Mono- and Bis-cross-bridged Tetraazamacrocycles with Thiol Pendant Arms for Biomolecule Conjugation

Abstract

Cross-bridged tetraazamacrocycles have made important contributions as ligands when their metal complex is intended for use under harsh conditions. Applications that have benefited from such complexes are: oxidation catalysis, medical imaging, and protein-binding drug molecules. Bis cross-bridged tetraazamacrocycles, and their transition metal complexes, have become one of the most effective classes of CXCR4 chemokine receptor antagonists. These cell surface receptors are important to a number of disease states, including HIV, cardiovascular disease, and cancer. Our group has continued to produce new analogues of these compounds in an effort to improve further the efficacy, specificity, and drug-like properties of this class of compounds. In this presentation, we will describe the synthesis, chemical characterization, and biological activity of a new series of bis cross-bridged tetraazamacrocyles in which the cross-bridged macrocycle is appended with either a thiol or primary amine pendant arm. These pendant arms are intended to allow conjugation to biologically active compounds, or biomolecules such as proteins and nucleic acids themselves. Once conjugated, the bis cross-bridged tetraazamacrocycle unit would serve as the targeting unit which would bind specifically to cells expressing high concentrations of CXCR4 on their surfaces, such as certain cancer cells. Synthetic and characterization methods and results for these novel compounds will be presented.