Halogenated benzimidazole carboxamides target integrin alpha4beta1 on T-cell and B-cell lymphomas.
Integrin alpha(4)beta(1) is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin alpha(4)beta(1) antagonists. We documented tumor uptake of derivatives labeled with (125)I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin alpha(4)beta(1) predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic ((18)F) or radiotherapeutic ((131)I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies.
Department of Chemistry, University of California, Davis, Davis, California 95616, USA.
Richard D
RD
Carpenter
Arutselvan
A
Natarajan
Edmond Y
EY
Lau
Mirela
M
Andrei
Danielle M
DM
Solano
Felice C
FC
Lightstone
Sally J
SJ
Denardo
Kit S
KS
Lam
Mark J
MJ
Kurth
D000595:Amino Acid Sequence; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D001562:Benzimidazoles; D005462:Fluorine Radioisotopes; D039041:Integrin alpha4beta1; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals