M. Brakta et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1489–1492
1491
52nd Southeast/56th Southwest Combined Regional ACS
Meeting, New Orleans, LA, Dec 6–8, 2000, No. 523, 276.
2. Montegomery, J. Med. Res. Rev. 1982, 2, 271.
3. Tritsch, D.; Jung, P.; Burger, A.; Biellmann, J. Bioorg.
Med. Chem. Lett. 2000, 10, 139.
4. Haines, D.; Tseng, C.; Marquez, V. J. Med. Chem. 1987,
30, 943.
5. Phadtare, S.; Zemlicka, J. J. Am. Chem. Soc. 1989, 111,
5925.
6. Qiu, Y.; Ksebati, M.; Ptak, R.; Fan, B.; Breitenbach, J.;
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41, 10.
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Court, B. A.; Zemlicka, J. J. Med. Chem. 1991, 34, 421.
8. Xu, Z.; Qiu, Y.; Chokekijchai, S.; Mitsuya, H.; Zemlicka, J.
J. Med. Chem. 1995, 38, 875.
Scheme 3. (i) ADA, 0.05 M Na2HPO4 pH 7.4.
9. Phadtare, S.; Zemlicka, J. Tetrahedron Lett. 1990, 31, 4 3.
10. Phadtare, S.; Zemlicka, J. J. Med. Chem. 1987, 30, 437.
11. (a) Alchemy 2000 3-D-molecular modeling program was
used to measure N9–C50 distances of 5–7. For each structure, we
constructed the 3-D-structure of the molecule, completed mole-
cular mechanics and PM3 single point (stable energy) and geo-
metry optimization energy minimizations, and measured
distances between N9–C50 (A) of the lowest energy conformation.
(b) Lesyng, B.; McCammon, J. Pharmac. Ther. 1995, 60, 149.
12. Zhou, X.; Rajaratnam, R.; Phadtare, S. Pharm. Pharmcol.
Commun. 1998, 4, 237.
15 and 16 (UV max 251 nm) (Scheme 3). The com-
1
pounds were characterized by the UV, H NMR, and
satisfactory elemental analysis.25,26
We also prepared additional analogues of 5 with larger
N9–C50 distance than 20,30-dideoxyadenosine such as
meta-CH2OH (N9–C50 5.75 A) and para-CH2OH (N9–
C50 6.52 A) and conducted ADA experiments under
similar conditions. These m- and p-CH2OH analogues
of 5 (not shown here) were not deaminated up to 7
days.27 Similarly an analogue of 7 with smaller N9–C50
distance than adenosine such as ortho-CH2OH (N9–C50
2.98 A) was also not deaminated by ADA up to 7 days.27
13. Rajaratnam, R.; Phadtare, S. Pharm. Pharmcol. Commun.
1998, 4, 205.
14. 9-[[o-(Chloromethyl)phenyl]methyl]adenine (8). Mp 210 ꢂC;
1H NMR (DMSO-d6, freshly dissolved) d 8.22 (1H, s, H8),
8.15 (1H, s, H2), 7.49 (1H, m, Ar), 7.32 (2H, m, Ar,) 7.27 (2H,
br s, NH2), 7.02 (1H, m, Ar), 5.53 (2H, s, CH2), 5.07 (2H, s,
CH2). Anal. calcd for C13H12ClN5: C 57.04, H 4.41, N 25.58.
Found: C 57.35, H 4.44, N 25.73.
In summary, the appropriate substitution of a hydroxy-
methyl group and adenine base on a benzene ring (o- or
m-) with N9–C50 distance similar to an adenosine seems
to be the most important factor for a substrate binding
to adenosine deaminase. Comparative studies with the
reported unsaturated compounds 1–2, clearly support
the findings that a more stable, p electron rich ‘phenyl’
spacer improved the ADA recognition as compared to
an unsaturated acyclic spacer for the substrate activity.
According to our studies, the substitution of a hydroxy-
methyl function at the appropriate position on the
benzene ring allows compounds 5 and 7 to bind to
ADA, and in that respect these phenylpurines do resemble
to the nucleoside analogues of adenosine. The in vitro
antiviral studies of these compounds are under progress.
We are currently synthesizing other purine and pyrimidine
analogues of 5–7 as potential chemotherapeutic agents.
15. 9-[[o-(Hydroxymethyl)phenyl]methyl]adenine (5). Mp 216 ꢂC;
UV (0.01 M Na2HPO4, pH 7.4) max 261 nm (e 13,900); 1H NMR
(DMSO-d6) d 8.16 (1H, s, H8), 8.14(1H, s, H ), 7.43 (1H, d,
2
Ar), 7.26 (3H, m, NH2+Ar), 7.19 (1H, t, Ar), 6.91 (1H, d,
Ar), 5.43 (2H, s, CH2), 5.33 (1H, t, OH), 4.69 (2H, d, CH2).
Anal. calcd for C13H13N5O: C 61.16, H 5.13, N 27.43. Found:
C 61.35, H 5.14, N 27.17.
16. Katagiri, N.; Ito, Y.; Shiraishi, T.; Maruyama, T.; Sato,
Y.; Chikara, K. Nucleosides Nucleotides 1996, 15, 631.
17. Santana, L.; Teijeira, M.; Uriate, E.; Balzarini, J.; De
Clercq, E. Bioorg. Med. Chem. Lett. 1998, 8, 1349.
18. N6-[o-(Hydroxyethyl)phenyl]-4-chloro-5-amino pyrimidine
(11). Mp 116 ꢂC; 1H NMR (DMSO-d6) d 9.28 (1H, s, NH),
8.17 (1H, s, H2), 7.61 (1H, t, Ar), 7.26 (1H, d, Ar), 7.20 (1H, t,
Ar), 7.09 (1H, t, Ar), 6.88 (2H, s, NH2), 4.53 (1H, t, OH), 3.57
(2H, q, CH2), 2.78 (2H, t, CH2). Anal. calcd for
C12H13ClN4O: C 54.44, H 4.94, N 21.16. Found: C 54.40, H
5.10, N 21.22.
19. N6-[m-(Hydroxymethyl)phenyl]-4-chloro-5-amino pyrimi-
dine (12). Mp 190 ꢂC; 1H NMR (DMSO-d6) d 8.58 (1H, s, H2),
7.85 (1H, d, Ar), 7.63 (2H, m, NH+Ar), 7.24(1H, m, Ar),
6.96 (1H, t, Ar), 5.44 (2H, br s, NH2), 5.40 (1H, t, OH), 4.48
(2H, d, CH2). Anal. calcd for C11H11ClN4O: C 52.70, H 4.42,
N 22.35. Found: C 52.69, H 4.55, N 22.53.
Acknowledgements
The authors wish to thank Dr. Karol Maskos of the
Coordinated Instrumentation Facility, Tulane Uni-
1
versity for the H NMR spectra. The work described
herein was supported in part by grants: DA-07970 from
National Institute of Drug Abuse, AA-09803 from
National Institute of Alcohol Abuse and Alcoholism, and
UR-3-CCU418652 from Centers of Disease Control.
20. 9-[o-(Hydroxyethyl)phenyl]-6-chloropurine (13). Mp 157 ꢂC;
1H NMR (DMSO-d6) d 8.86 (1H, s, H8), 8.77 (1H, s, H2), 7.58
(2H, m, Ar), 7.48 (2H, m, Ar), 4.55 (1H, t, OH), 3.43 (2H, m,
CH2), 2.48 (part of CH2 multiplet is overlapped with DMSO).
Anal. calcd for C13H11ClN4O: C 56.83, H 4.03, N 20.39.
Found: C 57.01, H 4.50, N 20.44.
References and Notes
21. 9-[m-(Hydroxymethyl)phenyl]-6-chloropurine (14). Mp
138 ꢂC; H NMR (DMSO-d6) d 9.08 (1H, s, H8), 8.84(1H, s,
1
H2), 7.83 (1H, s, Ar), 7.74(1H, d, Ar), 7.58 (1H, t, Ar), 7.47
(1H, d, Ar), 5.40 (1H, t, OH), 4.61 (2H, s, CH2). Anal. calcd
1. For preliminary report see: Porter, J.; Brakta, M.; Taylor,
A.; Jones, M.; Fonbah, W.; Phadtare, S. Abstract of Papers,