S. S. Stokes et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4556–4560
4559
Table 3
NH2
Physical properties including log D, solubility, and free fraction for selected com-
N
N
pounds (see Tables 1 and 2 for chemical structures).8
O
a
N
4, 5 or 6
O
+
Compds
log D
Solubility,
lM
hPPBb, % free
Cl
N
O
O
4
5
8
9
14
15
17
18
0.79
1.5
>1000
>1000
934
801
304
NTa
66
O
NTa
27
X
Y
2.35
1.78
3.18
2.65
>3.5
3.7
Cl
25
NTa
19
Y = H, X = OAc; 22
Y = H; X = OH 14
Y = F: X = OAc; 23
Y = OH; X = OAc 24
Y = OH; X = OH16
b
b
<1
21
NTa
4
a
NH2
NT = not tested.
Protein binding in human plasma.
b
N
N
N
c
d
23
15
N
O
NH2
NH2
O
N
N
F
N
N
O
a, b
c or d
25
N
N
N
N
Cl
Cl
O
O
NH2
OH
O
HO
TsO
N
OH
O
N
e
f
19
N
5
17
N
O
O
NH2
NH2
O
N
N
N
N
N
O
Cl
Cl
e, f
N
N
N
Cl
OR
26
O
O
O
OH
X
X
Scheme 2. Syntheses of ribose-modified 2-cyclopentoxyadenosines 14–17.
Reagents and conditions: (a) CH3CN/ H2O, 0 °C (not isolated); (b) 3.5 N NH3 in
MeOH, 0 °C (32%, 2 steps); (c) K2CO3, MeOH (not isolated); (d) NaN3, NH4Cl, DMF
(10%, 2 steps); (e) 3,4-dichlorobenzaldehyde, ZnCl2, 80 °C (45%); (f) LiAlH4, AlCl3,
Et2O/CH2Cl2 (11%).
O
OH
4-13
X = H: 20
X = F: 21
Scheme 1. Synthesis of 2-alkoxy-50-deoxyadenosines 4–13. Reagents and condi-
tions: (a) 2,2-dimethoxypropane, pTsOH, acetone, 45 °C (85%); (b) TsCl, pyridine,
ꢀ10 °C (85%); (c) LiEt3BH, THF (74%); (d) TBAF, CH2Cl2; (e) ROH, NaOH, THF, 75 °C
(10–85%); (f) AcOH or HCO2H, H2O, 85 °C (80–90%).
at AstraZeneca Boston for physical properties determinations. The
authors also thank Haris Jahic for compound purification support
and Haihong Ni for computational chemistry support.v
positive pathogens S. pneumoniae and S. aureus. Potent enzyme
inhibition against the intracellular target, NAD+-dependent DNA li-
gase, and moderate antibacterial activity against the Gram-positive
pathogens, S. pneumoniae and S. aureus, were achieved by modifi-
cation of the 2-cycloalkoxy substituent on the adenine ring and
the 30- and 50-substituents on the ribose. By combining 2-spirocycl-
opentylmethoxy and 30-b-chloro substituents, potent antibacterial
activity was achieved for 18. However, favorable physical proper-
ties (solubility and plasma protein binding) were only achieved
in active compounds when the log D values were maintained be-
tween 1.5 and 2.5, which dictated that 30-substituents other than
hydroxyl were unfavorable. The next generation of LigA adenosine
inhibitors were found to balance lipophilicity and potency such
that highly active compounds also exhibited excellent solubility
and high free fraction. These results will be reported in due course.
References and notes
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determined by a miniaturized shake-flask octanol:water assay using HPLC-UV
Acknowledgments
The authors thank the follow groups: the Biosciences Depart-
ment at AstraZeneca Boston, especially Irene Karantzeni, for deter-
mination of IC50 & MIC values; Discovery Enabling Capabilities &
Sciences of AstraZeneca Alderley Park and the Structural Biology
Department of AstraZeneca Boston for solving enzyme-inhibitor
X-ray structures; the Drug Metabolism
& Pharmacokinetics
Department at AstraZeneca Alderley Park for Caco-2 measure-
ments; and the Drug Metabolism & Pharmacokinetics Department