Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-tetraazamacrocycles That Inhibit Human Immunodeficiency Virus Replication. 2. Effect of Heteroaromatic Linkers on the Activity of Bicyclams

Abstract

A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.

Molecular Mechanism of Action of Monocyclam Versus Bicyclam Non-peptide Antagonists in the CXCR4 Chemokine Receptor

“…In addition, 12G5 is a relevant probe to use because the interactions of bicyclams with CXCR4 monitored by the inhibition of 12G5 binding follow a similar structureactivity relationship as for the inhibition of HIV cell entry (10,(27)(28)(29). Interestingly, in general the displacement of 125 I-12G5 binding was more sensitive and resulted in larger fold changes in the affinities (Table 1) compared with the changes observed in the inhibitory potencies measured in the PI turnover assay (Table 2).…”

“…1). Various aliphatic linkers have also been probed, yet the conformational constraint imposed by hetereoaromatic linkers results in higher affinity and potency of the bicyclam compounds (7,10,28,29,31). Despite the potent antiviral effects of AMD3100, the requirements for parenteral administration limit its long-term use as an anti-HIV compound (13)(14)(15).…”

Molecular Interactions of Cyclam and Bicyclam Non-peptide Antagonists with the CXCR4 Chemokine Receptor

“…12G5 was 125 I-labeled using Bolton-Hunter reagent (Amersham Pharmacia Biotech) as described (26). AMD3100, AMD3106, AMD3108, AMD2763, AMD2849, AMD3389, and AMD2936 were synthesized as described (9,11). Cyclam (1,4,8,11-tetraazacyclotetradecane) was purchased from Aldrich.…”

“…1). Of these, the pyridine nitrogen of the 2,4-disubstituted analog (AMD3108) has a strong tendency to form pendant interactions with the adjacent macrocyclic (cyclam) ring, which apparently constrains the conformation of the compound in a way that impairs its function (2,11). For sterical reasons, this pendant interaction is not possible in the 2,6-disubstituted analog (AMD3106), which therefore should be able to function in a manner very similar to AMD3100 (2).…”

env Chimeric Virus Technology for Evaluating Human Immunodeficiency Virus Susceptibility to Entry Inhibitors

“…DS (average molecular weight, 5,000) was purchased from Sigma (Bornem, Belgium). AMD3100 and AMD2763 were kindly provided by Gary Bridger and Geoffrey Henson (AnorMED, Langley, British Columbia, Canada) and were synthesized as described previously (5). The compounds T134 and T140 (2,26,27) were kindly provided by H. Nakashima (Kagoshima University, Japan).…”