F. Gao et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5518–5522
5521
Except for N-sulfonyloxaziridines, all of these reagents, and more,
were explored for the oxidation of 1b. The results are summarized
in Table 1.
showed poorer inhibition of AAC(60)-Ii than amide-linked inhibitor
1b. This supports the hypothesis that AAC(60)-Ii may catalyze the
reaction mainly via proximity effects.9,10
Ammonium persulfate was the best oxidant for the selective
oxidation of the sulfide 1a and 1b to the corresponding sulfoxides
3a and 3b (Scheme 4). The reactions were complete within 1 h
when 2 equivalents of oxidant were used. To our knowledge, this
is the first time that (NH4)2SO8 is successfully used for the selective
oxidation of a sulfide containing multiple functionalities, to a sulf-
oxide under aqueous conditions. Bisubstrates 3a and 3b were puri-
fied by reverse-phase HPLC. One of two possible diastereoisomers
was major (>90%) and the minor isomer was discarded. No attempt
was made to determine the absolute stereochemistry at the sulfur
atom because of the prohibitive cost of CoA. As for the oxidation of
the sulfides 1a and 1b to sulfones 4a and 4b, respectively, oxone
appeared to be the most efficient oxidant (Scheme 4).
Acknowledgments
This work was supported by the National Science and Engineer-
ing Research Council of Canada (NSERC) and by the Canadian Insti-
tute of Health Research (CIHR). A.L. was supported by an NSERC
scholarship. F.G. and K.V. were supported by scholarship awards
from the Chemical Biology Strategic Training Initiative of CIHR.
The authors are grateful to G. D. Wright at McMaster University
for sharing his AAC(60)-Ii expression plasmid.
Supplementary data
The bisubstrates 2b, 3a, 3b, 4a, and 4b were tested for inhibition
of AAC(60)-Ii. The results are shown in Table 2. The large error re-
ported for the Ki of 4a can be explained by the hygroscopic nature
of this compound, which decreased the accuracy of weight mea-
surements. All compounds tested were potent competitive inhibi-
tors with Kis ranging from low micromolar to nanomolar.
Supplementary data associated with this article can be found, in
References and notes
1. Gonzalez, L. S. S., III; Jeanne, P. Am. Fam. Phys. 1998, 58, 181.
2. Vakulenko, S. B.; Mobashery, S. Clin. Microbiol. Rev. 2003, 16, 430.
3. Wright, G. D. Curr. Opin. Microbiol. 1999, 2, 499.
Surprisingly, the bisubstrate with
a sulfonamide linker (2b)
showed a decreased inhibition compared to the corresponding
amide-linked bisubstrate (1b). This result suggests either that the
enzyme does not stabilize the tetrahedral intermediate or that 2b
is a poor mimic of the tetrahedral intermediate. The synthesis of
phosphonate-linked bisubstrates is currently under way to verify
these hypotheses.
In conclusion, we report here the synthesis of five new bisub-
strates containing a sulfonamide linker, or an amide linker adja-
cent to sulfoxide or sulfone groups. Four of these bisubstrates
were assembled in only two steps. We demonstrate for the first
time the utility of (NH4)2S2O8 in the selective oxidation of highly
functionalized sulfides to sulfoxides under aqueous conditions.
Although sulfonamides are expected to better mimic tetrahedral
intermediates than amides, sulfonamide-linked bisubstrate 2b
4. Wright, G. D. Curr. Opin. Chem. Biol. 2003, 7, 563.
5. Azucena, E.; Mobashery, S. Drug Resist. Update 2001, 4, 106.
6. Boehr, D. D.; Moore, I. F.; Wright, G. D. In Frontiers in Antimicrobial Resistance: a
Tribute to Stuart B. Levy; White, D. G., Alekshun, M.N.; McDermott, P. F., Eds.;
American Society for Microbiology: Washington DC, 2005. Chapter 1.
7. Magnet, S.; Blanchard, J. S. Chem. Rev. 2005, 105, 477.
8. Wright, G. D.; Ladak, P. Antimicrob. Agents Chemother. 1997, 41, 956.
9. Draker, K. A.; Wright, G. D. Biochemistry 2004, 43, 446.
10. Draker, K. A.; Northrop, D. B.; Wright, G. D. Biochemistry 2003, 42, 6565.
11. Gao, F.; Yan, X.; Baettig, O. M.; Berghuis, A. M.; Auclair, K. Angew. Chem., Int. Ed.
2005, 44, 6859.
12. Gao, F.; Yan, X.; Shakya, T.; Baettig, O. M.; Ait-Mohand-Brunet, S.; Berghuis, A.
M.; Wright, G. D.; Auclair, K. J. Med. Chem. 2006, 49, 5273.
13. Obreza, A.; Gobec, S. Curr. Med. Chem. 2004, 11, 3263.
14. Cama, E.; Shin, H.; Christianson, D. W. J. Am. Chem. Soc. 2003, 125, 13052.
15. Levenson, C. H.; Meyer, R. B. J. Med. Chem. 1984, 27, 228.
16. Brown, M. J. B.; Mensah, L. M.; Doyle, M. L.; Broom, N. J. P.; Osbourne, N.;
Forrest, A. K.; Richardson, C. M.; O’Hanlon, P. J.; Pope, A. J. Biochemistry 2000,
39, 6003.
17. Wybenga-Groot, L. E.; Draker, K.-A.; Wright, G. D.; Berghuis, A. M. Structure
1999, 7, 497.
18. Burk, D. L.; Ghuman, N.; Wybenga-Groot, L. E.; Berghuis, A. M. Protein Sci. 2003,
12, 426.
19. Truce, W. E.; Abraham, D. J.; Son, P. J. Org. Chem. 1967, 32, 990.
20. Brienne, M. J.; Varech, D.; Leclercq, M.; Jacques, J.; Radembino, N.; Dessalles, C.;
Mahuzier, G.; Gueyouche, C.; Bories, C., et al J. Med. Chem. 1987, 30, 2232.
21. Roestamadji, J.; Grapsas, I.; Mobashery, S. J. Am. Chem. Soc. 1995, 117, 11060.
22. Note: 1H NMR (DMSO-d6, 300 MHz) d 8.00 (s, 1H), 7.30 (m, 5H), 4.14 (d, J = 5.4,
2H), 3.32 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) d 136.8, 129.0, 128.3, 127.8,
47.3, and 40.4.
O
O
O
1.5 eq. (NH4)2S2O8
1 h RT
S CoA
S CoA
HN
HO
HO
H2N
n
HN
HO
HO
H2N
n
O
O
H2N
H2N
61% (3a)
63% (3b)
O
NH2
O
NH2
HO
HO
3a-b (n = 1,2)
OH
OH
1a-b (n = 1,2)
23. Truce, W. E.; Wellisch, E. J. Am. Chem. Soc. 1952, 74, 2881.
24. Li, M.; Wu, R. S.; Tsai, J. S. C.; Salamone, S. J. Bioorg. Med. Chem. Lett. 2003, 13,
383.
25. Reddick, J. J.; Cheng, J.; Roush, W. R. Org. Lett. 2003, 5, 1967.
26. Zhao, M. M.; Qu, C.; Lynch, J. E. J. Org. Chem. 2005, 70, 6944.
27. Baeckvall, J.-E. Modern Oxidation Methods 2004, 193.
28. Legros, J.; Dehli, J. R.; Bolm, C. Adv. Synth. Catal. 2005, 347, 19.
29. Mata, E. G. Phosphorus Sulfur 1996, 117, 231.
O
O
O
S CoA
S CoA
2 eq. Oxone
1 h RT
HN
HO
HO
H2N
n
HN
HO
HO
H2N
n
O
O
O
H2N
H2N
O
NH2
O
NH2
62% (4a)
55% (4b)
HO
HO
OH
OH
4a-b (n = 1,2)
30. Chen, B. C.; Murphy, C. K.; Kumar, A.; Reddy, R. T.; Clark, C.; Zhou, P.; Lewis, B.
M.; Gala, D.; Mergelsberg, I.; Scherer, D.; Buckley, J.; DiBenedetto, D.; Davis, F.
A. Org. Synth. 1996, 73, 159.
1a-b (n = 1,2)
31. Chen, M. Y.; Patkar, L. N.; Lin, C. C. J. Org. Chem. 2004, 69, 2884.
32. Chen, M.-Y.; Patkar, L. N.; Chen, H.-T.; Lin, C.-C. Carbohydr. Res. 2003, 338, 1327.
33. Davis, F. A.; Lal, S. G.; Durst, H. D. J. Org. Chem. 1988, 53, 5004.
34. Kropp, P. J.; Breton, G. W.; Fields, J. D.; Tung, J. C.; Loomis, B. R. J. Am. Chem. Soc.
2000, 122, 4280.
Scheme 4. Optimized conditions for the syntheses of bisubstrates 3a, 3b and 4a, 4b
via the selective oxidation of the sulfides 1a and 1b.
35. Kagan, H. B. Asymmetric oxidation of sulfides. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 327–356.
36. Velasco, M. A. SynLett 2005, 11, 1807.
37. Arjona, O.; Menchaca, R.; Plumet, J. J. Org. Chem. 2001, 66, 2400.
38. Arai, Y.; Matsui, M.; Koizumi, T. Synthesis 1990, 4, 320–323.
39. Brougham, P.; Cooper, M. S.; Cummerson, D. A.; Heaney, H.; Thompson, N.
Synthesis 1987, 11, 1015–1017.
Table 2
AAC(60)-Ii inhibition constants (Ki) for bisubstrates 2b, 3a, 3b, 4a, and 4b
Inhibitor 2b
Type Competitive Competitive Competitive Competitive Competitive
Ki ( M) 1.6 0.6 0.06 0.03 2.0 0.7 0.27 0.2 0.09 0.06
3a
3b
4a
4b
40. Kahne, D.; Walker, S.; Cheng, Y.; Vanengen, D. J. Am. Chem. Soc. 1989, 111,
6881–6882.
l