Design and Synthesis of Molecular Umbrellas

Abstract

This paper describes the design and synthesis of a series of conjugates derived from cholic acid, spermidine, and 5-(dimethylamino)-1-naphthalenesulfonyl (dansyl), which effectively shield the dansyl moiety from water. Direct coupling of cholic acid to both terminal amino groups of spermidine, and attachment of the environmentally-sensitive dansyl moiety to the remaining secondary amine, yields a “molecular umbrella” (Ia) whose fluorescent properties (λmax and emission intensity) reflect a nonpolar microenvironment in water and one that is relatively polar in intermediate dimethoxyethane/water mixtures. Comparison of Ia with analogous “single-walled” (II) and “no-walled” (III) umbrellas further indicates that a minimum of two walls is necessary in order to have “umbrella-like” properties. Examination of the fluorescent properties of a related double-walled umbrella, bearing a flexible (2-hydroxyethyl)carbamate moiety at the C-3 position of the sterol (Ib), reveals that “umbrella-like” properties are present even when facial amphiphilicity is not rigorously maintained; however, the molecule's ability to shield the fluorophore, as judged by its relative emission intensity, is diminished. “Methyl-capping” of the (2-hydroxyethyl)carbamate (i.e., Ic) enhances the umbrella's ability to provide a hydrophobic shelter in water. A tetra-walled analogue of Ia, bearing four cholic acid units (i.e., IV), has been synthesized and its dansyl group found to have reduced exposure toward water. The potential utility of molecular umbrellas in the area of drug delivery is briefly discussed.