Design and development of biological response modifiers

设计和制备了各种生物反应调节剂，包括核受体配体（激动剂/拮抗剂）和酶抑制剂，旨在开发用于治疗慢性疾病（癌症、糖尿病、类风湿疾病等）的药物。在方法上，提出了核受体基于亚结构、螺旋- 12的结构依赖的构象变化的功能调控假说和多模板假说。基于这些假设，(1)核受体[视黄酸受体（RARs）、类视黄酸X受体（RXRs）、雄激素受体、孕激素受体、雌激素受体、过氧化物酶体增殖物激活受体（PPARs）、farnsoid X受体（FXR）、肝X受体（LXRs）和维生素D受体]的配体（激动剂和拮抗剂）；(2)肿瘤坏死因子(TNF)-α生成、微管蛋白聚合、嘌呤霉素敏感氨基肽酶（PSA）、α-葡萄糖苷酶、肿瘤细胞侵袭、组蛋白去乙酰化酶（HDAC）、肝素酶、钙调磷酸酶、环加氧酶（COX）、氮氧化酶合成酶（NOS）、μ-钙蛋白酶、胸苷磷酸化酶和血管生成。本研究项目创造的典型化合物包括；(a)合成类维甲酸Am80 (tamibarotene)，自2005年以来作为治疗急性早幼粒细胞白血病的药物推出，目前正在进行治疗克罗恩病的II期临床试验；(b)合成类维甲酸TAC-101；(c)非甾体/非苯胺型结构的雄激素拮抗剂，对所谓的抗雄激素耐药细胞（如lncap细胞）有活性，携带点突变的雄激素受体(s),(d)结构中含有氮原子的新型维生素d拮抗剂（dram），(e)结构中含有碳硼烷基团的类固醇激素受体配体。我们的研究表明，上述假设在药物设计中具有广泛的实用性/适用性，并且沙利度胺相关的邻苯亚胺/同苯亚胺骨架和二苯基戊烷结构分别可作为各种生物活性化合物和类固醇相关活性化合物的支架。少

Various biological response modifiers, including nuclear receptor ligands (agonists/antagonists) and enzyme inhibitors, were designed and prepared, aiming development of agents for the treatment of chronic diseases (cancers, diabetes, rheumatoid diseases etc). Methodologically, functional regulation hypothesis of nuclear receptors based on the lingand-dependent conformational change of their substructure, helix 12, and multi-template hypothesis have been proposed. Based on these hypotheses,(1)ligands (agonists and antagonists) of nuclear receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), androgen receptor, progesterone receptor, estrogen receptor, peroxisome proliferators-activated receptors (PPARs), farnsoid X receptor (FXR), liver X receptors (LXRs), and viamine D receptor,(2)specfic and potent inhibitors of tumor necrosis factor (TNF)-α production, tubulin polymerization, puromycin-sensitive aminopeptidase (PSA), α-glucosidase, dipeptidylpeptidase (DPP) type IV, … More tumor cell invasion, histone deacetylase (HDAC), heparanase, calcineulin, cyclooxygenase (COX), nitrogen oxidase synthase (NOS), μ-calpain, thymidine phosphorylase, and angiogenesis, have been created.Typical compounds created in this research project includes;(a)a synthetic retinoid, Am80 (tamibarotene), which has been launched since 2005 as a medicament for the treatment of acute promyelocytic leukemia, and is now under phase II clinical trial for the treatment of Crohn's diseases,(b)a synthetic retinoid, TAC-101, which is now under phase III clinical trial for the treatment of liver cancer,(c)non-steroidal/non-anilide type structure of androgen antagonists which are active toward so-called anti-androgen-resistant cells (ex.LNCaP cells) bearing point mutated androgen receptor(s),(d)novel vitamin D antagonists (DLAMs) containing a nitrogen atom in their structure,(e)steroid hormone receptor ligands containing a carborane group in their structure.Our studies suggests the wide utility/applicability of the above-mentioned hypothesis for drug design, and the usefulness of thalidomide-related phthalimide/homophtalimide skeleton and diphenylpentane structure as the scaffold of various biologically active compounds and steroid-related active compounds, respectively. Less