Syntheses of novel myxopyronin B analogs as potential inhibitors of bacterial RNA polymerase

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 24, 2007, Pages 6797-6800

  Lira, Ricardo ^a   Xiang, Alan X ^a   Doundoulakis, Thomas ^a   Biller, William T ^a   Agrios, Konstantinos A ^a   Simonsen, Klaus B ^a   Webber, Stephen E ^a   Sisson, Wes ^a   Aust, Robert M ^a   Shah, Amit M ^a   Showalter, Richard E ^a   Banh, Virginia N ^a   Steffy, Kevin R ^a   Appleman, James R ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Antibacterial; Antibiotics; Curtius rearrangement; Myxopyronin B; Ortholithiation

Indexed keywords

ANTIINFECTIVE AGENT; DNA DIRECTED RNA POLYMERASE; DNA DIRECTED RNA POLYMERASE INHIBITOR; MYXOPYRONIN B; MYXOPYRONIN B DERIVATIVE; NORMYXOPYRONIN B; UNCLASSIFIED DRUG;

ANTIBACTERIAL ACTIVITY; ARTICLE; DRUG CYTOTOXICITY; DRUG STRUCTURE; DRUG SYNTHESIS; ESCHERICHIA COLI; IC 50; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; STAPHYLOCOCCUS AUREUS; T LYMPHOCYTE;

ANTI-BACTERIAL AGENTS; DNA-DIRECTED RNA POLYMERASES; ENZYME INHIBITORS; ESCHERICHIA COLI; INHIBITORY CONCENTRATION 50; LACTONES; METHYLATION; MOLECULAR STRUCTURE; STAPHYLOCOCCUS AUREUS;

BACTERIA (MICROORGANISMS); ESCHERICHIA COLI; STAPHYLOCOCCUS AUREUS;

EID: 35848947512     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.10.017     Document Type: Article

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12. 3OD) δ: 0.86 (t, J = 7.2 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.20-1.29 (m, 2H), 1.34-1.41 (m, 2H), 1.49-1.56 (m, 2H), 1.68-1.76 (m, 2H), 1.79 (s, 3H), 1.97-2.06 (m, 2H), 2.03 (s, 3H), 2.47-2.57 (m, 1H), 3.08 (s, 3H), 3.66 (s, 3H), 5.01-5.08 (m, 1H), 5.49-5.52 (m, 1H), 5.74 (s, 1H), 6.36-6.41 (m, 2H).
13. 3OD) δ: 0.95 (t, J = 7.2 Hz, 3H), 1.32-1.38 (m, 2H), 1.44-1.50 (m, 2H), 1.66-1.72 (m, 2H), 1.77 (s, 3H), 1.98 (s, 3H), 2.02-2.07 (m, 2H), 2.17 (t, J = 7.2 Hz, 2H), 2.40 (t, J = 7.6 Hz, 2H), 3.13 (s, 3H), 3.66 (s, 3H), 5.04-5.11 (m, 1H), 5.73 (s, 1H), 6.12-6.20 (m, 2H), 6.35-6.44 (m, 1H).
14. 3OD) δ: 0.95 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), 1.30-1.40 (m, 2H), 1.43-1.55 (m, 2H), 1.60-1.69 (m, 2H), 1.77 (s, 3H), 1.83-1.95 (m, 2H), 2.02 (s, 3H), 2.23 (t, J = 7.6 Hz, 2H), 2.73 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 5.02-5.09 (m, 1H), 6.28-6.34 (m, 2H), 6.76-6.79 (m, 2H), 6.95 (dd, J = 1.6, 11.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H).
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17. Compound 10 was synthesized based on the following route: {A figure is presented}.
18. 6) δ: 1.57-1.64 (m, 2H), 1.98-2.03 (m, 2H), 2.09 (s, 3H), 2.44-2.50 (m, 2H), 3.58 (s, 3H), 5.00-5.07 (m, 1H), 6.05 (s, 1H), 6.33-6.39 (m, 1H), 6.67 (s, 1H), 6.94 (d, J = 3.2 Hz, 1H), 7.14 (s, 1H), 7.91 (s, 1H), 9.23 (d, J = 9.6 Hz, 1H).
19. 6) δ: 1.59-1.67 (m, 2H), 1.98-2.05 (m, 2H), 2.48-2.55 (m, 2H), 3.57 (s, 3H), 4.98-5.05 (m, 1H), 6.22 (s, 1H), 6.32-6.38 (m, 1H), 6.55 (s, 1H), 7.42-7.44 (m, 1H), 7.48-7.53 (m, 1H), 7.96 (s, 1H), 8.12 (dd, J = 30.4, 16.0 Hz, 2H), 9.22 (d, J = 8.8 Hz, 1H), 11.45 (s, 1H).
20. 3OD) δ: 1.60 (s, 3 H), 1.66 (s, 3H), 1.73 (s, 3H), 1.69-1.77 (m, 2H), 2.00-2.15 (m, 8H), 2.54 (t, J = 8.4 Hz, 2H), 3.66 (s, 3H), 3.96 (d, J = 8.0 Hz, 2H), 5.07-5.10 (m, 1H), 5.25-5.28 (m, 1H), 6.14 (s, 1H), 6.42 (d, J = 14.4 Hz, 1H).
21. 3OD) δ: 0.89 (t, J = 7.2 Hz, 3H), 1.28-1.36 (m, 10H), 1.74-1.82 (m, 4H), 2.07-2.13 (m, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 3.66 (s, 3H), 5.04-5.11 (m, 1H), 6.42 (d, J = 12.8 Hz, 1H), 6.76 (s, 1H).
22. 3OD) δ: 0.90-0.93 (m, 3H), 1.35-1.40 (m, 4H), 1.74-1.82 (m, 4H), 2.07-2.12 (m, 2H), 2.65 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 3.66 (s, 3H), 5.03-5.11 (m, 1H), 6.42 (d, J = 12.8 Hz, 1H), 6.76 (s, 1H).
23. Johnson J.C., Shanoff M., Boezi J.A., and Hansen R.G. Anal. Biochem. 26 (1968) 137 The cited assay was adapted to 96-well plates to obtain reasonable throughput. NADPH formation typically was monitored by fluorescence (excitation wavelength, ∼340 nm; emission wavelength, ∼440 nm) rather than absorbance at 340 nm as in the original assay to improve sensitivity. Although compounds with strong absorbance at 340 nm can in principle influence the assay, we found it to be acceptable for all compounds discussed herein. Inhibitory potencies of selected compounds were also evaluated by effects on incorporation of radiolabeled nucleotide into RNA, and comparable results were obtained.
24. 50 determinations were made.