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
[reaction: see text] A concise, asymmetric synthesis of the polyketide spacer domain portion (C1-C13) of a highly potent bryostatin analogue was developed. The route utilizes asymmetric hydrogenation methodology to install the C3, C5, and C11 stereocenters, while a substrate directed syn reduction sets the C9 stereocenter. The spacer domain 1 is obtained in 10 steps with a 25% overall yield and is readily incorporated into the synthesis of 2.
Subject(s)
Lactones/chemistry , Lactones/chemical synthesis , Bryostatins , Macrolides , Molecular StructureABSTRACT
Short oligomers of arginine, either alone or when conjugated to therapeutic agents or large biopolymers, have been shown to cross readily a variety of biological barriers (e.g., lipid bilayers and epithelial tissue). Molecular modeling suggests that only a subset of the side chain guanidinium groups of these transporters might be required for transport involving contact with a common surface such as a plasma membrane or cell surface receptor. To evaluate this hypothesis, a series of decamers were prepared that incorporated seven arginines and three nonarginine residues. Several of these mixed decamers were comparable to the all arginine decamer in their ability to enter cells. More significantly, these decamers containing seven arginines performed almost without exception better than heptaarginine itself, suggesting that spacing between residues is also important for transport. The influence of spacing was more fully evaluated with a library of oligomers incorporating seven arginines separated by one or more nonconsecutive, non-alpha-amino acids. This study led to the identification of a new series of highly efficient molecular transporters.
