26][27] and the observed spectra ( Figure 2) were found to be qualitatively identical with the published data. …”

supporting

confidence: 84%

A Routine Experimental Protocol for qHNMR Illustrated with Taxol

2007

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Quantitative 1 H NMR (qHNMR) provides a value-added dimension to the standard spectroscopic data set involved in structure analysis, especially when analyzing bioactive molecules and elucidating new natural products. The qHNMR method can be integrated into any routine qualitative workflow without much additional effort by simply establishing quantitative conditions for the standard solution 1 H NMR experiments. Moreover, examination of different chemical lots of taxol and a Taxus brevifolia extract as working examples led to a blueprint for a generic approach to performing a routinely practiced 13 C-decoupled qHNMR experiment, and for recognizing its potential and main limitations. The proposed protocol is based on a newly assembled 13 C GARP broadband decoupled proton acquisition sequence that reduces spectroscopic complexity by removal of carbon satellites. The method is capable of providing qualitative and quantitative NMR data simultaneously and covers various analytes from pure compounds to complex mixtures such as metabolomes. Due to a routinely achievable dynamic range of 300:1 (0.3%) or better, qHNMR qualifies for applications ranging from reference standards to biologically active compounds to metabolome analysis. Providing a "cookbook" approach to qHNMR, acquisition conditions are described that can be adapted for contemporary NMR spectrometers of all major manufacturers. The world's pool of natural products plays an important role as an (in)exhaustible resource for evolutionary-shaped molecules. Natural products are valuable research tools, which in part is due to their biological potency (see comprehensive reviews [1][2][3][4] ). When natural products are used as biomedical agents, and in consistency with the pharmacophore model, it is the combination of their specific chemical structure and/or reactivity that forms their relationship with a biological target and ultimately defines their essential structural features. Consequently, chemical constitution plays a key role in biological activity, and, therefore, all structure related information obtainable from a biologically active agent is by default relevant. Ultimately, any variation of structural parameters has the potential to introduce variations in biological activity. This relationship holds regardless of the magnitude of the biological perturbation, i.e., whether there is slight or a substantial change in potency, or even an alteration in the type of biological response. The well-documented subtleties of mammalian hormonal steroids can serve as a distinguished example in this regard.⊥ Dedicated to Dr. Norman R. Farnsworth on the occasion of his 77 th birthday.* To whom correspondence should be addressed. Tel (312) 355-1949355- . Fax (312)-355-2693. gfp@uic.edu. Supporting Information Available.This material is available free of charge via the Internet at http://pubs.acs.org. Further information on qNMR methodology, instrument parameter files for the NMR major manufacturer's spectrometers, and original FIDs of the taxol qHNMR experime...

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confidence: 84%

A Routine Experimental Protocol for qHNMR Illustrated with Taxol

2007

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“…Monte Carlo conformational analysis using MACROMODEL 6.5 (38) yielded 858 fully optimized conformations for 13b. Subsequent NMR͞NAMFIS (NMR analysis of molecular flexibility in solution) treatment (35,39) integrated the latter and the ROESY spectra to yield three conformations in CDCl 3 , two of which differ by torsions in the C-4 to C-3Ј bridge but correspond to a total of 83% of 13b in the T-Taxol form. For details, see supporting information.…”

Section: Conformational Analysis For 13b In Solutionmentioning

confidence: 99%

“…Minireceptor evaluation predicted the ortho-bridged unsaturated esters 13a and 13b and the corresponding saturated analogs 14b and 14b to be at least equipotent to Taxol's action as microtubule stabilizers. Subsequent synthesis taking advantage of the olefin metathesis approach has led to both compounds, the NMR͞NAMFIS analysis for 13b demonstrating that Ͼ80% of the compound ¶ Taxol in either CDCl3 (35) NAMFIS-derived T-conformations for 13b (76% red, 7% green) superimposed on the tubulin-bound T-Taxol form (blue).…”

Section: Ligand-tubulin Structure: Solution Conformations By Nmr͞namfismentioning

confidence: 99%

“…35. The ortho-bridged T-form of 13b (red, both ligand and protein binding site subjected to MD relaxation similar to T-Taxol) superimposed on Taxol avoids the steric contact with Phe-270 at the bottom of the hydrophobic taxoid pocket experienced by the meta-bridged analog 16 (27).…”

Section: Figmentioning

confidence: 99%

“…In addition, studies have compared the conformations of Taxol and epothilone B by molecular modeling and other methods (29,(31)(32)(33). Separate investigations have proposed distinguishable conformations of the Taxol side chain, with a T-shaped conformation being favored on the basis of its fit with the election-density map of zinc-induced tubulin sheets (34,35). In the present work, we provide experimental evidence that Taxol can be constrained to the T-conformation in solution, and that this form both stabilizes genuine microtubules and induces cell death.…”

mentioning

confidence: 99%

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