´
J. Klimentova et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1981–1984
1984
´
ˇ
13. Hrabalek, A.; Dolezal, P.; Farsa, O.; Krebs,A.; Roman,
that of control (ER < 1 in all three vehicles). However,
the mechanism of its retarding activity is not known
and the effect should be evaluated for a wider spectrum
of permeants.
ˇ
M.; Sklubalova, Z. U.S. Patent 6,187,938, 2001.
´
14. Zbytovska, J.; Raudenkolb, S.; Wartewig, S.; Hubner, W.;
´
¨
´
ˇ
Rettig, W.; Pissis, P.; Hrabalek, A.; Dolezal, P.; Neubert,
R. H. H. Chem. Phys. Lipids 2004, 129, 97.
15. Mizushima, H.; Takahashi, M.; Yamamuro, A.; Matsuo,
T.; Yahagi, K. U.S. Patent 5,599,483, 1997.
In conclusion, this study showed that the permeation-en-
hancing activity of T12 is connected with the ammoni-
um-carbamate polar head; the most similar carbonates
19 and 20 and carbamates 25 and 26 did not reach its
activity. The results suggest that the exceptional activity
of T12 is connected with the lability of its polar head and
very probably arises from its ability to release CO2 in SC.
Further studies are to be done to describe the detailed
interaction of T12 with SC lipids.
16. General procedure for the preparation of the hydroxy-
amides 1–4: To a mixture of lactone (17.5 mmol) and
n-alkyl amine (19.3 mmol), 1 M methanolic solution of
MeONa (0.1–0.2 mL) was added. The mixture was heated
to 120 ꢁC for 1–2 h. After cooling to room temperature,
the products were purified by precipitating the methanolic
or ethanolic solution with 10% HCl.
17. Barry, J.; Bram, G.; Decodts, G.; Loupy, A.; Pigeon, P.;
Sansoulet, J. Tetrahedron Lett. 1982, 23, 5407.
18. General procedure for the preparation of the hydroxy-
esters
5
and 6: sodium salt of x-hydroxyacid
Acknowledgments
(6.5 mmol) and TBAI (0.65 mmol) were suspended in
dodecylbromide (8.3 mmol) and heated to reflux for
2 h. After cooling to room temperature, the mixture
was diluted with diethyl ether (10 mL) and filtered. The
filtrate was dried with Na2SO4, filtered and evaporated.
The resulting yellowish oil was chromatographed on
SiO2 (n-hexane/EtOAc 3:2).
The work was financially supported by the Ministry of
Education of the Czech Republic (Project Nos. 715/
G6/2005 and MSM0021620822).
19. Heyne, H. W.; Jones, H. J. Am. Chem. Soc. 1951, 73, 1361.
20. General procedure for the preparation of the compounds
7–17: a solution of hydroxy compound 1–5 (1 mmol) in
anhydrous pyridine (5 mL) was cooled to À20 ꢁC and
alkyl chloroformate (1.25 mmol) was added dropwise. The
mixture was stirred at À20 ꢁC for 1 h and warmed to room
temperature overnight. Then it was diluted with CHCl3
(10 mL), washed with water (3· 5 mL) and the organic
layer was dried over Na2SO4 and filtered. The pyridine
was removed by azeotropic distillation with toluene in
vacuo. The residue was dried in vacuo over H2SO4 for 1
day. The crude material was chromatographed on SiO2
(mixtures of n-hexane/EtOAc) to give the desired
products.
21. General procedure for the preparation of the compounds
21–24: to a solution of T12 (0.6 mmol) in dry CHCl3
(5 mL) and pyridine (1 mL) alkyl chloroformate
(1.5 mmol) was added drop wise. The mixture was stirred
at room temperature for 3 h. Then it was diluted with
CHCl3 (10 mL), washed with water (3· 5 mL) and the
organic layer was dried over Na2SO4 and filtered. The
pyridine was removed by azeotropic distillation with
toluene in vacuo. The residue was dried in vacuo over
H2SO4 for 1 day. The crude material was chromato-
graphed on SiO2 (mixtures of n-hexane/EtOAc) to give the
desired products.
Supplementary data
Supplementary data associated with this article can be
References and notes
1. Smith, E. W.; Maibach, H. I. In Percutaneous Penetration
Enhancers; Smith, E. W., Maibach, H. I., Eds.; CRC
Press: Boca Raton, 1995; pp 1–4.
2. Benson, H. A. E. Curr. Drug Deliv. 2005, 2, 23.
3. Prausnitz, M. R.; Mitragotri, S.; Langer, R. Nat. Rev.
Drug Discov. 2004, 3, 115.
4. Buyuktimkin, N.; Buyuktimkin, S.; Rytting, J. H. In
¨ ¨ ¨ ¨
Transdermal and Topical Drug Delivery Systems; Ghosh,
T. K., Pfister, W. R., Eds.; Interpharm Press: Buffalo
Grove, IL, 1997; pp 357–476.
5. Suhonen, T. M.; Bouwstra, J. A.; Urtti, A. J. Control
Release 1999, 59, 149.
6. Akimoto, T.; Nagase, Y. J. Control Release 2003, 88, 243.
´
´
´
ˇ
7. Vavrova, K.; Hrabalek, A.; Dolezal, P.; Holas, T.;
´
Klimentova, J. J. Control Release 2005, 104, 41.
8. Barry, B. W. J. Control Release 1987, 6, 85.
9. Williams, A. C.; Barry, B. W. Adv. Drug Deliv. Rev. 2004,
56, 603.
22. Pei-Lin, Wu; Chia-Hao, Su; Yi-Jeng, Gu J. Chin. Chem.
Soc.-Taip. 2000, 47, 271.
ˇ
23. Vavrova, K.; Hrabalek, A.; Dolezal, P.; Samalova, L.;
´
´
´
´
ˇ
´
´
Palat, K.; Zbytovska, J.; Holas, T.; Klimentova, J. Bioorg.
´
´
10. Dolezˇal, P.; Hrabalek, A.; Semecky, V. Pharm. Res. 1993,
10, 1015.
´
Med. Chem. 2003, 11, 5381.
´
ˇ
11. Hrabalek, A.; Dolezal, P.; Farsa, O.; Sklubalova, Z.;
´
ˇ
Kunes, J. Die Pharmazie 2000, 55, 759.
´
24. Møllgard, B. In Pharmaceutical Skin Penetration Enhance-
ment; Walters, K. A., Hadgraft, J., Eds.; Marcel Dekker:
New York, 1993; pp 229–242.
ˇ
12. Vavrova, K.; Zbytovska, J.; Hrabalek, A. Curr. Med.
´
Chem. 2005, 12, 2273.
´
´
´