1616
L. S. Jeong et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1612–1616
12. Yang, H.; Avila, M. Y.; Peterson-Yantorno, K.; Coca-
Prados, M.; Stone, R. A.; Jacobson, K. A.; Civan, M. M.
Curr. Eye Res. 2005, 30, 747.
13. Gao, Z. G.; Kim, S. K.; Biadatti, T.; Chen, W.; Lee, K.;
Barak, D.; Kim, S. G.; Johnson, C. R.; Jacobson, K. A. J.
Med. Chem. 2002, 45, 4471.
14. Gao, Z.-G.; Joshi, B. V.; Klutz, A.; Kim, S.-K.; Lee, H.
W.; Kim, H. O.; Jeong, L. S.; Jacobson, K. A. Bioorg.
Med. Chem. Lett. 2006, 16, 596.
15. Jeong, L. S.; Lee, H. W.; Kim, H. O.; Jung, J. Y.; Gao, Z.-
G.; Duong, H. T.; Rao, S.; Jacobson, K. A.; Shin, D. H.;
Lee, J. A.; Gunaga, P.; Lee, S. K.; Jin, D. Z.; Chun, M. W.
Bioorg. Med. Chem. 2006, 14, 4718.
16. General procedure for the synthesis of 6a–r: To a stirred
solution of per mmol of 40-hydroxymethyl analogues
(11a–j) in dry DMF (10 mL) was added pyridinium
dichromate (10.0 equiv), and the reaction mixture was
stirred at rt for 20 h. After being poured into water
(50 mL/mmol), the reaction mixture was stirred at rt for
1 h. The precipitate was filtered, and the filter cake was
washed with excess water and dried under high vacuum to
give brownish solid, which was used in the next step
without further purification. To a solution of per mmol of
acid derivatives (12a–j), EDC (1.5 equiv), HOBt (1.5
equiv), and appropriate amine (1.5 equiv) in CH2Cl2
(20 mL) was added DIPEA (3.0 equiv), and the mixture
was stirred at rt for 12 h. The reaction mixture was
evaporated, and the residue was purified by a silica gel
column chromatography (hexane/EtOAc = 10:1–5:1) to
give silyl amides as a white foam. To a stirred solution
of per mmol of silyl amides in THF (5 mL) was added
TBAF (2.5 equiv) and the reaction mixture was stirred at
rt for 1 h. The solvent was evaporated and the resulting
residue was purified by silica gel column chromatography
(CH2Cl2/EtOAc/MeOH = 20:20:1) to give 6a–r.
Compound 6c: yield 67%; white solid; mp 180.4–182.0 °C;
20
½aꢁD ꢀ 16:5 (c 0.10, MeOH); UV (MeOH) kmax 274 nm
1
(pH 7); H NMR (CD3OD) d 2.94 (s, 3 H, N–CH3), 3.03
(s, 3 H, N–CH3), 4.41 (d, 1H, J = 4.6 Hz, 40-H), 4.57 (br
dd, 1H, J = 4.6, 8.4 Hz, 30-H), 4.64 (m, 1H, 20-H), 4.73 (d,
2H, J = 5.7 Hz, N–CH2), 5.96 (d, 1H, J = 5.4 Hz, 10-H),
7.22–7.56 (m, 4H, aromatic H), 8.52 (s, 1H, H-8); 13C
NMR (CD3OD) d 36.6, 38.2, 44.6, 54.3, 64.6, 77.2, 80.7,
127.4, 128.8, 130.0, 131.1, 134.9, 141.4, 142.8, 143.1, 151.7,
155.8, 156.4, 172.8; FAB-MS m/z 528 (M++H); Anal.
(C19H20BrClN6O3S) C, H, N, S.
17. (a) Gao, Z.-G.; Blaustein, J. B.; Gross, A. S.; Melman, N.;
Jacobson, K. A. Biochem. Pharmacol. 2003, 65, 1675; (b)
Gao, Z.-G.; Jeong, L. S.; Moon, H. R.; Kim, H. O.; Choi,
W. J.; Shin, D. H.; Elhalem, E.; Comin, M. J.; Melman,
N.; Mamedova, L.; Gross, A. S.; Rodriguez, J. B.;
Jacobson, K. A. Biochem. Pharmacol. 2004, 67, 893.
18. van Tilburg, E. W.; von Frijtag Drabbe Kunzel, J.; de
¨
Groote, M.; IJzerman, A. P. J. Med. Chem. 2002, 45, 420.
19. Kim, S. K.; Jacobson, K. A. J. Chem. Inf. Model 2007, 47,
1225.