THE SYNTHESIS OF
ω
ꢀ(2ꢀARYLꢀ1,3ꢀDIOXOLANꢀ2ꢀYL)ALKYL PURINE DERIVATIVES
45
13C NMR (DMSOꢀ
d6): 24.20 (C2'); 36.93 (C3'); 44.33 the buffer for assaying HIVꢀ1 RT activity (50 mM Trisꢀ
HCl, pH 8.0, 10 mM MgCl2, and 200 mM KCl). For
testing inhibitory properties the compounds were
added into the reaction mixture as solutions in DMSO
up to a final concentration of 10%; the control reacꢀ
tions were performed with the addition of the same
volume of DMSO. The reaction was initiated by the
(C1'); 64.59 (2 C,
OCH2CH2O); 109.87 (OCO);
[125.61 (2 C, C3 and C5); 128.23 (C4); 128.37 (2 C,
C2 and C6); 141.91 (C1)] (Ph); 131.73 (C5); 145.35
(C8); 151.04 (C6); 151.94 (C2, C4); 155.95 (C6).
6ꢀMethylaminoꢀ9ꢀ[3ꢀ(2ꢀphenylꢀ1,3ꢀdioxolanꢀ2ꢀ
yl)propyl]purine (IIIp) was obtained by keeping a mixꢀ
addition of HIV RT and incubated for 20 min at 37°C.
ture of 6ꢀchloro derivative (IIIo) (30 mg, 0.09 mmol), The aliquots were loaded onto Whatman 3MM filters
(1 1 cm) impregnated with 0.5 M EDTA (1 L). The
×
μ
NH3CH3 HCl (90 mg, 1.33 mmol), and DBU (0.2 mL,
⋅
filters were washed from the labeled nucleotide not
incorporated into the DNA with 10% trichloroacetic
acid (5 25 mL) for 5 min each, then ethanol (25 mL),
1.33 mmol) in methanol (1.5 mL) for 14 h. The solvent
was evaporated and the residue was suspended in a
minimal volume of methylene chloride and chroꢀ
×
and dried in air. The radioactivity absorbed on the filꢀ
ters was measured using the Cherenkov method on an
Intertechnique Liquid Scintillation Counter SLꢀ4000.
Inhibition constants were calculated by the Dixon
procedure [13].
matographed on a silica gel column (
eluting in a gradient of ethanol in chloroform
20%. The target fractions were evaporated and the resꢀ
idue was recrystallized from an ethyl acetate–octane
5
×
2 cm, ~10 g)
0
→
mixture to give 96% of the target compound;
(B); oil. Mass: 340.2 [
+ H+]. Calc. 339.4
C18H21N5O2). 1H NMR:1.90 (4 H, m, H2', H3'); 3.18
(3 H, br s, 6ꢀNHCH3); [3.73; 3.98] (2 H , m 2,
OC 2C 2O); 4.17 (2 H, t, 6.7, H1'); 6.53 (1 H, br s,
6ꢀN CH3); 7.25–7.40 (5 H, m, Ph); 7.70 (s, 1 H,
H8); 8.36 (s, 1 H, H2). C NMR (CDCl3): 24.31
(C2'); 29.84 (6ꢀNH H3); 36.95 (C3'); 43.60 (C1');
64.47 (2 C, O H2 H2O); 109.86(O O); 119.45 (C5);
Rf 0.65
m/z
M
(
REFERENCES
×
2
×
1. Ludovici, D.W.L., Kukla, M.J., Grous, P.G., Krishꢀ
nan, S., Andries, K., de Buthune, M.P., Azijn, H., Pauꢀ
wels, R., de Clercq, E., Arnold, E., and Janssen, P.A.,
Bioorg. Med. Chem. Let., 2001, vol. 11, pp. 2225–2228.
H
H
J
H
13
C
2. Das, K.L., Lewi, P.J., Hughes, S.H., and Arnold, E.,
C
C
C
Prog. Biophys. Mol. Biol., 2005, vol. 88, pp. 209–231.
[125.54 (2 C, C3 and C5); 128.01 (C4); 128.19 (2 C,
C2 and C6); 142.01 (C1)] (Ph); 139.45 (C8); 151.02
(C4); 153.13 (C2); 155.35 (C6).
3. Paramonova, M.P., Babkov, D.A., ValuevꢀElliston, V.T.,
Ivanov, A.V., Kochetkov, S.N., Pannekuk, K., Ozerov, A.A.,
Bal’zarini, Ya., and Novikov, M.S., Khim.ꢀFarm. Zh.
2013, vol. 47, pp. 7–11.
,
6ꢀDimethylaminoꢀ9ꢀ[3ꢀ(2ꢀphenylꢀ1,3ꢀdioxolanꢀ2ꢀ
yl)propyl]purine (IIIq) was obtained by keeping a mixꢀ
ture of 6ꢀchloro derivative (IIIo) (30 mg, 0.09 mmol),
4. Komissarov, V.V., Knyazhanskaya, E.S., Atrohova, A.V.,
Gottikh, M.B., and Kritzyn, A.M., Russ. J. Bioorg.
Chem., 2014, vol. 40, pp. 532–540.
NH2(CH3)2 HCl (110 mg, 1.35 mmol), and DBU
⋅
(0.2 mL, 1.33 mmol) in methanol (1.5 mL) for 14 h.
The solvent was evaporated and the residue was susꢀ
pended in a minimal volume of methylene chloride and
5. Komissarov, V.V. and Kritzyn, A.M., Russ. J. Bioorg.
Chem., 2005, vol. 31, pp. 549–555.
6. Nesmeyanov, A.N. and Zakharkin, L.I., Izv. Akad.
Nauk SSSR, Otd. Khim. Nauk, 1955, pp. 224–238.
chromatographed on a silica gel column (
eluting in a gradient of ethanol in chloroform
20%. The target fractions were evaporated and
the residue was recrystallized from an ethyl acetate–
octane mixture to give 83%, f 0.81 (B), oil. Mass:
353.2 [
+ H+]. Calc. 339.4 (C19H23N5O2). 1H NMR:
1.91 (4 H, m, H2', H3'); 3.50 (6 H, br s, 6ꢀN(CH3 2);
[3.73; 3.97] (2 H , m 2, OC 2C 2O); 4.15 (2 H,
t, 6.8, H1'); 7.23–7.41 (5 H, m, Ph); 7.67 (s, 1 H,
H8); 8.30 (s, 1 H, H2). C NMR (CDCl3): 24.28
(C2'); 37.02 (C3'); 38.45 (N( H3)2); 43.36 (C1');
64.47 (2 C, H2 H2O); 109.91( ); 120.15 (C5);
5
×
2 cm, ~10 g)
7. Tietze, L.F. and Eicher, T., Reaktionen und Synthesen
im organischeꢀchemischen Praktikum und Forsꢀ
chungslaboratorium, New York: Georg Thieme Verlag
Stutgart, 1991.
0
→
R
m/z
M
8. Dudding, L.R., Nkabinde, N.C., and Mizrahi, V., Bioꢀ
chemistry, 1991, vol. 30, pp. 10498–10506.
)
×
2
×
H H
9. de Bnthune, M.P., Antiviral Res., 2010, vol. 85, pp. 75–90.
J
13
10. Baril, E., Mitchener, J., Lee, L., and Baril, B., Nucleic
Acids Res., 1977, vol. 4, pp. 2641–2654.
C
OC
C
OCO
11. Novikov, M.S., Ivanova, O.N., Ivanov, A.V., Ozerov, A.A.,
ValuevꢀElliston, V.T., Temburnikar, K., Gurskaya, G.V.,
Kochetkov, S.N., Pannecouque, C., Balzarini, J., and
SeleyꢀRadtke, K.L., Bioorg. Med. Chem., 2011, vol. 19,
pp. 5794– 5802.
[125.56 (2 C, Cꢀ3 and Cꢀ5); 127.97 (Cꢀ4); 128.16
(2 C, Cꢀ2 and Cꢀ6); 142.08 (Cꢀ1)] (Ph); 138.25 (C8);
150.51 (C4); 152.28 (C2); 154.95 (C6).
Evaluation of HIVꢀ1 RT activity in the system of
12. Le Grice, S.F. and GrüningerꢀLeitch, F., Eur. J. Bioꢀ
chem., 1990, vol. 187, p. 307.
activated DNA. A standard reaction mixture (20
contained 150 g/mL activated DNA, HIVꢀ1 RT
(0.05 g), 1.5 M ATP, other nucleoside 5'ꢀtriphosꢀ
phates (30 M of each), 0.02 MBq
ꢀ32P]dATP, and
μ
L)
μ
13. Dixon, M., Biochem. J., 1953, vol. 55, pp. 170–171.
μ
μ
μ
[
α
Translated by E. Shirokova
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41
No. 1
2015