In order to find new efficient and safe agents for gene delivery, we have designed and synthesized nine novel single- and double-charged amphiphiles on the base of 1,4-dihydropyridine (1,4-DHP) ring. Some biophysical properties of the amphiphilic dihydropyridines and their complexes with DNA were examined. We investigated the transfer of beta-galactosidase gene into fibroblasts (CV1-P) and retinal pigment epithelial (D 4O7) cell lines in vitro. The structure-property relationships of the compounds were investigated in various ways. The net surface charges of 1,4-DHP liposomes were highly positive (25-49 mV). The double-charged compounds condensed DNA more efficiently than single-charged and the condensation increases with the increasing +/- charge ratio between the carrier and DNA. Double-charged compounds showed also buffering properties at endosomal pH and these compounds were more efficient in transfecting the cells, but transfection efficiency of amphiphiles was cell type-dependent. The length of alkyl chains in double-charged compounds affected the transfection efficacy. The most active amphiphile (compound VI) was double-charged and had two C(12) alkyl chains. At optimal charge ratio (+/- 4), it was 2.5 times more effective than PEI 25 and 10 times better than DOTAP, known efficient polymeric and liposomal transfection agents. Formulation of amphiphiles with DOPE did not change their activities. Our data demonstrate some important effects of amphiphile structure on biophysics and activity. The data also suggest that cationic amphiphilic 1,4-DHP derivatives may find use as DNA delivery system.

No abstract

DIHYDROPYRIDINE WITH fl-ALANINE V. V. Kastron, I. S. Reine, and G. DubursWe have found that the reaction of 2,6-di(bromomethyl)-3,5-dimethoxycarbonyl-4-(2-difluoromethoxyphenyl)-l,4dihydropyridine (I) with fl-alanine ethyl ester at room temperature gives a 46% yield of a tricyclic compound, i.e., the derivative of 1,3,4,5,7,8-hexahydro(dipyrrolo)[3',4'-b;3,4-e]pyridine (II). If the reaction was conducted at a lower temperature, the nucleophilic substitution product (III) was isolated with a yield of 65%. Alkaline hydrolysis of the ester groups in the fl-alanine residue of compound (IlI) and brief treatment with a 1 N solution of sodium hydroxide led to the production of compound (IV) with a yield of 63%. More prolonged saponification led to intramolecular cyclization and the formation of the lactarn (V) with a yield of 75%. Compound can also be obtained by alkaline hydrolysis of compound (II) or as a result of the cyclization of compound (IV) in an alkaline medium at room temperature.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.