Structural development of bio-active compounds affecting nuclear receptor function

20世纪50年代，抗生素的全面商业化出现，导致致命疾病的性质从传染性/急性转变为非传染性/慢性。在这种情况下，不基于选择性毒性的生物反应调节剂（BRM’s）有望发挥作用。BRM有几种类型，包括在基因表达水平上直接作用于细胞的类维生素a，以及调节我们身体内部环境的沙利度胺（及相关分子）。我们一直从事基于这些生物活性化合物的药物化学/结构开发研究。类维生素a包括全黄烷-维甲酸（ATRA），维生素a（视黄醇）的一种主要活性形式，以及它的生物异构体，它们通过与核受体RAR结合而产生生物效应。ATRA已被用于分化治疗[通常用于治疗急性早幼粒细胞白血病（APL）]和皮肤病的治疗。我们对类维生素a的结构开发研究，包括计算机辅助分子设计，已经产生了类/亚型选择性激动剂、增效剂和RAR及其伴侣核受体RXR的拮抗剂。沙利度胺具有广泛的药理作用，包括抗恶病质、抗血管生成和抗转移活性。我们发现沙利度胺是一种多靶点药物。假设的沙利度胺靶事件/分子包括tnf - α产生、核雄激素受体、氨基肽酶和α -葡萄糖苷酶。通过对沙利度胺结构进行适当修饰，制备出了针对这些靶现象/分子的特异性强效化合物，有望成为新型免疫调节剂、抗血管生成剂和抗肿瘤促进剂的优良先导化合物。

The full-scale commercial appearance of antibiotics in the 1950's caused a shift of the nature of our lethal diseases from infectious/acute to non-infectious/chronic. In this situation, biological response modifiers (BRM's), which are not based on selective toxicity, are expected to be useful. There exist several types of BRM's, including retinoids which act directly on cells at the gene expression level, and thalidomide (and related molecules) which modulate internal circumstances of our body. We have been engaged in medicinal chemical/structural development studies based on these bio-active compounds. Retinoids include all-tarans-retinoic acid (ATRA), a major active form of vitamin A (retinol), and its bio-isosters, which elicit their biological effects by binding to their nuclear receptors, RAR's. ATRA has been used in differentiation therapy [typically for the treatment of acute promyelocytic leukemia (APL)] and the treatment of dermatological diseases. Our structural development studies of retinoids, including computer-assisted molecular design has yielded class/subtype-selective agonists, synergists and antagonists of RAR's and their partner nuclear receptors, RXR's. Thalidomide elicits a wide range of pharmacological effects, including anti-cachexia, anti-angiogenic and antimetastatic activities. We have found that thalidomide is a multi-target drug. Hypothetical target events/molecules of thalidomide include TNF-alpha production, nuclear androgen receptor, aminopeptidases, and alpha-glucosidase. Specific and potent compounds for each of these target phenomena/molecules have been : prepared by appropriate modification of the thalidomide structure, and are expected to be superior lead compounds for novel immunomodulators, anti-angiogenic agents, and anti-tumor promoting agents.