D. Liu et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3147–3150
3149
Scheme 4. Reagents and conditions: 60 equiv CH3I or C2H5I, 48 h, 70 ꢁC, 95%.
D.; Ulbrich, K.; Seymour, L. W. J. Gene Med. 2002, 4,
536–547.
cooling to 0 ꢁC, the reaction vessel was opened, and the
excess halogenated hydrocarbons was allowed to evapo-
rate and then evaporated under reduced pressure. The
crude residue was recrystallized from acetonitrile to
afford 1 (Scheme 4).14
4. (a) Hood, J. D.; Bednarski, M.; Frausto, R.; Guccione, S.;
Reisfeld, R. A.; Xiang, R.; Cheresh, D. A. Science 2002,
296, 2404–2407; (b) Cavazzana-Calvo, M.; Thrasher, A.;
Mavilio, F. Nature 2004, 427, 779–781.
5. Kokotos, G.; Verger, R.; Chiou, A. Chem. Eur. J. 2000, 6,
4211–4217.
6. Boomer, J. A.; Thompson, D. H. Chem. Phys. Lipids 1999,
99, 145–453.
7. Boomer, J. A.; Thompson, D. H.; Sullivan, S. M. Pharm.
Res. 2002, 19, 1292–1301.
In summary, we have described the synthesis of series of
carbamate-linked lipids 1a–d and 2a,b with the struc-
tural feature of having variable length of carbon chains
and quaternary ammonium or neutral tertiary amine
heads as well as iodide ions combined with them. Appli-
cation of these carbamate-linked lipids as DNA carriers
to deliver gene into cells in vitro and in vivo is now in
progress.
8. Bangham, A. D.; Standish, M. M.; Watkins, J. C. J. Mol.
Biol. 1965, 13, 238–253.
9. Alquist, F. N.; Slagh, H. R. US Pat. 2147226,
1939.
10. For the purpose of increase of yield at atmosphere
pressure, we carried out a L4,3 orthogonal test; Liu, D.
L.; Hu, J. J.; Qiao, W. H.; Li, Z. S.; Cheng, L. B.; Zhang,
S. B., in preparation.
References and notes
ˇ
1. Felgner, P. L.; Gadek, T. R.; Holm, M.; Roman, R.;
Chan, H. W.; Wenz, M.; Northrop, J. P.; Ringold, G. M.;
Danielsen, M. Proc. Natl. Acad. Sci. U.S.A. 1987, 84,
7413–7417.
11. (a) Cotarca, L.; Delogu, P.; Nardelli, A.; Sunjic´, V.
Synthesis 1996, 5, 553–576; (b) Wang, X. Z.; Li, X. Q.;
Shao, X. B.; Zhao, X.; Deng, P.; Jiang, X. K.; Li, Z. T.;
Chen, Y. Q. Chem. Eur. J. 2003, 9, 2904–2913.
2. For review of cationic lipid synthesis, see: (a) Miller, A. D.
Angew. Chem., Int. Ed. 1998, 37, 1768–1785, and a recent
review of ours; (b) Zhang, S. B.; Xu, Y. M.; Wang, B.;
Qiao, W. H.; Liu, D. L.; Li, Z. S. J. Controlled Release
2004, 100, 165–180.
12. Moniruzzaman, M.; Goodbrand, B.; Sundararajan, P. R.
J. Phys. Chem. B 2003, 107, 8416–8423.
13. Compound 2a: 1H NMR (400 M, CDCl3) d [5.82, 5.17,
5.07 (OCH, 2 · NH)], [4.29 (d, J = 11.2, 1H), 4.22 (d,
J = 11.2, 1H), OCH2], [3.24, 3.13, 2.94, (2 · NHCH2,
NCH2)], 2.72 (s, 6H, N(CH3)2), 1.48 (m, 4H, 2 ·
NHCH2CH2), 1.23 (s, 36H, 2 · (CH2)9), 0.86 (t, J = 5.6,
6.8, 6H, 2 · CH3); 13C NMR (400 M, CDCl3) d 155.98
(C@O), 67.22 (OCH), 63.92 (OCH2), 58.03 (NCH2), 44.23
(NHCH2), 41.44 (N(CH3)2), 32.11–17.70 ((CH2)10), 14.32
(CH3); MS m/z 542 [M+H]+. Compound 2b:1 H NMR
(400 M, CDCl3) d [5.10, 4.87 (OCH, 2 · NH)], 3.83 (d,
J = 9.6, 2H, OCH2), [3.15, 2.84, 2.76 (2 · NHCH2,
NCH2)], 2.45 (s, 6H, N(CH3)2), 1.49 (m, 4H, 2 · NHCH2-
CH2), 1.25 (s, 60H, 2 · (CH2)15), 0.86 (t, J = 4.6, 6.4, 6H,
2 · CH3); 13C NMR (400 M, CDCl3) d 155.98 (C@O),
70.73 (OCH), 64.86 (OCH2), 60.74 (NCH2), 45.96
(NHCH2), 41.34 (N(CH3)2), 32.12–22.89 ((CH2)16), 14.33
(CH3); MS m/z 710 [M+H]+.
3. (a) Leventis, R.; Silvius, J. R. Biochim. Biophys. Acta 1990,
1023, 124–132; (b) Bennett, M. J.; Malone, R. W.; Nantz,
M. H. Tetrahedron Lett. 1995, 36, 2207–2210; (c) Kikuchi,
I. S.; Carmona-Ribeiro, A. M. J. Phys. Chem. B 2000, 104,
2829–2835; (d) Kim, A.; Lee, E. H.; Choi, S. H.; Kim, C.
K. Biomaterials 2004, 25, 305–313; (e) Gao, X.; Huang, L.
Biochem. Biophys. Res. Commun. 1991, 179, 280–285; (f)
Bottega, R.; Epand, R. M. Biochemistry 1992, 31, 9025–
9030; (g) Walker, S.; Sofia, M. J.; Kakarla, R.; Kogan, N.
A.; Wierichs, L.; Longley, C. B.; Bruker, K.; Axelrod, H.
R.; Midha, S.; Babu, S.; Kahne, D. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 1585–1590; (h) Smith, A. E. Annu. Rev.
Microbiol. 1995, 4, 807–838; (i) Smith, L. C.; Duguid, J.;
Wadhwa, M. S.; Logan, M. J.; Tung, C. H.; Edwards, V.;
Sparrow, J. T. Adv. Drug Delivery Rev. 1998, 30, 115–131;
(j) Rittner, K.; Benavente, A.; Bompard-Sorlet, A.; Heitz,
F.; Divita, G.; Brasseur, R.; Jacobs, E. Mol. Ther. 2002, 5,
104–114; (k) El-Aneed, A. J. Controlled Release 2004, 94,
1–14; (l) Boussif, O.; LezoualcÕh, F.; Zanta, M. A.;
Mergny, M. D.; Scherman, D.; Demeneix, B.; Behr, J. P.
Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7297–7301; (m)
Lampel, P.; Eloma, M.; Ruponen, M.; Urtti, A.; Ma¨n-
nisto¨, P. T.; Raasmaja, A. J. Controlled Release 2003, 88,
173–183; (n) Wu, G. Y.; Wu, C. H. J. Biol. Chem. 1987,
262, 4429–4432; (o) Ward, C. M.; Pechar, M.; Oupicky,
14. Compound 1a: 1H NMR (400 M, CDCl3) d [5.98, 5.47,
5.39 (OCH, 2 · NH)], 4.30–4.17 (OCH2, NCH2), 3.50 (s,
9H, N(CH3)3), 3.15 (d, J = 6.8, 4H, 2 · NHCH2), 1.51 (d,
J = 6.4, 4H, 2 · NHCH2CH2), 1.26 (s, 36H, 2 · (CH2)9),
0.88 (t, J = 6.4, 6.4, 6H, 2 · CH3); 13C NMR (400 M,
CDCl3) d 155.78 (C@O), 66.76 (OCH), [63.27, 61.28
(OCH2, NCH2)], 55.08 (N(CH3)3), [41.58, 41.38
(2 · NHCH2)], 32.09–22.86 ((CH2)10), 14.30 (CH3); MS
m/z 556 [MÀI]+, 127 [I]À. Compound 1b: 1H NMR
(400 M, CDCl3) d [5.86, 5.48, 5.32 (OCH, 2 · NH)], [4.24,
3.79 (OCH2, NCH2)], 3.46 (s, 9H, N(CH3)3), 3.15 (d,