Efficient inhibition of SDF-1alpha-mediated chemotaxis and HIV-1 infection by novel CXCR4 antagonists.
CXC chemokine receptor-4, the receptor for stromal cell-derived factor-1alpha as well as human immunodeficiency virus type 1, belongs to the chemokine receptor family and has been shown to play a critical role in directing the migration of cancer cells to sites of metastasis as well as human immunodeficiency virus type 1 infection. We had previously reported that a duodenally absorbable CXC chemokine receptor-4 antagonist, KRH-1636, showed a potent anti-human immunodeficiency virus type 1 activity both in vivo and in vitro. In this study, we initially examined the effect of the compound and its derivatives on stromal cell-derived factor-1alpha-mediated chemotaxis of cancer cells in order to evaluate if they could be applicable as a novel inhibitor of cancer metastasis. We found that both KRH-2731 and KRH-3955 were highly potent antagonists of stromal cell-derived factor-1alpha-mediated chemotaxis, i.e. the derivatives exhibited 50% effective concentrations of less than 10 nM, for more than 1000-fold efficacy improvement over the prototype KRH-1636. We further demonstrated the greater anti-human immunodeficiency virus type 1 efficacy of the derivatives compared with the original KRH-1636. Taken together, the KRH-1636 derivatives KRH-2731 and KRH-3955 may be promising as a novel inhibitory drug for cancer metastasis as well as for human immunodeficiency virus type 1 infection.
Iwasaki
Yuki
Y
Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Japan.
Akari
Hirofumi
H
Murakami
Tsutomu
T
Kumakura
Sei
S
Dewan
Md Zahidunnabi
MZ
Yanaka
Mikiro
M
Yamamoto
Naoki
N
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D011725:Pyridines / Q000494:pharmacology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*
D019380:Anti-HIV Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D007093:Imidazoles; C473941:KRH 1636; C541387:N,N-dipropyl-N'-(4-((((1H-imidazol-2-yl)methyl)((1-methyl-1H-imidazol-2-yl) methyl)amino)methyl)benzyl)-N'-methylbutane-1,4-diamine; D011725:Pyridines; D019718:Receptors, CXCR4; D001120:Arginine