Development of Functional Molecules for Elucidation of the Physiological Roles of Several Nuclear Receptors and Their Endogenous Ligands

Abstract

Nuclear receptors and their endogenous ligands are involved in key biological functions, including development, homeostasis and metabolism, and functional molecules that can modulate receptor activities are of interest for basic research to elucidate the signaling pathways, as well as having potential therapeutic applications. Here, we summarize our recent work on the development of nuclear receptor ligands, focusing on thyroid hormone receptor (TR) antagonists, fluorescent ligands for progesterone receptors (PR), and inhibitors of histone methyltransferase (HMT). We have developed a series of potent TR antagonists bearing a thiazolidinedione group as a bioisoster of a polar amino acid group. Utilizing our library of fluorescent coumarin derivatives, we obtained a PR antagonist that exhibits fluorescence enhancement upon binding to PR. We also developed a series of HMT inhibitors based on the structure of adenosylmethionine (AdoMet), a cofactor in the methylation reaction, by introducing various alkylamino groups onto the nitrogen atom in place of the sulfur atom of AdoMet. Our compounds should be useful in functional analysis of these nuclear receptors and investigations of their signaling pathways.

Induction of Nur77-dependent apoptotic pathway by a coumarin derivative through activation of JNK and p38 MAPK

“…Coumarin and derivatives represent a class of potential anticancer drugs deserving further investigation of their anticancer activities and mechanisms (1,2). Recent studies have demonstrated that certain coumarin derivatives could regulate important biological functions by direct or indirectly acting on several nuclear receptors including estrogen receptor (40,41), peroxisome proliferator-activated receptor-γ (42), androgen receptor (43), progesterone receptor (44,45), pregnane X receptor (46), retinoic acid-related orphan receptor γt (47) and retinoid X receptor-alpha (36). Coumarin derivatives, SP500263 (40) and SS5020 (41), binds to estrogen receptor with high affinity and acts as a coumarin-based selective estrogen receptor modulators to inhibit the growth and breast cancer cells in vitro and in animals.…”