died before 48 hours that were observed at the precise moment
of death and the sole survivor) were inflamed and stiff. Spleens
were harvested from the 4 water-treated animals and the SCC1-
and all SCC8-treated animals to assay for bacteria as a marker
of dissemination from the lung. All of the animals that received
only nebulized water had bacteria in the spleen (Fig. 5). The only
animal that had bacteria in the spleen among the SCC1- and
SCC8-treated animals was the single SCC8 animal that died. Thus,
the SCC1 and SCC8 animals had a significantly less dissemination
of bacteria from the lungs to the spleen (SCC1 versus water, p =
0.0067; SCC8 versus water, p = 0.0357 by Fisher’s exact test of
the contingency table). Thus, as we have seen in previous studies,
survival appears related to bacteremia, as all of the animals that
died had bacteria recovered from their spleens.13,14 These findings
indicate that treatment with SCC1 and SCC8 can effectively
decrease the likelihood of bacteremia and death in a P. aeruginosa
pneumonia model.
evaporator and the crude material dissolved methanol and◦cooled
1
to give 1 as colorless crystals (7.6 g, 68%). Mp: 201–203 C. H
NMR (500 MHz, DMSO-d6) d 3.39 (s, 3H, CH3), 3.50 (q, 2H,
CH2), 3.87 (s, 3H, CH3), 3.94 (t, 2H, CH2), 4.70 (t, 1H, OH),
1
7.98 (s, 1H, CH). 13C{ H} NMR (125 MHz, DMSO-d6) d 29.3
(CH3), 33.1 (CH3), 42.4 (CH2), 57.7 (CH2), 106.6 (C), 142.8 (CH),
=
=
148.1 (C), 150.9 (C O), 154.4 (C O). Found: C, 48.00; H, 5.33;
N, 24.25. Calc. for C9H12N4O3: C, 48.19; H, 5.40; N, 25.00%.
TOF-MS-EA+: m/z 247 (M+ of C9H12N4O3Na).
1-(2-Hydroxyethyl)-3,7,9-trimethylxanthinium
iodide
(2).
Compound 1 (2.0 g, 8.9 mmol) was added to iodomethane
(30 mL, 92.7 mmol) in a pressure tube and DMF was added
dropwise until the solution appeared clear. The tube was sealed
and heated at 80 ◦C for 2 d with stirring. Volatiles were removed
by rotary evaporator and the resulting solid was washed with
acetone to give 2 as a pale yellow solid (2.4 g, 66%). Mp:
175-176 ◦C. 1H NMR (500 MHz, DMSO-d6) d 3.54 (t, 2H, CH2),
3.73 (s, 3H, CH3), 3.98 (t, 2H, CH2), 4.05 (s, 3H, CH3), 4.15 (s,
1
3H, CH3), 4.47 (bs, 1H, OH), 9.33 (s, 1H, CH). 13C{ H} NMR
(125 MHz, DMSO-d6) d 31.3 (CH3), 35.6 (CH3), 36.9 (CH3),
43.4 (CH2), 57.2 (CH2), 107.7 (C), 139.3 (C), 139.6 (CH) 150.0
=
=
(C O), 153.2 (C O). Found: C, 32.47; H, 4.00; N, 14.53. Calc.
for C10H15N4O3I: C, 32.79; H, 4.13; N, 15.30%. TOF-MS-EA+:
m/z 239 (M+ of C10H15N4O3).
X-Ray crystal structure analysis: formula C10H15IN4O3, Mw
=
˚
366.16, colorless crystal 0.37 ¥ 0.29 ¥ 0.19 mm, a = 15.0967(18) A,
◦
◦
˚
˚
b = 10.4071(13) A, c = 8.708(10) A, a = 90 , b = 104.119(2) ,
◦
g = 90 , V = 1326.8(3) A , Dcalc = 1.833 Mg cm-3, m =
3
˚
Fig. 5 Effects of nebulized SCC1 and SCC8 on the likelihood of bacterial
dissemination to the spleen in a mouse model of Pseudomonas pneumonia.
Bacteremia in all of the mice plotted as number of spleens in each treatment
group (SCC1 vs. water, p = 0.0067; SCC8 vs. water, p = 0.0357).
2.421 mm-1, Z = 4, monoclinic, space group P21/c (No. 14),
˚
l = 0.71073 A, T = 100 K, w and j scans, 10406 reflections
collected, 2684 independent (Rint) 0.0498, 167 refined parameters,
R1/wR2 (I ≥ 2s(I)) = 0.0410/0.1014 and R1/wR2 (all data) =
0.0489/0.1060, maximum (minimum) residual electron density
-3
˚
1.963 (-1.374) e A .
Experimental
1-(2-Hydroxyethyl)-3,7,9-trimethylxanthin-8-ylidene silver ac-
etate (SCC8). Xanthinium salt 2 (1.8 g, 4.9 mmol) was dissolved
in methanol (200 mL) and silver acetate (1.6 g, 9.8 mmol) was
added with stirring. The reaction was stirred 1.5 h during which
time a yellow precipitate of AgI was formed. The reaction mixture
was filtered and the volatiles removed by rotary evaporation. The
resulting solid was washed with acetone a◦nd dried to afford SCC8
as a white solid (1.5 g, 74%). Mp: 212-214 C. 1H NMR (500 MHz,
DMSO-d6) d 1.74 (s, 3H, CH3 of OAc), 3.54 (t, 2H, CH2), 3.75
(s, 3H, CH3), 3.98 (t, 2H, CH2), 4.07 (s, 3H, CH3), 4.20 (s, 3H,
General considerations
2-Iodoethanol, iodomethane, theobromine, and silver acetate
were purchased from Alfa Aesar and used as received. All
solvents were purchased from Fisher Scientific and used without
further purification. All reactions were carried out under aerobic
1
conditions. H and 13C NMR data were obtained on a Varian
500 MHz instrument. The spectra were referenced to deuterated
solvents. Elemental analyses were preformed by the University
of Illinois microanalysis laboratory. Mass spectrometry analyses
were preformed by the Ohio State University mass spectrometry
and proteomics facility. Crystal structure data sets were collected
on a Bruker SMART Apex CCD diffractometer with graphite-
1
CH3). 13C{ H} NMR (125 MHz, DMSO-d6) d 23.4 (CH3 of
OAc), 31.5 (CH3), 37.8 (CH3), 39.1 (CH3), 43.2 (CH2), 57.4 (CH2),
=
=
=
108.9 (C), 140.5 (C), 150.4 (C O), 153.2 (C O), 173.6 (C O of
OAc), 186.5 (C-Ag). Found: C, 35.48; H, 4.14; N, 13.40. Calc. for
C12H17N4O5Ag: C, 35.64; H, 4.24; N, 13.86%. TOF-MS-EA+: m/z
345/347 (M+ of C10H14N4O3Ag).
˚
monochromated Mo Ka radiation (l = 0.71073 A). Unit cell
determination was achieved by using reflections from three
different orientations.
X-Ray crystal structure analysis: formula C12H17AgN4O5, Mw =
˚
1-Hydroxyethyl-3,7-dimethylxanthine
(1). Theobromine
405.17, colorless crystal 0.43 ¥ 0.08 ¥ 0.07 mm, a = 23.896(3) A,
◦
◦
˚
˚
(9.0 g, 50 mmol) and potassium carbonate (7.6 g, 55 mmol)
were dissolved in DMF (150 mL). The solution was brought to
reflux at which time 2-iodoethanol (3.9 mL, 50 mmol) was added.
The solution was stirred for 1 h and an additional equivalent of
2-iodoethanol (3.9 mL, 50 mmol) was added. The reaction was
then stirred at reflux for 17 h. Volatiles were removed by rotary
b = 8.2797(11) A, c = 14.8598(19) A, a = 90 , b = 94.104(2) , g =
◦
90 , V = 2932.5(6) A , Dcalc = 1.835 Mg cm-3, m = 1.405 mm-1,
3
˚
˚
Z = 8, monoclinic, space group C2/c (No. 15), l = 0.71073 A,
T = 100 K, w and j scans, 11365 reflections collected, 2985
independent (Rint) 0.0476, 204 refined parameters, R1/wR2 (I ≥
2s(I)) = 0.0395/0.0931 and R1/wR2 (all data) = 0.0535/0.1001,
This journal is
The Royal Society of Chemistry 2009
Dalton Trans., 2009, 7308–7313 | 7311
©