J. Am. Cliem. Sac. 1995, 117, 383-391
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The Coordination of V02+ to Hydroxamate Binders As Studied by Orientation Selective ESEEM Spectroscopy V. Kofman,g S. A. Dikanov,+ A. Haran,' J. Libman,' A. Shanzer,' and D. Goldfarb*J Contribution from the Chemical Physics and Organic Chemistry Department,?, Weizmann Institute of Science. Rehovot 76100, Israel. and Institute of Chemical Kinetics and Combustion, Nr,i,osibirsk 630090, Russian Federarion Received May 6, 1994@
Abstract: The binding of V02+ to c h i d dihydroxamate binders facilitates the transport of V02+ through the cell membrane into the cell interior. where it was shown to simulate glucose metabolism (Shechter. Y.; Shisheva, A,; Lazar, R.; Libman, I.; Shanzer, A. Biochemistry 1992, 31. 2063). The unique structure of the binders relies on a modular dipodal topology which generates different binding cavities. The coordination of V02+to two homologues of these ligands. RL261 and RL239, having different dipod arms but identical donor groups, was investigated by orientation selective electron spin echo envelope modulation (ESEEM) spectroscopy. Relatively deep modulations were observed for the "N nuclei in the hydroxamate groups in both complexes owing to the fulfillment of the cancellation condition at -9 GHz. The Fourier transform (FT) ESEEM spectm showed four peaks, three corresponding , and v+, and one to the overtone, 2v,. In VO-RL261 the to the nuclear quadrupole resonance (NQR) lines, v ~ ,v-, NQR and the 2v, peaks appear at 1.75. 2.15, 3.9. and 6.0 MHz, respectively. whereas in VO-RL239 they are at 1.75. 2.05. 3.9, and 6.2 MHz. respectively. From the positions of these peaks the l4N quadrupole coupling constant, le2qQ//il. the asymmetry parameter, 7. and the isotropic hyperfine constant Iairo/,were estimated to be 4.0.0.87, and 2.5 MHz, respectively. for VO-RL261 and 3.8.0.91, and 2.8 MHz, respectively, for VO-RL239. The unique orientation indicates that the principal dependence of the v+ peak, which practically disappeared when the field was set to AII(~'V), axis of the quadrupole tensor, 2". is either parallel or perpendicular to the VO axis. In order to obtain more accurate values of the above parameters and to determine the anisotropic hyperfine component, a l , as well as the orientations of the hyperfine and quadrupole tensors with respect to the VO axis, a series of simulations were carried out. The best fit parameters showed that a1 is rather large (0.6-0.7 MHz) and cannot be neglected and that arrois smaller than expected, i.e.. 1.6-1.8 MHz. We also obtained that 2'' is to a good approximation parallel to the VO axis indicating that the two hydroxamate planes are perpendicular to the VO axis in both complexes. Two possible structures, one with a Cz symmetry, trans configuration. and one with a u, symmetry, cis configuration. were considered in the simulations and the latter was found to agree better with the experimental results. The slight differences in the parameters obtained for VO-RL261 and VO-RL239 are attributed to electronic effects induced by the different groups bounded to the hydroxamate carbonyl.
Introduction Vanadium plays a unique role among biologically relevant ions.' One of its special activities is its capability to mimic virtually all functions of insulin such as hexose uptake, glucose oxidation, and lipogenesis both in ~ i t r o ~and - ~in viv0.5.~It has also been shown that vanadyl ions?,' rather than vanadate ions, are the biologically active species. Recently, chiral dihydroxamate ligands (Figure 1) were found to effectively bind and transport vanadyl ions across hydrophobic membranes and thereby enhance their biologically activity in vi1i-0.~ The dihydroxamate ligands, all of dipodal topology, were assembled in a modular fashion from homologues dicarboxylates as anchors Depmment of Chemical Physics. Weizmann Institute of Science. Institute of Chemical Kinetics and Combustion. Present Address: Macromolecular Structure and Dynamics, Pacific Northwest Laboratones, Richland. WA 99352. ' Department of Organic Chemistry. Weizmann Institute of Science. *Abstract published in Advance ACS Absrrocrs, December 1. 1994. (1) Rehder, D. Angen,. Chem.. Inl. Ed. Engl. 1991.30, 148. Rehder, D. Biometnls 1992. 5. 3. (2) Shechter. Y.Dioberes 1990. 39. 1. (3) Shechter, Y . : Karlish. S. I. D. Narure 1980. 284. 556. (4)Shechter. Y . ; Shisheva, A,: Lazar. R.: Libman. I.: Shanzer. A. Biochemirtn 1992. 31. 2063. ( 5 ) Heyliger. C. E.: Tahiliani. A. G.:McNeill. J. H. Science 19x5. 227. 1474. (6) McMeill. J . A,: Yuen. V. G . ; Hoveyda, H. R.; Orvig, c. J . Med. Cheni. 1992. 35. 8. 5
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