DESIGN AND SYTHESIS OF NOVEL VITAMIN D3 ANALOGS (DELTANOIDS) AS CHEMOPROTECTORS

作为化学保护剂的新型维生素 D3 类似物（DELTANOIDS）的设计与合成

• 批准号: 6300288
• 负责人: GARY H POSNER
• 金额: $ 22.09万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6300288
• 关键词: benzanthracenes; breast neoplasms; carcinogen testing; carcinogenesis inhibitor; cell differentiation; chemical carcinogenesis; chemical structure function; chemoprevention; cholecalciferol; drug design /synthesis /production; intermolecular interaction; laboratory rat; receptor binding; retinoid binding proteins; tissue /cell culture; vitamin D receptors; vitamin analog

The major goal of this project is to design and synthesize vitamin D3 analogs (deltanoids) having high cancer chemoprotective activities without causing hypercalcemia. These deltanoids are expected to maintain the differentiating ability of cells and thus to prevent them from adopting a proliferative phenotype. To accomplish this goal, first a series of hybrid deltanoids will be prepared combining structural modifications on the A- ring with structural modifications on the side-chain (Aim 4.1). Based on literature precedent, it is expected that the effects of these structural changes on biological activity will be synergistic. Preliminary results indicate that modifications of the A ring will contribute to low calcemic activity, and, based on literature precedent, modifications of the side chain will contribute to high antiproliferative, differentiation-inducing, and cancer chemoprotective activities. The specific side-chain modifications have been chosen to represent the most potent inducers of cell differentiation and of cancer prevention. Preliminary biological evaluation of one example of such analogs in vitro shows that, in murine keratinocytes as well as in human leukemic cell, this compound has antiproliferative potency greater than that of calcitriol, and, significantly, it is essentially non-calcemic. These findings provide strong support for examination of SAR in other structurally modified deltanoids, as proposed here. Second, a series of non-classical deltanoids lacking the natural ring A or D will be prepared (Aim 4.2). A-ring aromatic analogs are targeted because of their rigid structural similarity to natural calcitriol and because of their inability to undergo undesirable previtamin equilibrium. Synthesis of a variety of related A-ring heteroaromatic deltanoids is proposed. These deltanoids will be relatively easy to synthesize. The results of in vitro testing will lead in Years 4 and 5, to larger-scale syntheses to prepare enough material for evaluation of the most promising new deltanoids for protection of animals against cancer (Aim 4.3). Collectively, these studies should provide important structure-activity and mechanistic insights into chemoprotective actions of vitamin D3 analogs.

该项目的主要目标是设计和合成维生素D3 具有高癌症化学保护活性的类似物（deltanoids），无需 引起高钙血症。 这些三角洲预计将维持 细胞的分化能力，从而阻止它们采用 增殖表型。 为了实现这一目标，首先要进行一系列混合 deltanoids将结合A-的结构修饰来制备 侧链上有结构修饰的环（目标 4.1）。 基于 文献先例，预计这些结构的影响 生物活性的变化将是协同的。 初步结果 表明 A 环的修饰将有助于降低血钙 活动，并根据文献先例，对侧面进行修改 链将有助于高抗增殖、分化诱导、 和癌症化学保护活性。 具体侧链 已选择修饰来代表最有效的诱导剂 细胞分化和癌症预防。 初步生物学 对此类类似物的一个例子的体外评估表明，在小鼠中 在角质形成细胞以及人类白血病细胞中，该化合物具有 抗增殖效力大于骨化三醇，并且， 值得注意的是，它基本上是非钙血症的。 这些发现提供了 大力支持对其他结构性修改中的 SAR 进行审查 deltanoids，如此处所提议的。 二、一系列非经典三角洲 将制备缺少天然环A或D的化合物（目标4.2）。 A形环 芳香族类似物因其严格的结构相似性而成为目标 天然骨化三醇，并且由于它们无法经历不良反应 前维生素平衡。 各种相关A型环的合成 提出了杂芳族三角洲化合物。 这些三角洲将相对 易于合成。 体外测试结果将在第4年领先 5、进行更大规模的合成，准备足够的材料进行评估 最有前途的新型 deltanoids 用于保护动物免受 癌症（目标 4.3）。 总的来说，这些研究应该提供重要的 化学保护作用的结构-活性和机制见解 维生素 D3 类似物。