Development of Novel Nuclear Receptor Regulators and Their Clinical Utility

视黄酸作为细胞分化和增殖的特异性调节剂，其天然和合成的类似物，被归类为类视黄酸，已经证明其在治疗皮肤病以及皮肤癌和白血病方面的功效。本课题设计并合成了几种调节类维生素a活性的新型化合物。二苯二氮卓类衍生物表现出独特的类维甲酸调节活性，这取决于取代基。LE135是RARβ（和α）选择性类维生素a拮抗剂。另一方面，LE135的结构异构体HX600表现出类视黄醇协同作用。机制研究表明，HX600与RXR-RAR异源二聚体的RXR位点结合，与RAR配体协同作用。在对类视黄醇增效剂构效关系的研究中，我们发现HX600的硝化类似物HX531是一种RXR拮抗剂，可以抑制类视黄醇的诱导分化活性。二苯胺衍生物是另一类类维甲酸增效剂。在这个系列中，n -烷基的大小和体积对活性有重要影响。其中DA023和DA124表现出比典型RXR激动剂lgd1069更高的协同效力。最后，我们开发了几种具有类维甲酸拮抗或协同活性的噻唑烷衍生物。一些噻唑烷二酮衍生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实验中显示出强大的类维生素a协同活性。

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. LE135 is RARβ (and α)-selective retinoid antagonist. On the other hand, HX600, which is a structural 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 LGD1O69, 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.