Bioconjugate-based molecular umbrellas

Abstract

Molecular umbrellas are "amphomorphic" compounds that can produce a hydrophobic or hydrophilic exterior when exposed to a hydrophobic or hydrophilic microenvironment, respectively. Such molecules are composed of two or more facial amphiphiles that are connected to a central scaffold. Molecular umbrellas that have been synthesized to date, using bile acids as umbrella "walls", polyamines such as spermidine and spermine as scaffold material, and l-lysine as "branches", have been found capable of transporting certain hydrophilic peptides, nucleotides, and oligonucleotides across liposomal membranes by passive diffusion. They have also have been shown to increase water solubility and hydrolytic stability of a hydrophobic drug, and to exhibit significant antiviral activity. The ability of a fluorescently labeled molecular umbrella to readily enter live HeLa cells suggests that such conjugates could find use as drug carriers.

Figure 1

Styllized illustration of a hydrophilic agent trying to cross a phospholipid bilayer.

Figure 2

Stylized illustration of a di-walled molecular umbrella, bearing a hydrophilic agent, which is in an exposed and a shielded conformation in aqueous and hydrocarbon environments, respectively.

Figure 3

A hypothetical mechanism of bilayer transport for a di-walled molecular umbrella.

Figure 4

Representative building blocks for the synthesis of molecular umbrellas. Typical “R” groups that have been used to date include: OCH₃, OH, OCONH₂, and OSO₃Na.

Figure 5

Common frameworks used in the synthesis of molecular umbrellas. Here, “X” represents the “handle” of the umbrella that can bind to a desired agent is attached. Typical “R” groups that have been used to date include: OCH₃, OH, OCONH₂, and OSO₃Na.

Figure 6

Structures of glutathione (GSH), di-walled molecular umbrellas that have been covalently attached to glutathione (1a and 1b), and a control conjugate, 2.

Figure 7

Synthetic scheme for the preparation of 1a.

Figure 8

Synthetic scheme for the preparation of 1b.

Figure 9

Stylized illlustration of a molecular umbrella-glutathione conjugate (USSG) crossing into a liposome loaded with glutathione (GSH), followed by thiolate-disulfide interchange to form oxidized glutathione (GSSG) and USH.

Figure 10

Structure of a single-walled (“skimpy”) molecular umbrella bearing glutathione (6a), a non-umbrella analog (6b) and a stylized illustration showing two skimpy molecuar umbrellas in a face-to-face orientation.

Figure 11

Cleavage of a molecular umbrella-glautathione conjugate by a glutathione molecule.

Figure 12

Thiol-induced reductive fragmentation of a o-dithiobenzyl carbamate liberating an organic amine.

Figure 13

Structure of a diwalled molecular umbrella bearing DADLE with a fully detachable handle.

Figure 14

Structures of di-walled molecular umbrellas bearing a thiolated form of AMP and ATP.

Figure 15

One possible pathway for the cleavage of a di-walled molecular umbrella by glutathione to liberate a nucleotide.

Figure 16

Structure of a di-walled molecular umbrella bearing a guanidinium handle, and a probable structure for the guanidinium moiety binding to a phosphate group.

Figure 17

Stylized illustration of a di-walled molecular umbrella-oligonucleotide conjugate crossing a phospholipid bilayer.

Figure 18

Structures of di-walled (11a, 11b) and tetra-walled (12a, 12b) molecular umbrellas bearing an oligonucleotide.

Figure 19

Chlorambucil undergoing a rate-limiting intramolecular displacement reaction.

Figure 20

Stylized illustration of a di-walled molecular umbrella, bearing a hydrophobic agent, which is shown in a shielded and an exposed conformation.

Figure 21

Structure of a di-walled molecular umbrella that has been conjugated to Chlorambucil.

Figure 22

Structures of molecular umbrellas bearing three (14), four (15, 16), six (17) and eight (18) persulfated choloyl groups.

Figure 23

Structure of a fluorescently-labeled, persulfated molecular umbrella, 19.