Etoposide. Conformational and Hydration Features

Document Type

Article

Publication Title

Magnetic Resonance in Chemistry

Department

Chemistry

ISSN

0749-1581

Volume

37

Issue

11

DOI

10.1002/(SICI)1097-458X(199911)37:11<788::AID-MRC526>3.0.CO;2-#

First Page

788

Last Page

798

Publication Date

11-1-1999

Abstract

The proton chemical shifts of the anticancer agent etoposide in CD3OD, dry CDCl3 and ‘wet’ CDCl3 were determined and all proton resonances were assigned. The general conformational features of etoposide were determined from NMR coupling constants, truncated NOE measurements, NOESY and ROESY experiments and molecular modeling (MM2, MM+, AMBER). A complete relaxation matrix analysis (CORMA/MARDIGRAS) was used to calculate proton– proton distances from ROESY cross-peak intensities and the resulting distance constraints were used for molecular dynamic calculations using AMBER 4.1. Temperature annealing and water– solute interactions were applied in these simulations. The glycosidic ring is roughly perpendicular to the polycyclic ring system with the axial protons oriented toward the aromatic ring. The lactone ring is in the half-chair (C2) form and the 3′,5′-dimethoxy-4′-hydroxy aryl ring is directed beneath the polycyclic ring system. The hydration of etoposide in chloroform solution containing added water was studied. Etoposide hydroxide protons show up as separate proton resonances but irradiation of the water line or any of the OH lines reveals rapid spin communication among this population. The chemical shifts of the 2″- and 3″-hydroxyl protons of the glycosidic ring are strongly dependent on the water-to-etoposide ratio. Selective saturation transfer experiments as a function of decoupler power or irradiation time and non-selective inversion– recovery T1 measurements were carried out. Hydration modeling studies showed several water bridges connect the glycosidic hydroxyl groups with the O-16 atom of the epipodophyllotoxin ring system and with the 4′-hydroxyl group of the pendant 2′,6′-dimethoxyaryl group. Despite the very clear presence of a ‘spine’ of hydration, the general conformational features of ‘wet’ etoposide are the same as those of the non-hydrated etoposide.

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