Azamacrocyclic Metal Complexes as CXCR4 Antagonists

Abstract

The chemokine receptor CXCR4 is a member of the seven transmembrane GPCR family, which is implicated in multiple diseases, including HIV infection, cancers, and rheumatoid arthritis. Low-molecular-weight nonpeptidic compounds, including AMD3100 and various pyridyl macrocyclic zinc(II) complexes, have been identified as selective antagonists of CXCR4. In the present study, structure-activity relationship studies were performed by combining the common structural features of alkylamino and pyridiyl macrocyclic antagonists. Several new zinc(II) or copper(II) complexes demonstrated potent anti-HIV activity, strong CXCR4-binding activity, and significant inhibitory activity against Ca(2+) mobilization induced by CXCL12 stimulation. These results may prove useful in the design of novel CXCR4 antagonists, and the compounds described could potentially be developed as therapeutics against CXCR4-relevant diseases or chemical probes to study the biological activity of CXCR4.

Small‐Molecule CD4 Mimics Containing Mono‐cyclohexyl Moieties as HIV Entry Inhibitors

“…However,t he cytotoxicity of these compounds was highert han that of compound 7 precisely because of the amino groups, which could interact with cell membranes. CD4 mimics containing ag uanidino group have been reported elsewhere, [35] thus mono-cyclohexyl compounds containing ag uanidino group (11,16,19,22,25)w ere evaluated in this study.A ll of thesec ompoundse xhibitedh igho rm oderate anti-HIV activity (Table 1c). Compoundsc ontaining as ingle guanidinog roup,Y IR-819 (19)a nd YIR-821 (22), and compound 25 with two guanidino groups have higher activity than compounds 7 and 24,s uggesting that guuanidino groups are more suitable fort he interaction with the carboxyl group in the Phe43 cavity.H owever,t he cytotoxicity of 19 was more pronounced than that of compound 7.…”

“…In the last two decades, we have developed several CXCR4 antagonists including peptides such as T140 and FC131 and several nonpeptides. [6][7][8][9][10][11] Additionally,s ome small compounds such as BMS-378806, [12] IC-9564 [13] and NBDs [14] have been identified that bind to gp120 and inhibitt he formation of the key protein-protein interaction betweeng p120 and CD4 and consequently viral attachment. Recently,s everal small-molecule CD4 mimics, which competitivelys uppress the binding of gp120 to CD4, [15][16][17][18][19][20][21][22][23][24][25][26] have been developed as an ovel class of HIV entry inhibitors.…”

Anti-HIV screening for cell-penetrating peptides using chloroquine and identification of anti-HIV peptides derived from matrix proteins

“…To date, we have also developed several other anti-HIV agents including coreceptor CXCR4 antagonists, [5][6][7][8][9] CD4 mimics, 10-14 fusion inhibitors [15][16][17] and integrase inhibitors. [18][19][20] There are however serious problems containing the emergence of mutant viral strains with multi-drug resistance, and these have encouraged us to search for new types of anti-HIV-1 drugs and to increase the repertoires of drugs with various mechanisms of action.…”

Benzenesulfonamides: A Unique Class of Chemokine Receptor Type 4 Inhibitors

“…Potent pyridine and dipyrimidine analogues have been synthesized by our research group [10] and by others. [11] Exploration of tunable areas around the dipyridine pharmacophore led us to prepare a new class of benzenesulfonamide analogues ( Figure 2). The central phenyl ring was retained because it has been shown to be important for inhibitory activity.…”