title: 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.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.forename: Taro
authors.initials: T
authors.lastname: Ozaki
authors.forename: Akira
authors.initials: A
authors.lastname: Sohma
authors.forename: Nami
authors.initials: N
authors.lastname: Ohashi
authors.forename: Chie
authors.initials: C
authors.lastname: Hashimoto
authors.forename: Kyoko
authors.initials: K
authors.lastname: Itotani
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Murakami
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D006678:HIV / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D001372:Aza Compounds; D054377:Chemokine CXCL12; D056831:Coordination Complexes; D019718:Receptors, CXCR4; D003300:Copper; D015032:Zinc; D002118:Calcium