Chemoprevention/Therapy Using Non-Calcemic Vitamin D

该项目的主要目标是合理设计和合成新的维生素D3类似物（类三角烷），并确定其有效性和安全性。本文提出的新型三角类药物有望具有较高的癌症化学保护和化疗活性，而不会引起高钙血症。首先（目标1），将构建一个杂化类三角化合物，将Hoffman- LaRoche的流行和有效的类三角化合物Ro 24-5531中最理想的氟原子取代模式与我们的类三角化合物QW 1624F2-2结合起来。这样一种新的侧链多氟化类三角化合物预计具有优于其母代类三角化合物的治疗效果。由于我们的一些概念性新砜类化合物在抑制dba诱导的小鼠皮肤肿瘤发生方面是有效和安全的（即非钙血症），因此将制备一系列新的砜类化合物（Aim 2），其中小的，合理的结构变化（例如16-取代）将迫使三角洲侧链进入西北方向，预计将提高化学保护效能，而不会引起高钙血症。此外，我们还将制备一些砜类deltanoid二聚体（Aim 3）作为分子探针，研究这些受体二聚化的化学诱导剂对细胞内信号转导过程的影响。此外，将制备一系列含有2,2-二甲基2,2-二氟取代基的a环2,2-二异构类三角化合物（Aim 4），这些取代基在空间和电子上有望延缓1-和3-OH位置的代谢，从而提高这些新类三角化合物的生物寿命和功效。最有希望的这些新型抗增殖但不含钙的类三角洲化合物将以15-30毫克的剂量合成，用于癌症化学预防和动物化疗试验，重点是皮肤癌和乳腺癌（Aim 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.