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

本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而不 引起高钙血症。 预计这些三角洲类将保持 细胞的分化能力，从而防止它们采用 增殖表型 为了实现这一目标，首先， 将制备结合A- 在侧链上具有结构修饰的环（目的4.1）。 基于 文献先例，预计这些结构的影响， 对生物活性的改变将是协同的。 初步结果 表明A环的修饰将有助于降低钙 活动，并根据文献先例，修改方 链将有助于高抗增殖，诱导分化， 和癌症化学保护活性。 特定的侧链 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 体外评价这种类似物的一个实例表明，在鼠中 角质形成细胞以及人白血病细胞中，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，它基本上是无钙的。 这些发现提供 强有力支持对其他结构修改的 如本文所述，三角洲型。 第二，一系列非经典三角洲 将制备缺乏天然环A或D的化合物（目标4.2）。 a环 芳香族类似物由于其刚性结构相似性而成为目标 天然骨化三醇，并且由于它们不能经历不期望的 前维生素平衡 多种相关A-环的合成 杂芳δ烷类化合物。 这些三角洲类相对来说 易于合成。 体外测试的结果将在第4年领先 5.大规模合成，以制备足够的评价材料 最有前途的新的三角洲类保护动物， 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。

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.