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

该项目的主要目标是设计和合成维生素D3。 具有很高的癌症化学保护活性的类似物(Deltanid)，没有 导致高钙血症。预计这些Deltanid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，首先是一系列混合动力车 将结合对A-A-的结构修饰来制备Deltanid 侧链上有结构修饰的环(目标4.1)。基于 根据文献先例，预计这些结构性因素的影响 生物活性的变化将是协同作用的。初步结果 表明A环的修饰有助于低钙血症 活动，并根据文献先例，对一侧进行修改 链将有助于高度抗增殖，诱导分化， 和癌症的化学保护作用。特定的侧链 修饰已经被选择来代表最有效的诱导剂 细胞分化和癌症预防。初步生物学 对这类类似物的一个例子的体外评估表明，在小鼠体内 角质形成细胞以及人类白血病细胞中，这种化合物具有 比骨化三醇更强的抗增殖能力，以及， 值得注意的是，它基本上不含钙质。这些发现提供了 为其他结构调整的特区审查提供有力支持 Deltanid，如这里所提议的。第二，一系列非经典Deltanid 将制备缺少天然环A或D的化合物(目标4.2)。A形环 芳香族类似物之所以成为目标，是因为它们具有严格的结构相似性 天然的骨化三醇，因为他们不能忍受 维他命预防平衡。一类相关A环的合成 提出了杂芳烃类化合物。这些Deltanid将相对地 易于合成。体外测试的结果将在第四年领先 和5，更大规模的合成，为评估准备足够的材料 最有希望的保护动物的新的Deltanid 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-活性和机制研究 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.