Two charge density studies on macrolideantibiotics: erythromycin and roxithromycin

J. Holstein1,3, B. Dittrich3, C. Paulmann2,5, W. Morgenroth3,4,5, P. Luger1

1Institut fur Chemie / Kristallographie der Freien Universitat Berlin, Fabeckstr. 36a, D-14195Berlin, Germany

2Mineralogisch-Petrologisches Institut, Universitat Hamburg, Grindelallee 48, D-20146 Hamburg,Germany

3Institut fur Anorganische Chemie, Georg August Universitat, Tammannstr. 4, D-37077 Gottingen,Germany

4Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark5c/o DESY/HASYLAB, Notkestr. 85, 22607 Hamburg, Germany

Macrolide antibiotics are known to eliminate the protein synthesis in the bacterial ribosome byblocking the tunnel that channels the nascent peptides away form the peptidyl transferase center.[1] Due to this biological attribute the electronic properties of these compounds, especially of func-tional groups, which interact with nucleotids of the peptidyl transferase cavity are of interest. Twohigh resolution X-Ray experiments were executed:For roxithromycin 405336 Bragg reflections of have been collected at 100K (wavelength 0.56 A)at beamline F1 up to a resolution of 1,25 A−1 in sinθ/λ (d=0.40 A) and were merged to 39480unique refections. At the D3-beamline 177822 reflections (23653 unique) of erythromycin havebeen collected at 9K (wavelenght 0.5166 A) up to a resolution of 0.91 A−1 in sinθ/λ (d=0.55 A).Their chemical structure is based on a 14-membered lactone cycle, substited by a desosamine and

Figure 1: ORTEP [2] representation of themolecular structure (50% probability) of ery-thromycin

Figure 2: Structure of roxithromycin

a clandinose sugar.The newly discovered modification of erythromycin is disordered. The ADP‘s are much larger,than expected for a 9 K measurement (figure 1). Therefore no charge density analysis should beperformed. The dataset of roxithromycin was refined with the program package XD [3] using theaspherical atom multipole formalism according to the method of Hansen and Coppens [4] .To obtain first results based on the invariant atom formalism [5] the progam INVARIOMTOOL [6]

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was used. The figures 3 and 4 were generated with the program Moliso [8]. They show the electro-static potential mapped on an isosurface of the electron density on a level of 0.5 e·A−3 and 0.0067e·A−3, calculated using the method of Su and Coppens [7]. Figure 3 shows an extended negativeregion (red) which is accumulated around the oxygen atoms. The region around the dimethylamingroup (figure 4) is positively charged.

Figure 3: electrostatic potential on an isosurfaceof the electron density on a level of 0.5 e·A−3

Figure 4: electrostatic potential on an isosurfaceof the electron density on a level of 0.0067 e·A−3

(van der Waals surface)

References

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[2] M.N. Burnett, C.K. Johnson, ORTEP-III, Oak Ridge Thermal Ellipsoid Plotting Programfor Crystal Structure Illustrations, ORNL-6895, Oak Ridge National Laboratory, (1996).

[3] XD2006 - A computer program for multipole refinement, topological analysis of chargedensities and evaluation of intermolecular interaction energies from experimental or theo-retical structure factors. Volkov, A.; Macchi, P.; Farrugia, L. J.; Gatti, C.; Mallinson, P.;Richter, T.; Koritsanszky, T. (2006).

[4] N. K. Hansen, P. Coppens, Acta Cryst. A, 1978, 34, 909-921

[5] B. Dittrich, T. Koritsanszky, P. Luger, Angew. Chem, 2004, 116, 2773-2776

[6] C. B. Hubschle, B. Dittrich, INVARIOMTOOL, Ein Programm zur Erleichterung des In-variomtransfers, 2004, Freie Universitat Berlin

[7] Z. W. Su, P. Coppens, Acta Cryst. A, 1992, 48, 188-197

[8] C. B. Hubschle, MOLISO, A Program for Colour Mapped Isosurfaces,J. Appl. Crystallogr.,2006, 39, 901

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