Lipopeptide antifungal agents: Amine conjugates of the semi-synthetic pneumocandins L-731,373 and L-733,560

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 15, 1997, Pages 2021-2026

  Zambias, Robert A ^a   James, Catherine ^a   Abruzzo, George K ^a   Bartizal, Kenneth F ^a   Hajdu, Richard ^a   Thompson, Randy ^a   Nollstadt, Karl H ^a   Marrinan, Jean ^b   Balkovec, James M ^a  

^a Department of Medicinal Chemistry ^*  (United States)

^b Antibiotic Discov Devmt Merck R   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMPHOTERICIN B; ANTIFUNGAL AGENT; GLUCAN SYNTHASE; L 733560; LIPOPEPTIDE; PNEUMOCANDIN DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIFUNGAL ACTIVITY; ARTICLE; ASPERGILLOSIS; ASPERGILLUS; ASPERGILLUS FUMIGATUS; CANDIDA; CANDIDA ALBICANS; CHIMPANZEE; CONJUGATION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IN VITRO STUDY; INTRAVENOUS DRUG ADMINISTRATION; NONHUMAN;

EID: 0030816775     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00359-4     Document Type: Article

References (16)

1. (a) Turner, W. W.; Rodriguez, M. J. Curr. Pharmaceut. Des. 1996, 2, 209.
2. (b) Walsh, T. J.; Hiemenz, J. W.; Anaissie, E. Infect. Dis. Clin. North Am. 1996, 10, 365.
3. (c) Graybill, J. R. Clin. Infect. Dis. 1996, 22, S166.
4. (d) Hiemenz, J. W.; Walsh, T. J. Clin. Infect. Dis. 1996, 22, S133.
5. (e) Balkovec, J. M. Expert Opin. Invest. Drugs 1994, 3, 65.
6. Bouffard, F. A.; Zambias, R. A.; Dropinski, J. F.; Balkovec, J. M.; Hammond, M. L.; Abruzzo, G. K.; Bartizal, K. F.; Marrinan, J. A.; Kurtz, M. B.; McFadden, D. C.; Nollstadt, K. H.; Powles, M. A.; Schmatz, D. M. J. Med. Chem. 1994, 37, 222.
7. (a) Bartizal, K.; Scott, T.; Abruzzo, G. K.; Gill, C. J.; Pacholok, C.; Lynch, L.; Kropp, H. Antimicrob. Agents Chemother. 1995, 39, 1070.
8. (b) Abruzzo, G. K.; Flattery, A. M.; Gill, C. J.; Kong, L.; Smith, J. G.; Krupa, D.; Pikounis, V. B.; Kropp, H.; Bartizal, K. Antimicrob. Agents Chemother. 1995, 39, 1077.
9. (c) Schmatz, D.; Powles, M. A.; McFadden, D.; Nollstadt, K.; Bouffard, F. A.; Dropinski, J. F.; Liberator, P.; Andersen, J. Antimicrob. Agents Chemother. 1995, 37, 1320.
10. Zambias, R. A.; James, C.; Hammond, M. L.; Abruzzo, G. K.; Bartizal, K. F.; Nollstadt, K. H.; Douglas, C.; Marrinan, J.; Balkovec, J. M. Bioorg. Med. Chem. Lett. 1995, 5, 2357.
11. 0 Analogs L-731,373 and L-733,560" presented at the National ACS Meeting, Chicago, IL: Abstract No. MEDI 213, August 23-28, 1995.
12. Schmatz, D. M.; Abruzzo, G.; Powles, M. A.; McFadden, D. C.; Balkovec, J. M.; Black, R. M.; Nollstadt, K.; Bartizal, K. J. Antibiot. 1992, 45, 1886.
13. Bartizal, K.; Scott, T.; Abruzzo, G. K.; Gill, C. J.; Pacholok, C.; Lynch, L.; Kropp, H. Antimicrob. Agents Chemother. 1995, 39, 1070.
14. Bartizal, K.; Abruzzo, G.; Trainor, C.; Krupa, D.; Nollstadt, K.; Schmatz, D.; Hammond, M.; Balkovec, J.; Van Middlesworth, F. Antimicrob. Agents Chemother. 1992, 36, 1648.
15. Abruzzo, G. K.; Flattery, A. M.; Gill, C. J.; Kong, L.; Smith, J. G.; Krupa, D.; Pikounis, V. B.; Kropp, H.; Bartizal, K. Antimicrob. Agents Chemother. 1995, 39, 1077.
16. The preparation of 7c is a representative experimental procedure: The hydrochloride salt of 3 (8.02 g, 7.64 mmol) and bis-carbobenzyloxy-L-ornithine (7.65 g, 19.1 mmol) were dissolved in 73 mL of dry, dimethylamine-free, N,N-dimethylformamide. Diisopropylethylamine (1.33 mL, 7.64 mmol), 1-hydroxybenzotriazole (2.58 g, 19.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.66 g, 19.1 mmol) were added. The reaction was stirred under a nitrogen atmosphere at room temperature for 18 h. The reaction mixture was purified directly in two equal batches by preparative HPLC (50 X 250 mm Deltapak C18, 60 mL/min, water/acetonitrile/0.1% TFA: step gradient 70/30 [until DMF has eluted] to 35/65 [as product begins to elute], 48 mL fractions, 220 and 277 nm) to give 7.54 g (69%) of 5 (n = 5, X = NHCBz) as a white amorphous solid after lyophilization.