Retinobenzoic Acids. 6. Retinoid Antagonists with a Heterocyclic Ring

Abstract

Several candidate retinoid antagonists were designed on the basis of the ligand superfamily concept and synthesized. Retinoidal activities of these benzimidazole and benzodiazepine derivatives were examined by assay of differentiation-inducing activity on human promyelocytic leukemia cell line HL-60. The parent benzimidazole derivative, 4-(5,6,7,8-tetrahydro-5,5,8,8- tetramethylnaphth-[2,3-d]imidazol-2-yl)benzoic acid (7a), and related compounds with a small alkyl group instead of the hydrogen on the nitrogen (1N) atom of the imidazole ring exhibited retinoidal activity, and the potency strongly depended on the bulkiness of the substituent. The compounds having a phenyl or benzyl group on the nitrogen lacked differentiation-inducing activity on HL-60 cells and acted as antagonists to the potent retinoid 4-[(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid (Am80). Among the compounds possessing a seven-membered heterocyclic ring as a linking group, 4-(5H-7,8,9,10-tetrahydro-5,7,7,10,10- pentamethylbenzo[e]- naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid (16) also exhibited the antagonistic activity. The binding abilities of these compounds to retinoic acid receptors alpha and beta were consistent with their potency for the inhibition of HL-60 cell differentiation induced by the retinoid Am80.

Retinoic Acid Receptor β Mediates the Growth-Inhibitory Effect of Retinoic Acid by Promoting Apoptosis in Human Breast Cancer Cells

“…6c). Ro 41-5253 but not LE135, an RAR␤-selective antagonist (18,46), was also able to inhibit all-trans RA-induced RAR␤ expression in MB231/RAR␣2 (Fig. 6c).…”

“…To investigate whether the induction of RAR␤ by RA can mediate the RA-induced growth inhibition in hormone-dependent cells, we used an RAR␤-selective antagonist (LE135) (18,46) to suppress RAR␤ activity in the cells. This retinoid can specifically inhibit RAR␤-but not RAR␣-or RAR␥-mediated activation of target genes (46).…”

9,13‐di‐cis‐Retinoic acid induces the production of tPA and activation of latent TGF‐β via RARα in a human liver stellate cell line, LI90

“…The pan-RAR-selective retinoid (Ch55), the RARa-selective retinoid (Am580), and the RAR|3-selective antagonist (LE135) were synthesized and characterized as described previously [17][18][19][20][21]. The RAR|3-selective retinoid (CD2019) and RARy-selective retinoid (CD437) were kindly provided by Dr. S. Michel (CIRD/GALDERMA, Sophia Antipolis, France) [22,23].…”

AGN193109 Is a Highly Effective Antagonist of Retinoid Action in Human Ectocervical Epithelial Cells

“…Various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (␣, ␤, or ␥) within each class (1,37,38,43). However, few antagonists of retinoid action have been described and they are mostly low affinity antagonists that have been poorly characterized at the receptor level (12,20,21,39).…”