Extending the β-lactamase-dependent prodrug armory: S- aminosulfeniminocephalosporins as dual-release prodrugs

Journal of Organic Chemistry

Volumn 64, Issue 9, 1999, Pages 3132-3138

  Smyth, Timothy P ^a   O'Connor, Michael J ^a   O'Donnell, Michael E ^a  

^a UNIVERSITY OF LIMERICK   (Ireland)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOSULFENIMINOCEPHALOSPORIN DERIVATIVE; CEPHALOSPORIN DERIVATIVE; PRODRUG; UNCLASSIFIED DRUG;

ANTIBODY DIRECTED ENZYME PRODRUG THERAPY; ARTICLE; DRUG HYDROLYSIS; DRUG RELEASE; DRUG STRUCTURE; DRUG SYNTHESIS; REACTION ANALYSIS;

EID: 0033617138     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo981993a     Document Type: Article

References (53)

1. (a) Wermuth, C. G.; Gaignault, J.-C.; Marchandeau, C. In Practice of Medicinal Chemistry; Wermuth, C. G., Ed.; Academic Press: London, 1996; Chapter 31.
2. (b) Clearance of the intact precursor from the body must be faster than the rate of its background hydrolysis/ breakdown; β-lactams are readily cleared from the blood stream via tubular secretion: Ehlert, C.; Strunz, H.; Visser, K.; Wiese, M.; Seydel, J. K. J. Pharm. Sci. 1998, 87, 101 and references therein.
3. An alarming proportion of bacterial pathogens exhibit high-level resistance to β-lactam antibiotics due to the presence of β-lactamase enzymes, and to date over 190 varieties of these enzymes have been characterized: (a) Neu, H. C. Science 1992, 257, 1064. Nicolas- Chanoine, M. H. Int. J. Antimicrob. Agents 1996, 7, S21-S26. (b) Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211.
4. An alarming proportion of bacterial pathogens exhibit high-level resistance to β-lactam antibiotics due to the presence of β-lactamase enzymes, and to date over 190 varieties of these enzymes have been characterized: (a) Neu, H. C. Science 1992, 257, 1064. Nicolas-Chanoine, M. H. Int. J. Antimicrob. Agents 1996, 7, S21-S26. (b) Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211.
5. An alarming proportion of bacterial pathogens exhibit high-level resistance to β-lactam antibiotics due to the presence of β-lactamase enzymes, and to date over 190 varieties of these enzymes have been characterized: (a) Neu, H. C. Science 1992, 257, 1064. Nicolas- Chanoine, M. H. Int. J. Antimicrob. Agents 1996, 7, S21-S26. (b) Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211.
6. For leading references see: (a) Svensson, H. P.; Frank, I. S.; Berry, K. K.; Senter, P. D. J. Med. Chem. 1998, 41, 1507 and references therein. (b) Bagshawe, K. D.; Begent, R. H. J. Adv. Drug Delivery Rev. 1996, 22, 365. (c) Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Antoniw, P. Tumour Targeting 1995, 1, 17. (d) Rodrigues, M. L.; Carter, P.; Wirth, C.; Mullins, S.; Lee, A.; Blackburn, B. K. Chem. Biol. 1995, 2, 223.
7. For leading references see: (a) Svensson, H. P.; Frank, I. S.; Berry, K. K.; Senter, P. D. J. Med. Chem. 1998, 41, 1507 and references therein. (b) Bagshawe, K. D.; Begent, R. H. J. Adv. Drug Delivery Rev. 1996, 22, 365. (c) Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Antoniw, P. Tumour Targeting 1995, 1, 17. (d) Rodrigues, M. L.; Carter, P.; Wirth, C.; Mullins, S.; Lee, A.; Blackburn, B. K. Chem. Biol. 1995, 2, 223.
8. For leading references see: (a) Svensson, H. P.; Frank, I. S.; Berry, K. K.; Senter, P. D. J. Med. Chem. 1998, 41, 1507 and references therein. (b) Bagshawe, K. D.; Begent, R. H. J. Adv. Drug Delivery Rev. 1996, 22, 365. (c) Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Antoniw, P. Tumour Targeting 1995, 1, 17. (d) Rodrigues, M. L.; Carter, P.; Wirth, C.; Mullins, S.; Lee, A.; Blackburn, B. K. Chem. Biol. 1995, 2, 223.
9. For leading references see: (a) Svensson, H. P.; Frank, I. S.; Berry, K. K.; Senter, P. D. J. Med. Chem. 1998, 41, 1507 and references therein. (b) Bagshawe, K. D.; Begent, R. H. J. Adv. Drug Delivery Rev. 1996, 22, 365. (c) Bagshawe, K. D.; Sharma, S. K.; Springer, C. J.; Antoniw, P. Tumour Targeting 1995, 1, 17. (d) Rodrigues, M. L.; Carter, P.; Wirth, C.; Mullins, S.; Lee, A.; Blackburn, B. K. Chem. Biol. 1995, 2, 223.
10. (a) O'Callaghan, C. H.; Sykes, R. B.; Staniforth, S. E. Antimicrob. Agents Chemother. 1976, 245.
11. (b) Mobashery, S.; Lerner, S. A.; Johnston, M. J. Am. Chem. Soc. 1986, 108, 1685.
12. (c) Pratt, R. F.; Faraci, W. S. J. Am. Chem. Soc. 1986, 108, 5328.
13. (d) Albrecht, H. A.; Beskid, G.; Christenson, J. G.; Durkin, J. W.; Fallat, V.; Georgopapadakou, N. H.; Keith, D. D.; Konzelmann, F. M.; Lipshitz, E. R.; McGarry, D. H.; Siebelist, J.-A.; Wei, C.-C.; Weigele, M.; Yang, R. J. Med. Chem. 1991, 34, 669. Albrecht, H. A.; Beskid, G.; Christenson, J. G.; Georgopapadakou, N. H.; Keith, D. D.; Konzelmann, F. M.; Pruess, D. L.; Rossman, P. L.; Wei, C.-C. J. Med. Chem. 1991, 34, 2857.
14. (d) Albrecht, H. A.; Beskid, G.; Christenson, J. G.; Durkin, J. W.; Fallat, V.; Georgopapadakou, N. H.; Keith, D. D.; Konzelmann, F. M.; Lipshitz, E. R.; McGarry, D. H.; Siebelist, J.-A.; Wei, C.-C.; Weigele, M.; Yang, R. J. Med. Chem. 1991, 34, 669. Albrecht, H. A.; Beskid, G.; Christenson, J. G.; Georgopapadakou, N. H.; Keith, D. D.; Konzelmann, F. M.; Pruess, D. L.; Rossman, P. L.; Wei, C.-C. J. Med. Chem. 1991, 34, 2857.
15. (e) Expulsion of the C-2′ moiety, following cleavage of the β-lactam ring, has also been shown to occur with penems: Perrone, E.; Jabés, D.; Alpegiani, M.; Andreini, B. P.; Bruna, C. D.; Nero, S. D.; Rossi, R.; Visentin, G.; Zarini, F.; Franceshi, G. J. Antibiot. 1992, 45, 589.
16. Smyth, T. P.; O'Donnell, M. E.; O'Connor, M. J.; St Ledger, J. O. J. Org. Chem. 1998, 63, 7600.
17. Kirby, A. J. Adv. Phys. Org. Chem. 1980, 183. Kirby, A. J.; Logan, C. J. J. Chem. Soc., Perkin Trans. 2 1978, 642; Menger, F. M. Acc. Chem. Res. 1985, 18, 128; 1993, 26, 206.
18. Kirby, A. J. Adv. Phys. Org. Chem. 1980, 183. Kirby, A. J.; Logan, C. J. J. Chem. Soc., Perkin Trans. 2 1978, 642; Menger, F. M. Acc. Chem. Res. 1985, 18, 128; 1993, 26, 206.
19. Kirby, A. J. Adv. Phys. Org. Chem. 1980, 183. Kirby, A. J.; Logan, C. J. J. Chem. Soc., Perkin Trans. 2 1978, 642; Menger, F. M. Acc. Chem. Res. 1985, 18, 128; 1993, 26, 206.
20. Kirby, A. J. Adv. Phys. Org. Chem. 1980, 183. Kirby, A. J.; Logan, C. J. J. Chem. Soc., Perkin Trans. 2 1978, 642; Menger, F. M. Acc. Chem. Res. 1985, 18, 128; 1993, 26, 206.
21. 5
22. 3I with Proton Sponge.
23. Included in the Supporting Information.
24. 5 A more detailed picture of the reaction mechanism in aqueous solution must await further work.
25. (b) Products derived from reactions of sulfenic acids in aqueous solution are described in: Hogg, D. R.; Vipond, P. W. Int. J. Sulfur Chem. C 1971, 6, 17.
26. (c) Products derived from further hydrolytic reaction of an exo-methylene thiazine type structure (related to 9 in Scheme 3 here) are described in: Taibi-Tranche, P.; Massova, I.; Vakulenko, S. B.; Lerner, S. A.; Mobashery, S. J. Am. Chem. Soc. 1996, 118, 7441.
27. 5 see the Experimental Section for further details.
28. -1 on acidification), indicating that the side chain was ionized. The involvement of this side chain anion as a general base, acting in an intramolecular fashion, may have been the cause of the more rapid rate of hydrolysis of the β-lactam ring in 4 over that in 4m.
29. 5 a lower limit of 300 min was obtained as the half-life for this direct displacement reaction by water; that limit was set by the half-life for hydrolysis of the β-lactam ring of the penicillin structure.
30. 1H NMR data in a short time scale.
31. The methodology used is described in detail in ref 5. Low levels of inhibition against β-lactamase type IV from Enterobacter cloacae (Sigma) were observed.
32. The data in Figures 2 and 4 indicate that expulsion of acetate from 5m was slower than expulsion of N-methyl-p-toluenesulfonamide.
33. Evidence for synergy between the two cytotoxic agents doxorubicin and paclitaxel has been reported: Holmes, F. A.; Kudelka, A. P.; Kavanagh, J. J.; Huber, M. H.; Ajani, J. A.; Valero, V. In Taxane Anticancer Agents - Basic Science and Current Status; Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series 583; American Chemical Society: Washington, DC, 1995; Chapter 3. These two cytotoxic agents have been individually combined with a cephalosporin as (β-lactamase-dependent) site-specific release prodrugs for use in ADEPT; see ref 3d and: Vrudhula, V. M.; Svensson, H. P.; Senter, P. D. J. Med. Chem. 1995, 38, 1380.
34. Evidence for synergy between the two cytotoxic agents doxorubicin and paclitaxel has been reported: Holmes, F. A.; Kudelka, A. P.; Kavanagh, J. J.; Huber, M. H.; Ajani, J. A.; Valero, V. In Taxane Anticancer Agents - Basic Science and Current Status; Georg, G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series 583; American Chemical Society: Washington, DC, 1995; Chapter 3. These two cytotoxic agents have been individually combined with a cephalosporin as (β-lactamase-dependent) site-specific release prodrugs for use in ADEPT; see ref 3d and: Vrudhula, V. M.; Svensson, H. P.; Senter, P. D. J. Med. Chem. 1995, 38, 1380.
35. L-Histidinol is known to potentiate the cytotoxicity of certain alkylating agents: Warrington, R. C.; Fang, W. D. Br. J. Cancer 1989, 60, 652; J. Nat. Can. Inst. 1989, 81, 798. The release of alkylating agents from cephalosporin prodrugs is well-established; see ref 3 and: Alexander, R. P.; Bates, R. W.; Pratt, A. J.; Kraunsoe, J. A. E. Tetrahedron 1996, 52, 5983.
36. L-Histidinol is known to potentiate the cytotoxicity of certain alkylating agents: Warrington, R. C.; Fang, W. D. Br. J. Cancer 1989, 60, 652; J. Nat. Can. Inst. 1989, 81, 798. The release of alkylating agents from cephalosporin prodrugs is well-established; see ref 3 and: Alexander, R. P.; Bates, R. W.; Pratt, A. J.; Kraunsoe, J. A. E. Tetrahedron 1996, 52, 5983.
37. L-Histidinol is known to potentiate the cytotoxicity of certain alkylating agents: Warrington, R. C.; Fang, W. D. Br. J. Cancer 1989, 60, 652; J. Nat. Can. Inst. 1989, 81, 798. The release of alkylating agents from cephalosporin prodrugs is well-established; see ref 3 and: Alexander, R. P.; Bates, R. W.; Pratt, A. J.; Kraunsoe, J. A. E. Tetrahedron 1996, 52, 5983.
38. For details of MDR inhibitors see: Ojima, I.; Bounaud, P.-Y.; Bernacki, R. J. CHEMTECH 1998, 28, 31 and references therein. A cephalosporin prodrug which would effect corelease of a taxane-based MDR inhibitor and a taxoid is an intriguing prospect - synergy between such inhibitors and paclitaxel has been demonstrated by Ojima et al., while the release of paclitaxel from a cephalosporin prodrug has been described in ref 3d.
39. See refs 3 and 4d and references therein.
40. 5
41. The bactericidal efficacy of quinolones and β-lactams has been shown to correlate with different parameters. In the case of quinolones, which exert their antibiotic effect inside the cytoplasm, this efficacy is highly correlated with their concentration, whereas the correlation in the case of penicillins in particular, and by extension with cephalosporins, is with the dosage time span during which the β-lactam concentration is moderately higher than the MIC level: Cars, O. Diagn. Microbiol. Infect. Dis. 1997, 27, 29. The fact that gram positive bacteria express β-lactamases extracellularly, whereas gram negative bacteria express these enzymes within the periplasmic space, may mean that a single broad-spectrum-type β-lactamase-dependent prodrug will not be viable. This should not be a limitation, however, in a scenario where administration of a particular drug will only follow on first characterizing the infectious agent, as is likely to be the case in a regime designed to contain resistance and prolong the viability of future drugs: Chopra, I.; Hodgson, J.; Metcalf, B.; Poste, G. Antimicrob. Agents Chemother. 1997, 41, 497. Levy, S. B. Sci. Am. 1998 (March), 32 and references therein.
42. The bactericidal efficacy of quinolones and β-lactams has been shown to correlate with different parameters. In the case of quinolones, which exert their antibiotic effect inside the cytoplasm, this efficacy is highly correlated with their concentration, whereas the correlation in the case of penicillins in particular, and by extension with cephalosporins, is with the dosage time span during which the β-lactam concentration is moderately higher than the MIC level: Cars, O. Diagn. Microbiol. Infect. Dis. 1997, 27, 29. The fact that gram positive bacteria express β-lactamases extracellularly, whereas gram negative bacteria express these enzymes within the periplasmic space, may mean that a single broad-spectrum-type β-lactamase-dependent prodrug will not be viable. This should not be a limitation, however, in a scenario where administration of a particular drug will only follow on first characterizing the infectious agent, as is likely to be the case in a regime designed to contain resistance and prolong the viability of future drugs: Chopra, I.; Hodgson, J.; Metcalf, B.; Poste, G. Antimicrob. Agents Chemother. 1997, 41, 497. Levy, S. B. Sci. Am. 1998 (March), 32 and references therein.
43. The bactericidal efficacy of quinolones and β-lactams has been shown to correlate with different parameters. In the case of quinolones, which exert their antibiotic effect inside the cytoplasm, this efficacy is highly correlated with their concentration, whereas the correlation in the case of penicillins in particular, and by extension with cephalosporins, is with the dosage time span during which the β-lactam concentration is moderately higher than the MIC level: Cars, O. Diagn. Microbiol. Infect. Dis. 1997, 27, 29. The fact that gram positive bacteria express β-lactamases extracellularly, whereas gram negative bacteria express these enzymes within the periplasmic space, may mean that a single broad-spectrum-type β-lactamase-dependent prodrug will not be viable. This should not be a limitation, however, in a scenario where administration of a particular drug will only follow on first characterizing the infectious agent, as is likely to be the case in a regime designed to contain resistance and prolong the viability of future drugs: Chopra, I.; Hodgson, J.; Metcalf, B.; Poste, G. Antimicrob. Agents Chemother. 1997, 41, 497. Levy, S. B. Sci. Am. 1998 (March), 32 and references therein.
44. 26a). The phenolic group provides a useful linkage for attachment to a prodrug nucleus, and this linkage should also mask the inherent toxicity of the phenolic moiety within the prodrug, as the key acid-dissociable site would be blocked.
45. A in streptogramins (Barrière, J. C.; Paris, J. M. Drugs of the Future 1993, 18, 833), (ii) combination of trimethoprim with a sulfonamide, and (iii) combination of a β-lactamase inhibitor (e.g. clavulanic acid) with a transpeptidase inhibitor (e.g. amoxycillin).
46. For leading references see: (a) Two-Component Signal Transduction; Hoch, J. A., Silhavy, T. J., Eds.; ASM Press: Washington, DC, 1995. (b) Barrett, J. F.; Isaacson, R. E. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, CA, 1995; Chapter 12. (c) Goldschmidt, R. M.; Macielag, M. J.; Hlasta, D. J.; Barrett, J. F. Curr. Pharm. Des. 1997, 3, 125.
47. For leading references see: (a) Two-Component Signal Transduction; Hoch, J. A., Silhavy, T. J., Eds.; ASM Press: Washington, DC, 1995. (b) Barrett, J. F.; Isaacson, R. E. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, CA, 1995; Chapter 12. (c) Goldschmidt, R. M.; Macielag, M. J.; Hlasta, D. J.; Barrett, J. F. Curr. Pharm. Des. 1997, 3, 125.
48. For leading references see: (a) Two-Component Signal Transduction; Hoch, J. A., Silhavy, T. J., Eds.; ASM Press: Washington, DC, 1995. (b) Barrett, J. F.; Isaacson, R. E. In Annual Reports in Medicinal Chemistry; Bristol, J. A., Ed.; Academic Press: San Diego, CA, 1995; Chapter 12. (c) Goldschmidt, R. M.; Macielag, M. J.; Hlasta, D. J.; Barrett, J. F. Curr. Pharm. Des. 1997, 3, 125.
49. (a) Macielag, M. J.; Demers, J. P.; Fraga-Spano, S. A.; Hlasta, D. J.; Johnson, S. G.; Kanojia, R. M.; Russell, R. K.; Sui, Z.; Weidner-Wells, M. A.; Werblood, H.; Foleno, B. D.; Goldschmidt, R. M.; Loeloff, M. J.; Webb, G. C.; Barrett, J. F. J. Med. Chem. 1998, 41, 2939.
50. (b) Lam, C.; Turnowsky, F.; Högenauer, G.; Schutze, E. J. Antimicrob. Chemther. 1987, 20, 37.
51. Volz, K. In Two-Component Signal Transduction; Hoch, J. A., Silhavy, T. J., Eds.; ASM Press: Washington, DC, 1995; Chapter 4, and references therein.
52. Casey, M.; Leonard, J.; Lygo, B.; Procter, G. Advanced Practical Organic Chemistry; Blackie: Glasgow, Scotland, 1990; Chapter 9.
53. See Chapter 5 of ref 28.