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Determination of solution structure of anti-cancer drug etoposide by NMR and computer simulation

Author

Kangling Zhang, University of the Pacific

Date of Award

1997

Document Type

Thesis - Pacific Access Restricted

Degree Name

Master of Science (M.S.)

Department

Chemistry

First Advisor

Michael J. Minch

First Committee Member

Larry O. Spreer

Second Committee Member

Ravindra C. Vasavada

Third Committee Member

Celestia [?]

Fourth Committee Member

Raush D. A[?]

Abstract

2.9 mM etoposide in CDCl₃ and CDCl₃/(D₂0) were studied at 300 and 500 MHz NMR.

One dimensional (1D) NMR spectra and truncated lD Nuclear Overhauser Effect (NOE) buildup experiments were used to find direct information on the structure of etoposide. Results showed that the E-ring rotates freely about the C_1’-C₄ bond and is oriented to the side where H_2’, H₄ project. The C and D rings have a "trans" junction at C₂-C₃ bond. The ethylidene-glucopyranosyl group approaches the D ring allowing close interaction between H_1” and H₈.

Water spin - transfer experiments were done to determine the interaction between water and the etoposide molecule. Chemical shifts of 2" -OH, 3" -OH were found to be affected remarkably by changes in water concentration due to the hydration of these hydroxide groups by H-bonding with water. Relaxation experiments were done to measure the longitudinal relaxation time and the whole molecular tumbling speed in solution (τ_c is 0.6 ns at 500 MHz). Higher than average T₁ differences between wet sample and dry samples were observed for 4'-0H, H₈, H₃, H₅, H_2”. It is suggested that some water residues are associated with these nuclei. The 4'-0H is obviously hydrated by water via H-bonding (as above).

Two dimensional NOE spectroscopy (NOESY & ROESY) experiments were done to give the distance constraints for running molecular dynamics (MD). Computer simulation and modeling were carried out to build up the molecule with restraint molecular dynamics (rMD) calculations by Amber 4.1. Temperature annealing, time-averaged distance restraint and water-solute interactions were applied to in these simulations. Several water bridges were found by calculation to correspond to the interactions seen to effect hydrogens by NMR. The hydration of etoposide also accounts for the slower relaxation rates in partially aqueous CDCl₃ solution.

Pages

104

Recommended Citation

Zhang, Kangling. (1997). Determination of solution structure of anti-cancer drug etoposide by NMR and computer simulation. University of the Pacific, Thesis - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2323