COMMUNICATIONS 2486  WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001 1433-7851/01/4013-2486 $ 17.50+.50/0 Angew. Chem. Int. Ed. 2001, 40, No. 13 Reactions of Organoselenenyl Iodides with Thiouracil Drugs: An Enzyme Mimetic Study on the Inhibition of Iodothyronine Deiodinase** Wolf-Walther du Mont,* Govindasamy Mugesh, Cathleen Wismach, and Peter G. Jones The monodeiodination of the prohormone thyroxine (T4) to the biologically active hormone 3,5,3'-triiodothyronine (T3) is the first step in thyroid hormone action and the type I iodothyronine deiodinase (ID-1), an enzyme containing selenocysteine in its active site, is responsible for most of this conversion [Eq. (1)]. [1] ID-1 is an integral membrane O NH 2 H COOH I I I I HO O NH 2 H COOH I I I HO T4 T3 ID-1 (1) protein the highest amounts of which are found in the liver, kidney, and thyroid. The 5'-deiodination catalyzed by ID-1 is a ping-pong, bisubstrate reaction in which the selenol group of the enzyme (E-SeH) first reacts with thyroxine (T4) to form a enzyme selenenyl iodide (E-SeI) complex with release of deiodinated iodothyronine (T3). Subsequent reaction of the selenenyl iodide with an unidentified cytoplasmic thiol cofactor (possibly glutathione, GSH) releases I  ions and regenerates the E-SeH active site (Scheme 1). [2] PTU N N S H O CH 2 CH 2 CH 3 Se E I I E-SeH E-SeI RSH RSSR T4 T3 1 + Scheme 1. Proposed mechanism for iodothyronine deiodination of thy- roxin T4 by ID-1 and the inhibition of ID-1 by PTU. It was proposed that the drug 6-n-propyl-2-thiouracil (PTU), derived from thiourea, inhibits the activity of the enzyme, probably by reacting with the selenenyl iodide intermediate to form a stable selenenyl sulfide. [2] The selenenyl sulfide 1 is considered to be a dead-end product since this compound does not react with thiols under physiological conditions. Owing to this property, PTU is often used in the treatment of severely hyperthyroid (Graves disease) patients and is therefore well known as an antithyroid drug. The formation of a mixed selenenyl sulfide adduct (1, Scheme 1) in the reaction of the selenenyl iodide with PTU has been proposed mainly on the basis of the following assumptions. 1) The PTU inhibition is noncompetitive with respect to thyroxine and competitive with respect to thiol cofactor, which suggests that PTU and cofactor react with the same enzyme intermediate. [1a] 2) The thiouracil derivatives are particularly reactive towards protein sulfenyl iodide (S I) groups [1a] and presumably even more reactive towards selen- enyl iodide (Se I) groups. However, since the discovery that the ID-1 is a selenium-containing enzyme, the reactions of thiourea drugs with E-SeI and their mechanisms have never been experimentally verified. In contrast to ID-1, the other two deiodinases (ID-2 and ID-3) are insensitive to PTU. [1c] It is, therefore, still a matter of debate as to whether PTU reacts with a covalent Se I species or if it reacts with the enzyme active site (E-SeH). Moreover, no reasons have been given for the insensitivity of ID-2 and ID-3 towards PTU. [1c] Herein, we report the first model studies on the reactivity of PTU towards selenenyl iodides as a basis for the deiodinase inhibition. The reactions of organoselenenyl iodides as enzyme- mimetic substrates with thiourea derivatives have not been studied previously as areneselenenyl iodides such as PhSeI are themselves generally unstable and disproportionate in solu- tion. [3a] Even the sterically hindered areneselenenyl iodides such as 2 have been found to exist in equilibrium with iodine and the corresponding diselenide in solution. [3b,c] The ªnon- existenceº of stable binary Se I compounds is associated with the very similar electronegativities of Se and I, that is, the lack of ionic contribution to the resonance energy in the covalent Se I bond. [4] However, the recent observations that the [7] M. L. Falck-Pedersen, T. Benneche, K. Undheim, Acta Chem. Scand. 1993, 47 , 63 ± 67. [8] J. D. Roberts, S. W. Sauer, J. Am. Chem. Soc. 1949, 71, 3925 ± 3929. [9] a) D. H. R. Barton, S. W. McCombie, J. Chem. Soc. Perkin Trans. 1 1975, 1574 ± 1585; b) D. H. R. Barton, D. Crich, A. Lobberding, S. Z. Zard, Tetrahedron 1986, 42, 2329 ± 2338; c) for a review see: D. Crich, L. Quintero, Chem. Rev. 1989, 89, 1413 ± 1432. [10] Y.-L. Zhong, T. K. M. Shing, J. Org. Chem. 1997 , 62, 2622 ± 2624. [11] S. Yamada, T. Suzuki, H. Takayama, J. Org. Chem. 1983, 48, 3483 ± 3488. [12] We thank Professor A. D. Rodríguez of the University of Puerto Rico for kindly providing us with an authentic sample as well as spectra of colombiasin A (1). [13] a)K. Mikami, M. Terada, Y. Motoyama, T. Nakai, Tetrahedron: Asymmetry 1991, 2, 643 ± 646; b) K. Mikami, Y. Motoyama, M. Terada, J. Am. Chem. Soc. 1994, 116, 2812 ± 2820; c) J. D. White, Y. Choi, Org. Lett. 2000, 2, 2373 ± 2376. [14] Based on the chirality of the catalyst used to induce the asymmetry [13] in 4 and the rotation ([a] 23 D  618, c  1 mg mL 1 , CHCl 3 ) of the synthetic natural product obtained from this intermediate, we tentatively assign the shown absolute stereochemistry of colombias- in A. Further studies to confirm this assignment are in progress. [*] Prof. Dr. W.-W. du Mont, Dr. G. Mugesh, Dipl.-Chem. C. Wismach, Prof. Dr. P. G. Jones Institut für Anorganische und Analytische Chemie Technische Universität Braunschweig Postfach 3329, 38023 Braunschweig (Germany) Fax: ( 49) 531-391-5387 E-mail: w.du-mont@tu-bs.de [**] This study was supported by the Alexander von Humboldt-Stiftung in the form of a research fellowship to G. M.