Structure-activity relationship study of CXCR4 antagonists bearing the cyclic pentapeptide scaffold: identification of the new pharmacophore

Tanaka, Tomohiro; Tsutsumi, Hiroshi; Nomura, Wataru; Tanabe, Yasuaki; Ohashi, Nobukimi; Esaka, Ai; Ochiai, Chihiro; Sato, Jun; Itotani, Kyoko; Murakami, Tsutomu; Ohba, Kihachiro; Yamamoto, Naoki; Fujii, Nobutaka; Tamamura, Hirokazu

doi:10.1039/b812029c

Cited by 19 publications

(19 citation statements)

References 28 publications

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“…[10,11] Inhibitory activity against X4-HIV-1 (NL4-3 strain)-induced cytopathogenicity in MT-4 cells was assessed and is shown in Table 2. [38] A correlation between CXCR4 binding activity and anti-HIV activity was observed. For compound 16 and its zinc complex, anti-HIV activity was significantly stronger than CXCR4 binding activity, and for the zinc complexes of compounds 20-22, the CXCR4 binding activity is two to four-times stronger than the anti-HIV activity.…”

Section: Resultsmentioning

confidence: 92%

“…[38] The percent inhibition of all compounds at 1 mm is shown in Table 1. Seven compounds (16,17,(20)(21)(22)28, and 29, Table 1) resulted in greater than 87 % inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…A CXCR4 binding assay for compounds, based on the inhibition of [ 125 I]CXCL12 binding to Jurkat cells, was performed as reported by Tanaka et al [38] CXCR4 antagonistic activity was evaluated as described by Ichiyama et al [27] , measuring inhibitory activity against Ca 2 + mobilization induced by CXCL12 stimulation in HOS cells expressing CXCR4. Anti-HIV activity was determined by inhibitory activity against X4-HIV-1(NL4-3)-induced cytopathogenicity in MT-4 cells as reported by Tanaka et al [38] An X4 HIV-1 infectious molecular clone (pNL4-3) was obtained from the AIDS Research and Reference Reagent Program.…”

Section: Biological Assaysmentioning

confidence: 99%

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Azamacrocyclic Metal Complexes as CXCR4 Antagonists

et al. 2011

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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.

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Section: Resultsmentioning

confidence: 92%

“…[38] The percent inhibition of all compounds at 1 mm is shown in Table 1. Seven compounds (16,17,(20)(21)(22)28, and 29, Table 1) resulted in greater than 87 % inhibition.…”

Section: Resultsmentioning

confidence: 99%

Section: Biological Assaysmentioning

confidence: 99%

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Azamacrocyclic Metal Complexes as CXCR4 Antagonists

et al. 2011

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“…14,16,20,21 The L- analogue resulted in a 6-fold reduction in affinity, 14 while introduction of a halogen on the phenyl ring led to further affinity reduction. 21 Similarly, replacement of the 4-hydroxyl group with a 4-amino or a 4-methoxy group resulted in 13-fold and 64-fold reduction in affinity, respectively.…”

Section: Design and Sar For Positionmentioning

confidence: 99%

“…By now, the role of the G protein-coupled C-X-C chemokine 20 receptor 4 (CXCR4) in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases is well established, 1 and several different antagonists for CXCR4 -both peptides and nonpeptides -have been described in the literature over the last two decades. 2 The prototype non-peptide antagonist plerixafor 25 (AMD3100), which is administered by subcutaneous injection, was approved for stem-cell mobilization in 2008 and is currently the only marketed CXCR4 antagonist.…”

Section: Introductionmentioning

confidence: 99%

Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

et al. 2013

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The cyclopentapeptide CXCR4 antagonist FC131 (cyclo(-Arg 1 -Arg 2 -2-Nal 3 -Gly 4 -D-Tyr 5 -), 2; 2-Nal = 3-(2-naphthyl)alanine) represents an excellent starting point for development of novel drug-like ligands with therapeutic potential in HIV, cancer, stem-cell mobilization, inflammation, and autoimmune diseases. While the structure-activity relationships for Arg 1 , Arg 2 , and Gly 4 are well established, less is 10 understood about the roles of the aromatic residues 2-Nal 3 and D-Tyr 5 . Here we report further structureactivity relationship studies of these two positions, which showed that (i) the distal aromatic ring of the 2-Nal 3 side chain is required in order to maintain high potency, and (ii) replacement of D-Tyr 5 with conformationally constrained analogues results in significantly reduced activity. However, a simplified analogue that contained Gly instead of D-Tyr 5 was only 13-fold less potent than 2, which means that the 15 D-Tyr 5 side chain is dispensable. These findings were rationalized based on molecular docking, and the collective structure-activity data for the cyclopentapeptides suggest that appropriately designed Arg 2 -2-Nal 3 dipeptidomimetics have potential as CXCR4 antagonists.

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Low‐Molecular‐Weight CXCR4 Ligands with Variable Spacers

et al. 2012

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Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14-mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized. Three types of aromatic spacers, 1,4-phenylenedimethanamine, naphthalene-2,6-diyldimethanamine, and [1,1'-biphenyl]-4,4'-diyldimethanamine, were used to build four pharmacophore groups. As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1-propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were also used. Several compounds showed significant CXCR4 binding affinity, and zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity.

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Structure-activity relationship study of CXCR4 antagonists bearing the cyclic pentapeptide scaffold: identification of the new pharmacophore

Cited by 19 publications

References 28 publications

Azamacrocyclic Metal Complexes as CXCR4 Antagonists

Azamacrocyclic Metal Complexes as CXCR4 Antagonists

Structure–activity relationship studies of the aromatic positions in cyclopentapeptide CXCR4 antagonists

Low‐Molecular‐Weight CXCR4 Ligands with Variable Spacers

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