Design and Synthesis of Novel Retinoid Synergists Having a Dibenzodiazepine Skeleton

Based on the structures of potent RXR agonists 2 and 3, novel dibenzodiazepine derivatives 4 -6, containing two diphenylamine substructures, were designed as RXR modulator candidates and synthesized by utilizing Pd-catalyzed and Cu-promoted diphenylamine-generating reactions as key reactions.These compounds showed retinoid-synergistic activity, enhancing the HL-60 cell differentiation-inducing ability of the RAR agonist Am80.Retinoids have a broad spectrum of biological activities related to cellular differentiation and proliferation, and are essential for normal embryonic development in vertebrates. 1 Their biological responses are mediated by binding to and activation of retinoic acid receptors (RARs), 2 which act in the form of heterodimers with another class of retinoid nuclear receptors, retinoid X receptors (RXRs). 3All-trans retinoic acid (ATRA) binds to RARs, and its 9-cis isomer (9-cisRA) binds to both RARs and RXRs (Figure 1). 4 Various synthetic retinoids, such as Am80 (1), bind only to RARs with an affinity that correlates well with most retinoidal activities. 5RXRs are transcriptionally silent partners of RARs, and RAR-RXR heterodimers activated by RAR ligands regulate the expression of specific genes. 3We have developed several RXR-specific agonists and reported their retinoid synergistic activities. 6For example, RXR agonists, such as HX600 (2) 7 and DA023 (3), 8 themselves exhibited no retinoidal activity, but strongly enhanced the potency of ATRA or Am80 (1).Since RXRs form heterodimers with various nuclear receptors, such as vitamin D 3 receptor, thyroid hormone receptors and peroxisome proliferator-activated receptors, RXR ligands may modulate the behaviors of the partner receptors, as well