title: Synthesis and Characterization of a Highly Potent and Selective Isotopically Labeled Retinoic Acid Receptor Ligand, ALRT1550.
abstract: The syntheses of two labeled homologues of (2E,4E,6E)-7-(3,5-di-tert-butylphenyl)-3-methylocta-2,4,6-trienoic acid (ALRT1550, 2), [(13)CD(3)]ALRT1550 (3) and [(3)H]ALRT1550 (4), are described in this report. ALRT1550 is an exceptionally potent antiproliferative agent which is currently in phase I/II clinical trials for acute chemotherapy. Both homologues were prepared from commercially available 3,5-di-tert-butylbenzoic acid. Homologue [(13)CD(3)]ALRT1550 was labeled at the 7-position of the trienoic acid chain via addition of [(13)CD(3)]MgI to a Weinreb amide precursor. The preparation of [(3)H]ALRT1550 utilized novel methodology to synthesize a sterically hindered and site-specific tritium-labeled tert-butyl group. Saturation binding and Scatchard analysis of this ligand at the retinoic acid receptors are also described, along with competition binding (K(i)) values for a series of known retinoids using [(3)H]ALRT1550 or [(3)H]ATRA as the labeled probes.
authors.affiliation: Departments of Medicinal Chemistry and Endocrine Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, California 92121.
authors.forename: Youssef L.
authors.initials: YL
authors.lastname: Bennani
authors.forename: Kristin S.
authors.initials: KS
authors.lastname: Marron
authors.forename: Dale E.
authors.initials: DE
authors.lastname: Mais
authors.forename: Karen
authors.initials: K
authors.lastname: Flatten
authors.forename: Alex M.
authors.initials: AM
authors.lastname: Nadzan
authors.forename: Marcus F.
authors.initials: MF
authors.lastname: Boehm