Synthesis and Characterization of a Highly Potent and Selective Isotopically Labeled Retinoic Acid Receptor Ligand, ALRT1550.
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.
Bennani
Youssef L.
YL
Departments of Medicinal Chemistry and Endocrine Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, California 92121.
Marron
Kristin S.
KS
Mais
Dale E.
DE
Flatten
Karen
K
Nadzan
Alex M.
AM
Boehm
Marcus F.
MF