Chemoprevention/Therapy Using Non-Calcemic Vitamin D

该项目的主要目标是合理设计和合成并确定新的维生素D3类似物（deltanoids）的有效性和安全性。 本文提出的新型Deltanoids预期具有高的癌症化学保护和化学治疗活性，而不引起高钙血症。 首先（目的1），将构建一种杂合的三角形化合物，其将霍夫曼-拉罗什的流行的和有效的三角形化合物Ro 24-5531的最期望的氟原子取代模式与我们的三角形化合物QW 1624 F2 -2组合。 预期这种新的侧链多氟化类三角形化合物具有优于其母体类三角形化合物中任一种的治疗特性上级。 由于我们的一些概念上新的砜类δ烷在抑制DMBA诱导的小鼠皮肤肿瘤发生方面是有效和安全的（即非钙离子），因此将制备一系列新的砜类δ烷（Aim 2），其中小的合理结构变化（例如16-取代）将迫使δ烷侧链进入西北方向，预期这将提高化学保护效力而不会引起高钙血症。 此外，一些砜类deltanoid二聚体（目标3）将被制备为分子探针，研究这种化学诱导剂的受体二聚化对细胞内信号转导过程的影响。此外，将制备一系列A-环2，2-二取代的δ烷类化合物（Aim 4），其掺入2，2-二甲基和2，2-二氟取代基，预期这些取代基在空间和电子上延迟1-和3-OH位置的代谢，从而增加这些新的δ烷类化合物的生物寿命和功效。 这些新的抗增殖但非钙调素的δ烷类化合物中最有前途的将以15-30 mg规模合成，用于动物中的癌症化学预防和化学疗法测试，重点是皮肤癌和乳腺癌（目标5）。总的来说，这些研究将为维生素D3类似物的癌症化学保护和化学治疗作用以及分子生物学提供重要的结构-活性见解。

The major goals of the Project are to rationally design and synthesize and to determine the efficacy and safety of new vitamin D3 analogs (deltanoids). The novel deltanoids proposed here are expected to have high cancer chemoprotective and chemotherapeutic activities without causing hypercalcemia. First (Aim 1), a hybrid deltanoid will be constructed that combines the most desirable fluorine atom substitution pattern of Hoffman- LaRoche's popular and potent deltanoid Ro 24-5531 with our deltanoid QW 1624F2-2. Such a new side-chain polyfluorinated deltanoid is expected to have a therapeutic profile superior to that of either of its parent deltanoids. Because some of our conceptually new sulfone deltanoids are potent and safe (i.e. non-calcemic) at inhibiting DMBA-induced skin tumorigenesis in mice, a series of new sulfone deltanoids (Aim 2) will be prepared in which small, rational structural changes (e.g. 16- substitution) will force the deltanoid side-chain into a northwest orientation that is expected to raise chemoprotective potency without causing hypercalcemia. Also, a few sulfone deltanoid dimers (Aim 3) will be prepared as molecular probes to study the effect of such chemical inducers of receptor dimerization on intracellular signal transduction processes. Additionally, a series of A-ring 2,2-disbustituted deltanoids (Aim 4) will be prepared incorporating 2,2-dimethyland 2,2- difluoro substituents that are expected sterically and electronically to retard metabolism at the 1- and 3-OH positions, thereby increasing the biological lifetime and efficacy of these new deltanoids. The most promising of these new antiproliferative but non-calcemic deltanoids will be synthesized on 15-30 mg scale for cancer chemoprevention and chemotherapy testing in animals with focus on skin and breast cancers (Aim 5). Collectively, these studies will provide important structure- activity insights into the cancer chemoprotective and chemotherapeutic actions and molecular biology of vitamin D3 analogs.