ABSTRACT
[reaction: see text] Nine fluorescently labeled structurally varied polyguanidino dendrimers based on diamino acid monomeric units were individually synthesized in an efficient, scalable sequence using a trifluoroacetamide protecting group-perguanidinylation strategy. While the dendrimers varied significantly in their ability to enter a human lymphocyte cell line, the best transporters out-performed an oligoarginine reference standard.
Subject(s)
Amino Acid Transport Systems/chemical synthesis , Dendrimers/chemical synthesis , Fluorescent Dyes/chemical synthesis , Guanidine/chemistry , Polymers/chemical synthesis , Amino Acid Transport Systems/chemistry , Amino Acid Transport Systems/pharmacokinetics , Cell Line , Dendrimers/chemistry , Dendrimers/pharmacokinetics , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacokinetics , Humans , Lymphocytes/drug effects , Lymphocytes/metabolism , Molecular Structure , Polymers/chemistry , Polymers/pharmacokinetics , Protein Transport/drug effectsABSTRACT
A number of artificial carriers for the transport of zwitterionic aromatic amino acids across bulk model membranes (U-tube type) have been prepared and evaluated. 1,2-Dichloroethane and dichloromethane were employed in the organic phase. All compounds are based on a bicyclic chiral guanidinium scaffold that ideally complements the carboxylate function. The guanidinium central moiety was attached to crown ethers or lasalocid A as specific subunits for ammonium recognition as well as to aromatic or hydrophobic residues to evaluate their potential interaction with the side chains of the guest amino acids. The subunits were linked to the guanidinium through ester or amide connectors. Amides were found to be better carriers than esters, though less enantioselective. On the other hand, crown ethers were superior to lasalocid derivatives. As expected, transport rates were dependent on the carrier concentration in the liquid membrane. Reciprocally, enantioselectivities were much higher at lower carrier concentrations. The results show that our previously proposed three-point binding model (J. Am. Chem. Soc. 1992, 114, 1511-1512), involving the participation of the aromatic or hydrophobic residue to interact with the side chains of the amino acid guest, is unnecessary to explain the high enantioselectivities observed. Molecular dynamics fully support a two-point model involving only the guanidinium and crown ether moieties. These molecules constitute the first examples of chiral selectors for underivatized amino acids acting as carriers under neutral conditions.
