5176
T. K. Venkatachalam et al. / Bioorg. Med. Chem. 14 (2006) 5161–5177
5
.5. Estimation of products
2. Deeks, S. G.; Volberding, P. A. AIDS Clin. Rev 1997–
998, 145.
. Grob, P. M.; Wu, J. C.; Cohen, K. A.; Ingraham, R. H.;
1
3
The amount of products observed during the reaction of
these phosphoramidates was estimated from the area
obtained from the HPLC profiles. Authentic samples
of the products when possible were run to identify the
peaks observed during the reaction. Additionally confir-
mation of the product structures in the past was ob-
tained using an LC/MS instrument. The rate of
reaction was computed by using first order rate con-
stants and an average of eight to nine time points were
used for this estimate. The rate constants reported refer
to rate/h as some of the reactions were too slow to ob-
tain meaningful results.
Shih, C. K.; Hargrave, K. D.; Mctague, T. L.; Merluzzi,
V. J. AIDS Res. Hum. Retrovirus 1992, 8, 145.
4
. Bell, F. W.; Cantrell, A. S.; Hogberg, M.; Jaskunas, S. R.;
Johansson, N. G.; Jordan, C. L.; Kinnick, M. D.; Lind, P.;
Morin, J. M., Jr.; Noreen, R.; Oberg, B.; Palkowitz, J. A.;
Parrish, C. A.; Pranc, P.; Sahlberg, C.; Ternansky, R. T.;
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X. J. Med. Chem. 1995, 38, 4929.
5. Cantrell, A. S.; Engelhardt, P.; Hogberg, M.; Jaskunas, S.
R.; Johansson, N. G.; Jordan, C. L.; Kangasmetsa, J.;
Kinnick, M. D.; Lind, P.; Morin, J. M., Jr.; Muesing, M.
A.; Noreen, R.; Oberg, B.; Pranc, P.; Sahlberg, C.;
Ternansky, R. J.; Vasileff, R. T.; Vrang, L.; West, S. J.;
Zhang, H. J. Med. Chem. 1996, 39, 4261.
5
.6. Statistical analysis
6
. Vig, R.; Venkatachalam, T. K.; Uckun, F. M. Antiviral
Chem. Chemother. 1998, 9, 445.
Hydrolysis rates were determined by fitting single expo-
nential decay equations to the disappearance of each
isomer substrate in the presence of enzyme. For simplic-
ity the reaction was considered to be first order. An
average of two to three runs were done for each of the
enzymes and the standard deviation calculated.
7
. Mao, C.; Vig, R.; Venkatachalam, T. K.; Sudbeck, E.
A.; Uckun, F. M. Bioorg. Med. Chem. Lett. 1998, 8,
2213.
8. Furman, P. A.; Fyfe, J. A.; Clair, M. H. St.; Weinhold, K.;
Rideout, J. L.; Freeman, G. A.; Nusinoff, L. S.; Bolognesi,
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Acad. Sci. U.S.A. 1986, 83, 8333.
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. Hao, Z.; Cooney, D. A.; Hartman, N. R.; Perno, C.
F.; Fridland, A.; De Vico, A. L.; Sarngadharan, M. G.;
Border, S.; Johns, D. G. Mol. Pharmacol. 1988, 34,
5
5
.7. Physical constants of compounds
0
.7.1. Stavudine-5 -a-naphthyl methoxy L-alaninyl phos-
4
31.
1
phate (2). H NMR (300 MHz, CDCl ) d 1.34 (m, 3H,
ala Me), 1.78 (m, 3H, 5-Me), 3.64 (m, 3H, OMe), 4.0–
3
10. Balzarini, J.; Cooney, D. A.; Dalal, M.; Kang, G. J.;
Cupp, J. E.; De Clercq, E.; Broder, S.; Johns, D. G. Mol.
Pharmacol. 1987, 32, 798.
11. McGuigan, C.; Cahard, D.; Sheeka, H. M.; De Clercq, E.;
Balzarini, J. J. Med. Chem. 1996, 39, 1748.
2. McGuigan, C.; Cahard, D.; Sheeka, H. M.; De Clercq, E.;
Balzarini, J. Bioorg. Med. Chem. Lett. 1996, 6, 1183.
13. Starnes, M. G.; Cheng, Y. C. J. Biol. Chem. 1987, 262, 988.
4. Hao, Z.; Cooney, D. A.; Farquhar, D.; Perno, C. F.;
Zhang, K.; Masood, R.; Wilson, Y.; Hartman, N. R.;
Balzarini, J.; Johns, D. G. Mol. Pharmacol. 1990, 37,
4
5
6
7
7
8
.08 (m, 2H, Ala NH, AlaCH), 4.31–4.43 (m, 2H, H-
0
0
0
0
), 5.00–5.05 (m, 1H, H-4 ), 5.89–5.92 (m, 1H, H-3 ),
0
.26–6.36 (m, 1H, H-2 ), 7.00–7.02 (m, 1H, H-1 ),
.24–7.27 (m, 3H, H-6, Ar), 7.47–7.54 (m, 2H, Ar),
.65–7.67 (m, 1H, Ar), 7.83–7.84 (m, 1H, Ar), 8.01–
1
1
3
.07 (m, 1H, Ar), 8.41 (br s, 1H, NH); C NMR
75 MHz, CDCl ) d 12.1, 12.3, 20.8, 21.0, 21.1, 50.2,
1
(
3
5
1
1
1
0.8, 52.5, 52.6, 66.8, 67.4, 84.6, 84.7, 89.7, 89.9, 111.4,
15.0, 115.1, 121.1, 121.2, 125.1, 125.2, 125.4, 125.5,
26.5, 126.8, 127.3, 127.4, 127.9, 133.1, 133.4, 134.8,
1
57.
15. Johnson, M. A.; Ahluwalia, G.; Connelly, M. C.; Cooney,
D. A.; Broder, S.; Johns, D. G.; Fridland, A. J. Biol.
Chem. 1988, 263, 15354.
6. Johnson,M.A.;Fridland,A. Mol. Pharmacol.1989,36,291.
7. McGuigan, C.; Pathirana, R. N.; Balzarini, J.; De Clercq,
E. J. Med. Chem. 1993, 36, 1048.
18. McGuigan, C.; Pathirana, R. N.; Mahmood, N.; Devine,
K. G.; Hay, A. J. Antiviral Res. 1992, 17, 311.
9. Vig, R.; Mao, C.; Venkatachalam, T. K.; Tuel-Ahlgren,
L.; Sudbeck, E. A.; Uckun, F. M. Bioorg. Med. Chem.
3
1
35.5, 135.7, 150.7, 163.4, 174.0; P NMR (121 MHz,
CDCl ) d 2.94, 3.40; UV (MeOH) kmax: 266 nm. HPLC:
7
3
1
1
.10, 7.80 min. % purity: 98.0.
0
5
.7.2. Stavudine-5 -b-naphthyl methoxy L-alaninyl phos-
1
phate (3). H NMR (300 MHz, CDCl ) d 1.38 (m, 3H,
ala Me), 1.88 (m, 3H, 5-Me), 3.68 (m, 3H, OMe), 4.0–
3
1
4
5
3
7
7
.05 (m, 2H, Ala NH,AlaCH), 4,30–4.39 (m, 2H, H-
0
0
0
), 5.02–5.05 (m, 1H, H-4 ), 5.84–5.92 (m, 1H, H-
0
1
998, 1789.
0
), 6.30–6.37 (m, 1H, H-2 ), 7.0–7.02 (m, 1H, H-1 ),
20. Venkatachalam, T. K.; Tai, T. L.; Vig, R.; Chen, C. L.;
Jan, S. T.; Uckun, F. M. Bioorg. Med. Chem. Lett.
1998, 8, 3121.
.26–7.31 (m, 3H, H-6, Ar), 7.47–7.50 (m, 2H, Ar),
.76–7.83 (m, 3H, Ar), 8.21 (br s, 1H, NH);
1
3
C
2
1. Uckun, F. M.; Samuel, P.; Qazi, S.; Chen, C. L.;
Pendergrass, S.; Venkatachalam, T. K. Antiviral Chem.
Chemother. 2002, 13, 197.
NMR (75 MHz, CDCl ) d 12.34, 12.36, 21.04, 21.10,
3
5
0.1, 50.2, 52.6, 66.6, 67.15, 84.5–84.7, 89.8, 89.6,
11.4, 116.5, 116.6, 116.8, 119.9, 150.6, 163.3, 174.1;
1
3
1
22. Siccardi, D.; Gumbleton, M.; Omidi, Y.; McGuican, C.
Eur. J. Pharm. Sci. 2004, 22, 25.
2
P NMR (121 MHz, CDCl ) d 2.66, 3.21; UV
3
(
MeOH) kmax: 266 nm; HPLC: 8.75, 9.4 min. % purity:
3. Congiatu, C.; McGuican, C.; Jiang, W. G.; Davies, G.;
Mason, M. D. Nucleosides Nucleotides Nucleic acids 2005,
9
8.0.
2
4, 485.
2
2
4. Congiatu, C.; Brancale, A.; Mason, M. D.; Jiang, W. G.;
McGuican, C. J. Med.Chem. 2006, 49, 452.
5. Venkatachalam, T. K.; Samuel, P.; Li, G.; Qazi, S.; Mao,
C.; Pendergrass, S.; Uckun, F. M. Bioorg. Med.Chem.
2004, 12, 3371.
References and notes
1
. Goldschmidt, R. H.; Dong, B. J. J. Am. Board of Fam.
Pract. 1997, 10, 144–167.