title: Nitrogen positional scanning in tetramines active against HIV-1 as potential CXCR4 inhibitors.
abstract: The paradigm, derived from bicyclams and other cyclams, by which it is necessary to use the p-phenylene moiety as the central core in order to achieve high HIV-1 antiviral activities has been reexamined for the more flexible and less bulky structures 4, previously described by our group as potent HIV-1 inhibitors. The symmetrical compounds 7{x,x} and the non-symmetrical compounds 8{x,y} were designed, synthesized and biologically evaluated in order to explore the impact on the biological activity of the distance between the phenyl ring and the first nitrogen atom of the side chains. EC50 exactly followed the order 7{x,x} < 8{x,x} < 4{x,x} indicating that, for such flexible tetramines, the presence of two methylene units on each side of the central phenyl ring increases the biological activity contrary to AMD3100. A computational study of the interactions of 4{3,3}, 7{3,3} and 8{3,3} with CXCR4 revealed interactions in the same pocket region with similar binding modes for 4{3,3} and 7{3,3} but a different one for 8{3,3}.
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: Raimon
authors.initials: R
authors.lastname: Puig de la Bellacasa
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: Albert
authors.initials: A
authors.lastname: Gibert
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Planesas
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: Laia
authors.initials: L
authors.lastname: Ros-Blanco
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: Xavier
authors.initials: X
authors.lastname: Batllori
authors.affiliation: AIDS Research Institute IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, 08916 Badalona, Spain.
authors.forename: Roger
authors.initials: R
authors.lastname: Badía
authors.affiliation: AIDS Research Institute IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, 08916 Badalona, Spain.
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.affiliation: AIDS Research Institute IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, 08916 Badalona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Esté
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixidó
authors.affiliation: Grup d'Enginyeria Molecular, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta, 390, E-08017 Barcelona, Spain. j.i.borrell@iqs.url.edu.
authors.forename: José I
authors.initials: JI
authors.lastname: Borrell
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001952:Bridged-Ring Compounds; D019718:Receptors, CXCR4; C010349:tetramethylenedisulfotetramine; D009584:Nitrogen