Synthetic retinoids: Recent developments concerning structure and clinical utility
Synthetic retinoids: Recent developments concerning structure and clinical utility
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DOI：
10.1021/jm0581821
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发表时间：
2005-09-22
影响因子：
7.3
通讯作者：
Shudo, K
中科院分区：
文献类型：
--
作者：
Kagechika, H;Shudo, K
小的疏水分子，如类固醇激素和激活的维生素A和D，通过结合和激活特定的核受体来控制包括生长、发育、代谢和动态平衡在内的各种生物现象。1核受体是配体诱导的转录因子，调节其靶基因的表达。在过去的20年里，核受体及其特异性配体的生理功能已被详细阐明。据报道，在人类基因组中编码的核受体家族有48个成员，2各种内源性和合成的核孤儿受体配体已有报道。因此，核受体已成为癌症、代谢综合征、自身免疫性疾病等领域药物开发的重要分子靶点之一。维甲酸是维生素A的活性代谢物维甲酸的天然和合成类似物，是脊椎动物细胞增殖、分化和形态发生的特异性调节剂。3、4“维甲酸”一词最初是由维生素A的化学结构定义的，但现在被认为是Sporn等人提出的两类核受体的生物学术语，即维甲酸受体(RARs)和维甲酸X受体(RXRs)，它们介导维甲酸的生物活性。1985年。5维甲酸的现代药物化学始于20世纪70年代，主要研究其在肿瘤学和皮肤科领域的化学预防和治疗作用。6、7尽管类维甲酸具有有益的活性，但由于其高毒性，其治疗范围仍然有限，只有少数类维甲酸，如全反式维甲酸(ATRA，1a，图1)和2(依托维甲酸酯)用于治疗银屑病，8直到最近才用于临床。维甲酸核受体有两类，RARs和RXRs，它们都有三个亚型(R、和γ)。RARs和RXRs的内源性配体分别为ATRA和9-顺式维甲酸(9cRA，1b)，而9cRA与RARs的亲和力与RXRs一样高。9，10因此，9cRA是所有六种维甲酸核受体的泛激动剂。RXR-RAR异源二聚体的RAR位点与类维甲酸的结合是维甲酸类化合物的主要作用。RXR是RARs的沉默伙伴，RXR激动剂本身不能激活RXR-RAR异二聚体，尽管RXR激动剂变构增加了RAR配体的效力(维甲酸协同作用)。11-13除了所谓的类维甲酸活性外，RXRs还通过与各种核受体异源二聚，在核受体作用中发挥重要作用。RXRs的异二聚体伙伴包括内分泌核受体，如RARs、维生素D3受体(VDR)和甲状腺激素受体(TRs)，以及一些孤儿核受体，如过氧化体增殖物激活受体(PPAR)、肝X受体(LXRs)和法尼醇X受体(FXRs)。后者的核受体已被证明是关键
Small hydrophobic molecules such as steroid hormones and activated vitamins A and D control various biological phenomena, including growth, development, metabolism, and homeostasis, by binding to and activating specific nuclear receptors. 1 Nuclear receptors are ligand-inducible transcription factors that regulate the expression of their target genes. In the past 2 decades, the physiological functions of nuclear receptors and their specific ligands have been clarified in detail. There are reported to be 48 members of the nuclear receptor family encoded in the human genome, 2 and various endogenous and synthetic ligands for nuclear orphan receptors have been reported. Thus, nuclear receptors have become one of the most significant molecular targets for drug discovery in the fields of cancer, metabolic syndrome, autoimmune diseases, and so on. Retinoids are natural and synthetic analogues of retinoic acid, an active metabolite of vitamin A, and are specific modulators of cell proliferation, differentiation, and morphogenesis in vertebrates. 3, 4 The term “retinoid” is first defined by the chemical structure of vitamin A but is now recognized as the biological term for the ligands of two classes of nuclear receptors that mediate the biological activities of retinoic acid, that is, retinoic acid receptors (RARs) and retinoid X receptors (RXRs), as proposed by Sporn et al. in 1985. 5 Modern medicinal chemistry of retinoids started in the 1970s, mainly focusing on their chemopreventive and therapeutic utility in the fields of oncology and dermatology. 6, 7 Despite the beneficial activities of retinoids, the scope of retinoid therapy is still limited owing to high toxicity, and only a few retinoids, such as all-trans retinoic acid (ATRA, 1a, Figure 1) and 2 (etretinate) for the treatment of psoriasis, 8 have been clinically used until recently.Among various nuclear receptor ligands, retinoids are unique. There are two classes of retinoid nuclear receptors, RARs and RXRs, both having three subtypes (R,, and γ). Endogenous ligands for RARs and RXRs were identified as ATRA and 9-cis-retinoic acid (9cRA, 1b), respectively, while 9cRA can bind to RARs with as high affinity as to RXRs. 9, 10 Thus, 9cRA is a pan-agonist for all six retinoid nuclear receptors. Most of the retinoidal activities are elicited by the binding of retinoids to the RAR site of RXR-RAR heterodimers. RXRs are the silent partners of RARs, and RXR agonists alone cannot activate the RXR-RAR heterodimers, though RXR agonists allosterically increase the potencies of RAR ligands (retinoid synergism). 11-13 Besides so-called retinoidal activities, RXRs have significant roles in nuclear receptor actions by heterodimerizing with various nuclear receptors. The heterodimeric partners of RXRs include endocrine nuclear receptors, such as RARs, vitamin D3 receptor (VDR), and thyroid hormone receptors (TRs), and some orphan nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and farnesoid X receptors (FXRs). Nuclear receptors of the latter class have proven to be key