Communications
Scheme 1. Synthesis of caged imatinib derivatives 2 (R=DMNB) and 3
R=coumarylmethyl). Reagents and conditions: a) DMNB-Br (for 5a), 4-(bro-
momethyl)-7-methoxychromen-2-one (coumarylbromomethyl) (for 5b),
Li CO , DMF; b) 4-[(4-methylpiperazin-1-yl)methyl]benzoyl chloride, pyridine,
8C!RT. Full synthetic details are provided in the Supporting Information.
(
Figure 6. Biological activity of imatinib and caged prodrug 2 in an in vitro
PDGF-Rb assay without and with irradiation at l=365 nm (5.4 W) for 10 min
2
3
(
ÆSD, n=3, see Supporting Information for details).
0
cess. Thus, we will investigate further PPG systems in order to
optimize the uncaging of imatinib. Our study further validates
the powerful caging technique in the kinase field and provides
a valuable pharmacological tool to study the biological effects
of imatinib in novel settings and in greater detail. Finally, our
approach holds great promise for future applications involving
other kinase inhibitors as well.
Experimental Section
All modeling was performed on a DELL 8 core system. For prepara-
tion, visualization, and building the 3D structures, Maestro (ver-
sion 10.0.013, release 2014-4, Schrçdinger LLC, New York, NY, USA)
was used.
Synthesis of N-(4,5-dimethoxy-2-nitrobenzyl)-N-(4-methyl-3-((4-
Figure 5. Time-dependent photoinduced cleavage of caged imatinib pro-
drug 2 upon irradiation with UV light (l=365 nm, 5.4 W). After 5 min irradia-
tion, 70% of 3 was cleaved to produce imatinib.
(pyridine-3-yl)pyrimidine-2-yl)amino)phenyl)-4-((4-methylpipera-
zin-1-yl)methyl)benzamide (2): Compound 5a (330 mg, 700 mmol)
was dissolved in dry pyridine (20 mL). The reaction mixture was
cooled to 08C, and 4-[(4-methylpiperazin-1-yl)methyl]benzoyl chlo-
ride (288 mg, 1.00 mmol) was added in portions under a nitrogen
atmosphere. The solution was stirred for 3 h at room temperature,
cantly less biologically active without UV irradiation (2 PDGF-
Rb IC =5.8 mm). In contrast, testing 2 in the assay irradiated
50
at l=365 nm (5.4 W) for 10 min revealed an inhibition of
PDGF-Rb (IC =0.089 mm) similar to that of native imatinib
and H O (100 mL) was added. The mixture was extracted with
2
EtOAc (3100 mL), and the combined organic layers were dried
over anhydrous Na SO . The solvent was removed under vacuum,
50
(
Figure 6). Notably, the residual biological activity of caged pro-
2
4
and the residue was purified by flash chromatography (SiO2 re-
drug 2 results from minor impurities of uncaged imatinib in
the sample (~1% based on HPLC analysis). Thus, at total com-
pound concentrations >10 mm in the assay, the inhibitory ef-
fects on PDGF-Rb cannot be differentiated. However, their dif-
ference regarding blockage of PDGF-Rb is still significant in the
range of typical in vitro assay concentrations (0.01–1 mm).
In conclusion, we have demonstrated that a caged prodrug
of the kinase inhibitor imatinib could be successfully generated
and characterized. Compound 2 was photoactivated by UV
light at a wavelength of 365 nm within 10 min in an in vitro
PDGF-Rb assay to restore the biological activity of the parent
imatinib. In contrast to imatinib, 1 can be almost quantitatively
uncaged within 3 min. This indicates a significant influence of
the leaving group (active inhibitor) toward the uncaging pro-
versed phase, MeOH/H O) to give compound 2 as a pale-yellow
2
1
solid (40 mg, yield: 8%). H NMR (300 MHz, [D ]DMSO): d=2.09 (s,
6
3
2
H, pip-CH ), 2.14 (s, 3H, CH ), 2.21 (mc, 8H, pip-H-2,3,5,6), 3.33 (s,
3 3
H, pip-CH ), 3.74 (s, 3H, OCH ), 3.82 (s, 3H, OCH ), 5.38 (bs, 2H,
2
3
3
3
4
CH ), 6.79 (dd, 1H, J=8.1 Hz, J=2.1 Hz, ph-H-6), 7.03 (s, 1H, nitro-
benz-H-6), 7.05 (d, 1H, J=8.1 Hz, ph-H-5), 7.13 (d, 2H, J=8.2 Hz,
benz-H-3,5), 7.34 (d, 2H, J=8.2 Hz, benz-H-2,6), 7.44 (d, 1H, J=
2
3
3
3
3
3
3
5
.2 Hz, pyrim-H-5), 7.49 (ddd, 1H, J=8.0 Hz, J=4.0 Hz, pyr-H-5),
4
7
.61 (s, 1H, nitrobenz-H-3), 7.62 (d, 1H, J=2.0 Hz, ph-H-2), 8.36
3
4
3
(
td, 1H, J=8.0 Hz, J=2.0 Hz, pyr-H-4), 8.44 (d, 1H, J=5.1 Hz,
4
pyrim-H-6), 8.69 (d, 1H, J=4.0 Hz, pyr-H-6), 8.80 (s, 1H, pyrim-NH),
4
13
9
.23 ppm (d, 1H, J=1.7 Hz, pyr-H-2);
C NMR (75.5 MHz,
[
D ]DMSO): d=17.5 (q, CH ), 45.6 (q, pip-CH ), 50.6 (t, CH ), 52.3,
6
3
3
2
54.6 (d, pip-C-2,3,5,6), 55.8, 55.9 (q, OCH ), 61.4 (t, pip-CH ), 107.9
3
2
(d, pyrim-C-5), 108.2 (d, nitrobenz-C-3), 110.5 (d, nitrobenz-C-6),
ChemMedChem 2015, 10, 1335 – 1338
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