Reactivity Studies of Anticancer Active Dirhodium Complexes with 2-Aminothiophenol Karn Sorasaenee, Jose´ Ramo´n Gala´ n-Mascaro´ s, and Kim R. Dunbar* Department of Chemistry, Texas A&M UniVersity, College Station, Texas 77843 Received July 27, 2001 Introduction The study of biologically active inorganic compounds has led to the development of several important chemotherapeutic drugs in the past few decades, the most notable example of which is cis-[PtCl 2 (NH 3 ) 2 ](cis-DDP). 1 In addition to com- pounds of platinum, many other transition metal complexes have been found to exhibit considerable antineoplastic activities, including those of general formulae Rh 2 (μ-O 2 CR) 4 and [Rh 2 (μ-O 2 CR) 2 (N-N) 2 L 2 ]X 2 (N-N ) 2,2′-bipyridine and 1,10-phenanthroline; L ) solvent molecules; X ) Cl, Br). 2,3 The latter family of compounds is of particular interest due to their improved anticancer activity against different tumor lines (e.g., human oral carcinoma KB) as compared to their Rh 2 (μ-O 2 CR) 4 L 2 counterparts (L ) solvent molu- cules). 3 A perusal of the literature reveals a scarcity of information vis-a`-vis the cellular metabolism of these dirhodium compounds, but it is known from preliminary studies that DNA replication is significantly inhibited and that protein synthesis is slightly affected. 4 Work carried out in our laboratories over the past 10 years has confirmed that dirhodium compounds react with nucleic acids to yield unprecedented adducts that involve the use of the purine nucleobases as bridging ligands. 5 In this current report, we now turn to another aspect of the possible metabolic fate of the metal complexes, namely the formation of products with S-containing biomolecules. Several brief reports on the reactivity of dirhodium carboxylate compounds with cysteine have appeared in the literature, but the results are preliminary and even contradictory. 4,6 Obviously the topic merits further investigation if we are to advance toward an understanding of the real biological targets of dirhodium compounds. 7 In this paper, reactivity studies of [Rh 2 (μ-O 2 CCH 3 ) 2 (phen) 2 - (CH 3 CN) 2 ][PF 6 ] 2 (1) with the model ligand 2-aminothiophe- nol are reported. 8 This work was carried out with the more general aim of gaining structural information on the possible reaction products of these dirhodium compounds with sulfuhydryl-containing amino acids and peptides such as cysteine and glutathione (GSH), depicted in Chart 1. Experimental Section Materials and Methods. Acetonitrile and ethanol were dried over 3 and 4 Å molecular sieves, respectively, and distilled under a nitrogen atmosphere prior to use. Toluene was freshly distilled from Na/K before use. The starting materials [Rh 2 (μ-O 2 CCH 3 ) 2 - (bpy) 2 (CH 3 CN) 2 ][BF 4 ] 2 and [Rh 2 (μ-O 2 CCH 3 ) 2 (phen) 2 (CH 3 CN) 2 ]- [PF 6 ] 2 were prepared by literature methods. 9 The reagent 2-ami- nothiophenol was purchased from Aldrich and used as received. Physical Measurements. The 1 H NMR spectrum of 2 was recorded on a Unity-300 NMR spectrometer. Infrared spectral measurements were performed on a Nicolet Nexus 470 FTIR * To whom correspondence should be addressed. E-mail: dunbar@ mail.chem.tamu.edu. (1) (a) Rosenberg, B.; Van Camp, L.; Krigas, T. Nature 1965, 205, 698. (b) Rosenberg, B.; Van Camp, L.; Trosko, J. E.; Mansour, V. H. Nature 1969, 222, 285. (c) Rosenberg, B.; Van Camp, L. Cancer Res. 1970, 30, 1799. (d) Jamieson, E. R.; Lippard, S. J. Chem. ReV. 1999, 99, 2467, and references therein. (2) (a) Bear, J. L.; Yao, C.-L.; Liu, L.-M.; Capdevielle, F. J.; Korp, J. D.; Albright, T. A.; Kang, S.-K.; Kadish, K. M. Inorg. Chem. 1989, 28, 1254. (b) Bear, J. L. In Precious Metals 1985: Proceedings of the Ninth International Precious Metals Conference; Zysk, E. E., Bonucci, J. A., Eds.; International Precious Metals: Allentown, PA, 1986. (c) Howard, R. A.; Sherwood, E.; Erck, A.; Kimball, A. P.; Bear, J. L. J. Med. Chem. 1977, 20, 943. (3) (a) Pruchnik, F. P.; Dus, D. J. Inorg. Biochem. 1996, 61, 55. (b) Trynda-Lemiesz, L.; Pruchnik, F. P. J. Inorg. Biochem. 1997, 66, 187. (c) Pruchnik, F. P.; Kluczewska, G.; Wilczok, A.; Mazurek, U.; Wilczok, T. J. Inorg. Biochem. 1997, 65, 25. (4) (a) Bear, J. L.; Gray, H. B.; Rainen, L.; Chang, I. M.; Howard, R.; Serio, G.; Kimball, A. P. Cancer Chemother. Rep. 1975, 59, 611. (b) Rao, P. N.; Smith, M. L.; Pahtak, S.; Howard, R. A.; Bear, J. L. J. Natl. Cancer Inst. 1980, 64, 905. (c) Howard, R. A.; Kimball, A. P.; Bear, J. L. Cancer Res. 1979, 39, 2568. (d) Howard, R. A.; Spring, T. G.; Bear, J. L. Cancer Res. 1976, 36, 4402. (5) (a) Crawford, C. A.; Matonic, J. H.; Streib, W. E.; Huffman, J. C.; Dunbar, K. R.; Christou, G. Inorg. Chem. 1993, 32, 3125. (b) Dunbar, K. R.; Matonic, J. H.; Saharan, V. P.; Crawford, C. A.; Christou, G. J. Am. Chem. Soc. 1994, 116, 2201. (c) Day, E. F.; Crawford, C. A.; Folting, K.; Dunbar, K. R.; Christou, G. J. Am. Chem. Soc. 1994, 116, 9339. (d) Crawford, C. A.; Day, E. F.; Saharan, V. P.; Folting, K.; Huffman, J. C.; Dunbar, K. R.; Christou, G. Chem. Commun. 1996, 1113. (e) Catalan, K. V.; Mindiola, D. J.; Ward, D. L.; Dunbar, K. R. Inorg. Chem. 1997, 36, 2458. (f) Catalan, K. V.; Hess, J. S.; Maloney, M. M.; Mindiola, D. J.; Ward, D. L.; Dunbar, K. R. Inorg. Chem. 1999, 38, 3904. (g) Asara, J. M.; Hess, J. S.; Lozada, E.; Dunbar, K. R.; Allison, J. J. Am. Chem. Soc. 2000, 122, 8. (6) Pneumatikakis, G.; Psaroulis, P. Inorg. Chim. Acta 1980, 46, 97. (7) Hess, J. S. M.S. Thesis, Michigan State University, 1998. (8) Reactions of 1 with thiol-containing biomolecules, such as cysteine and glutathione, are also being performed in our laboratory. These products are still under investigation, but preliminary results indicate that a reduction is occurring under anaerobic conditions. The current model chemistry led to more tractable products and allowed for the structural determination of products in the presence of oxygen. (9) Crawford, C. A.; Matonic, J. H.; Huffman, J. C.; Folting, K.; Dunbar, K. R.; Christou, G. Inorg. Chem. 1997, 36, 2361. Inorg. Chem. 2002, 41, 433-436 10.1021/ic010799v CCC: $22.00 © 2002 American Chemical Society Inorganic Chemistry, Vol. 41, No. 2, 2002 433 Published on Web 01/03/2002