Metal complexes of pyridine-fused macrocyclic polyamines targeting the chemokine receptor CXCR4

Abstract

The chemokine receptor CXCR4 acts as a key cell surface receptor in HIV infections, multiple forms of cancer, and various other pathologies, such as rheumatoid arthritis and asthma. Macrocyclic polyamines and their metal complexes are known to exert anti-HIV activity, many acting as HIV entry inhibitors by specifically binding to CXCR4. Three series of pyridopentaazacylopentadecanes, in which the pyridine ring is fused to zero, one, or two saturated six-membered rings, were synthesized by manganese(II)-templated Schiff-base cyclization of triethylenetetramine with various dicarbonyl compounds. By evaluating these macrocyclic polyamines and their complexes with Mn²⁺, Cu²⁺, Fe³⁺, and Zn²⁺, we have discovered novel CXCR4-binding compounds. The MnCl₂ complex of a new pentaazacyclopentadecane with one fused carbocyclic ring (11) was found to have the greatest potency as an antagonist of the chemokine receptor CXCR4 (IC₅₀: 0.014 μM), as evidenced by inhibiting binding of CXCL12 to PBMCs (peripheral blood mononuclear cells). Consequently, this compound inhibits replication of the CXCR4-using (X4) HIV-1 strain NL4-3 in the TZM-bl cell line with an IC₅₀ value of 0.52 μM and low cytotoxicity (CC₅₀: >100 μM). In addition, 18 other compounds were evaluated for their interaction with CXCR4 via their ability to interfere with ligand chemokine binding and HIV entry and infection. Of these, the metal complexes of the two more hydrophobic series with one or two fused carbocyclic rings exhibited the greatest potency. The Zn²⁺ complex 21 was among the most potent, showing that redox activity of the metal center is not associated with CXCR4 antagonist activity.