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Activation of Leinamycin by Thiols: a Theoretical Study

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Activation of Leinamycin by Thiols: a Theoretical Study Activation of Leinamycin by Thiols: A Theoretical Study Leonid Breydo and Kent S. Gates* Departments of Chemistry and Biochemistry, University of Missouri-Columbia, Columbia, Missouri 65211 [email protected] Received August 27, 2002 Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2′) of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3′) and the sulfinyl sulfur (S1′) of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3df,p)//B3LYP/6-31G* level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol- mediated activation of leinamycin involves initial attack of thiolate at the S2′-position of the antibiotic’s 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan- 5-one intermediate (3). Introduction of oxygen radicals,11,12 while the 1,2-oxathiolan-5-one form of leinamycin (3) undergoes a unique rearrangement Structurally novel natural products that possess potent to produce a DNA-alkylating episulfonium ion (5).13 The biological activity are of significant interest because their studies described here embrace the previous assump- - mechanisms of action are often unique and unexpected.1 3 tion10,13,14 that the oxathiolanone 3 represents an “acti- For this reason, we have been inspired to study the DNA- vated” form of leinamycin that serves as the immediate - damaging natural product leinamycin.4 7 This natural precursor to the episulfonium ion (5). This notion is product possesses a unique chemical structure, displays supported by a wealth of precedents showing that sulfe- potent anticancer activity, and reacts with DNA by a nyl carboxylates react readily with alkenes to yield completely novel sequence of reactions. DNA damage by episulfonium ions (Scheme 2).15 leinamycin is triggered by attack of thiols on the 1,2- The products formed in the reaction of leinamycin with dithiolan-3-one 1-oxide heterocycle of the antibiotic thiols have been rationalized by a mechanism involving - (Scheme 1).7 9 This reaction produces two crucial reactive initial attack of thiols on the central, sulfenyl sulfur (S2′) intermediates: an 1,2-oxathiolan-5-one (3) and a hydro- of the 1,2-dithiolan-3-one 1-oxide heterocycle as shown disulfide (or persulfide) 4.10 The hydrodisulfide interme- in Scheme 1.10,13 However, the carbonyl carbon (C3′) and diate (4) mediates oxidative DNA damage via production the sulfinyl sulfur (S1′) are also expected to be electro- philic. Thus, it is important to consider whether nucleo- * Address correspondence to this author. Phone: (573) 882-6763. philic attack of thiol at these sites might contribute to Fax: (573) 882-2754. either the activation or destruction of leinamycin. To (1) Gates, K. S. In Comprehensive Natural Products Chemistry; Kool, E. T., Ed.; Pergamon: New York, 1999; Vol. 7, pp 491-552. (2) Verdine, G. L. Nature 1996, 384 (supplement), 11-13. (11) Behroozi, S. J.; Kim, W.; Dannaldson, J.; Gates, K. S. Biochem- (3) Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat. Prod. Rep. istry 1996, 35, 1768-1774. 2000, 17, 215-234. (12) Mitra, K.; Kim, W.; Daniels, J. S.; Gates, K. S. J. Am. Chem. (4) Hara, M.; Takahashi, I.; Yoshida, M.; Kawamoto, I.; Morimoto, Soc. 1997, 119, 11691-11692. M.; Nakano, H. J. Antibiot. 1989, 42, 333-335. (13) Asai, A.; Hara, M.; Kakita, S.; Kanda, Y.; Yoshida, M.; Saito, (5) Hara, M.; Asano, K.; Kawamoto, I.; Takiguchi, T.; Katsumata, H.; Saitoh, Y. J. Am. Chem. Soc. 1996, 118, 6802-6803. S.; Takahashi, K.; Nakano, H. J. Antibiot. 1989, 42, 1768-1774. (14) Breydo, L.; Zang, H.; Mitra, K.; Gates, K. S. J. Am. Chem. Soc. (6) Hara, M.; Saitoh, Y.; Nakano, H. Biochemistry 1990, 29, 5676- 2001, 123, 2060-2061. 5681. (15) (a) Havlik, A. J.; Kharasch, N. J. Am. Chem. Soc. 1956, 78, (7) Gates, K. S. Chem. Res. Toxicol. 2000, 13, 953-956. 1207-1210. (b) Putnam, R. E.; Sharkey, W. H. J. Am. Chem. Soc. 1957, (8) Hara, M.; Yoshida, M.; Nakano, H. Biochemistry 1990, 29, 79, 6526-6529. (c) Brydon, A.; Cameron, G. G.; Hogg, D. R. Int. J. 10449-10455. Sulfur Chem. A 1972, 2, 289-290. (d) Morishita, T.; Furukawa, N.; (9) For activation of leinamycin by other nucleophiles, see: Zang, Oae, S. Tetrahedron 1981, 37, 2539-2546. (e) Schank, K.; Frisch, A.; H.; Breydo, L.; Mitra, K.; Dannaldson, J.; Gates, K. S. Bioorg. Med. Zwanenburg, B. J. Org. Chem. 1983, 48, 4580-4582. (f) Morin, R. B.; Chem. Lett. 2001, 11, 1511-1515. Jackson, B. G.; Mueller, R. A.; Lavagnino, E. R.; Scanlon, W. B.; (10) Behroozi, S. B.; Kim, W.; Gates, K. S. J. Org. Chem. 1995, 60, Andrews, S. L. J. Am. Chem. Soc. 1963, 85, 1896-1897. (g) Vedejs, 3964-3966. E.; Mullins, M. J. J. Org. Chem. 1979, 44, 2947-48. 10.1021/jo020568l CCC: $22.00 © 2002 American Chemical Society 9054 J. Org. Chem. 2002, 67, 9054-9060 Published on Web 11/13/2002 Activation of Leinamycin by Thiols SCHEME 1 SCHEME 2 but nonetheless provides a reasonable estimate of the molecular geometry in solution. The solvent dielectric constant for dichloromethane ( ) 8.93) was used because this solvent has been used in some of the experimental work on this system.10 Frequency calculations were performed at all station- ary points at the B3LYP/6-31G* level using an Onsager address this question, we have used computational model, and a correct number of imaginary frequencies methods to examine the attack of methyl thiolate on each were found. Zero-point vibrational and thermal correc- of the three electrophilic centers in a simple analogue of tions were calculated at the same level and were not the 1,2-dithiolan-3-one 1-oxide heterocycle found in leina- scaled.21 All transition states were analyzed either by mycin. calculating an intrinsic reaction coordinate (IRC) or by visual inspection of the transition vector with the pro- gram Vibrate.22 Since entropy plays an important role Computational Methods in bimolecular reactions described here, all energies are All calculations were carried out utilizing Gaussian 94 reported as Gibbs free energy (∆G) values at 298 K. or Gaussian 98.16 All geometries were optimized and Solvation energies were calculated on the optimized frequencies calculated at the B3LYP/6-31G* level of geometries utilizing three SCRF models: integral equa- theory17,18 in the solvent model using the self-consistent tion formalism polarized continuum model (IEFPCM),23 reaction field (SCRF) method based on the Onsager polarized continuum model (PCM),24-26 and isodensity model.19,20 Reoptimization of several representative struc- polarized continuum model (IPCM)25 at the B3LYP/6- tures at higher levels (B3LYP/6-31+G* or MP2/6-31G*) 31G* level. In the models used, solvent is assumed to be did not lead to significant changes in geometry. The a continuous medium with a dielectric constant that representation of solvent used here is somewhat crude surrounds a cavity containing the solute and the shape of the cavity is adjusted to fit the shape of the solute (16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, M. A.; molecule to afford more accurate solvation energies. All Gill, P. M. W.; Johnson, B. G.; Robb, M. A.; Cheeseman, J. R.; Keith, three models show qualitatively similar results, and PCM T. A. P.; Petersson, G. A.; Montgomery, J. A.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, and IEFPCM afford nearly identical solvation energies O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennuci, B.; Pomelli, (see Tables S1 and S2 and Scheme 4). Values shown in C.; Adamo, C.; Clifford, S.; Ochterski, G.; Cui, Q.; Morokuma, K.; Scheme 4 are derived from IEFPCM calculations because Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; this model is considered best for calculation of the Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; solvation energies of charged molecules.27 Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. A.; Chen, W.; Wong, M. W.; Andres, J. L.; Reprogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. (21) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513. P.; Head-Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 98, Revision (22) Glaser, R.; Chladny, B. S.; Hall, M. K. QCPE Bull. 1993, 13, A.7; Gaussian, Inc.: Pittsburgh, PA, 1998. 75. (17) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (23) Cances, E.; Menucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107, (18) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789. 3032-3041. (19) Wong, M. W.; Frisch, M. J.; Wiberg, K. B. J.
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