Development of Novel Nuclear Receptor Modulators

维甲酸是细胞分化和增殖的特殊调节剂。它的天然和合成类似物被归类为维甲酸，已经证明它们在治疗皮肤病以及皮肤癌和白血病方面有效。在这个项目中，我们设计并合成了几种新的调节维甲酸活性的化合物。二苯并二氮杂氮类化合物具有独特的维甲酸调节活性，依赖于取代基。LE135为视黄酸受体β(和α)选择性维甲酸拮抗剂。另一方面，LE135的结构异构体HX600具有维甲酸协同活性。机理研究表明，HX600与RXR-RAR杂二聚体的RXR位点结合，与RAR配体协同作用。在对维甲酸增效剂构效关系的研究中，我们发现HX600的硝化产物HX531是一种RXR拮抗剂，它能抑制维甲酸的诱导分化活性。二苯胺类化合物是另一类维甲酸增效剂。在这个系列中，N-烷基的大小和体积对活性很重要。其中，DA023和DA124表现出比典型的RXR激动剂LGD1069更强的协同作用。最后，我们开发了几个具有维甲酸激动剂或协同活性的噻唑烷类化合物。一些噻唑烷二酮类化合物被认为是过氧化物酶体增殖物激活受体γ(PPARγ)的特异性配体。TZ191和TZ335等化合物是RXR激动剂，在HL-60细胞中显示出很强的维甲酸协同活性。尤其是，由于维甲酸增效剂在低浓度下具有潜在的维甲酸抑制作用，因此它们可能在维甲酸治疗领域中得到应用。RXR配体可以调节除维甲酸以外的其他核受体配体的作用。对他们行为的进一步调查正在进行中。

Retinoic acid acts as a specific modulator of cellular differentiation and proliferation. Its natural and synthetic analogs, classified as retinoids, have already proven their efficacy in the treatment of dermatological diseases as well as skin cancer and leukemia. In this project we have designed and synthesized several kinds of novel compounds which regulate the activities of retinoids.Dibenzodiazepine derivatives exhibited unique retinoid-reguratory activity, depending on the substituents. LE135is RARβ (and α)-selective retinoid antagonist. On the other hand, HX600, which is a strtuctural isomer of LE135, exhibited retinoid synergistic activity. Mechanistic investigation showed that HX600 binds to RXR site of RXR-RAR heterodimers to synergize with RAR ligands. During the investigation on the structure-activity relationships of retinoid synergists, we found a nitrated anaolg of HX600, yielding HX531, is an RXR antagonist which can inhibit the differentiation-inducing activities of retinoids. Diphenylamine derivatives are another class of retinoid synergists. In this series, size and bulkiness of the N-alkyl group are significant for the activity. Among them, DA023 and DA124 exhibited higher synergistic potency than LGD1069, a typical RXR agonist.Finally, we developed several thiazolidine derivatives with retinoid agonistic or synergistic activities. Some thiazolidinedione derivatives are known as the specific ligands for peroxisome proliferator-activated receptor γ (PPARγ). Compounds such as TZ191 and TZ335 are RXR agonists and exhibited potent retinoid synergistic activity in HL-60 assay.The compounds described here regulate specifically the action of retinoids. Especially, since retinoid synergists can potenciate retinoidal action at low concentration, they may find application in the field of retinoid therapy. RXR ligand can modulate the action of other nuclear receptor ligands besides retinoids. Further investigations on their actions are in progress.