Chemoprevention/Therapy Using Non-Calcemic Vitamin D

使用非钙血症维生素 D 进行化学预防/治疗

• 批准号: 6540912
• 负责人: GARY H POSNER
• 金额: $ 32.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540912
• 关键词: breast neoplasms; chemoprevention; cholecalciferol; drug design /synthesis /production; drug screening /evaluation; fluorine; laboratory rat; neoplasm /cancer nutrition therapy; nonhuman therapy evaluation; nutrition aspect of cancer; nutrition related tag; sulfones; vitamin analog; vitamin therapy

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.

该项目的主要目标是合理地设计和合成，并确定新的维生素D3类似物(Deltanid)的有效性和安全性。本文提出的新的三角烷类化合物有望在不引起高钙血症的情况下具有较高的癌症化学保护和化学治疗活性。首先(目标1)，将构建一个将Hoffman-LaRoche广受欢迎且有效的Deltanid Ro 24-5531的最理想的氟原子取代模式与我们的Deltanid QW 1624F2-2相结合的混合Deltanid。这种新的侧链多氟类Deltanid有望具有比其母类Deltanid更好的治疗效果。由于我们的一些概念上的新型磺酸类化合物在抑制DMBA诱导的小鼠皮肤肿瘤方面是有效而安全的(即非降钙性)，因此将制备一系列新的磺酸类化合物(AIM 2)，其中微小的、合理的结构变化(例如16-取代)将迫使Deltanid侧链向西北方向移动，预计将在不导致高钙血症的情况下提高化学保护效力。此外，还将制备几个磺酸类二聚体(AIM 3)作为分子探针，以研究这种受体二聚的化学诱导剂对细胞内信号转导过程的影响。此外，还将制备一系列含有2，2-二甲基兰2，2-二氟取代基的A环2，2-二氟烷类化合物(AIM 4)，这些取代基有望在空间和电子上延缓1-和3-羟基的新陈代谢，从而增加这些新的Deltano类化合物的生物寿命和功效。最有希望的这些新的抗增殖但非钙化的Deltanid将在15-30 mg的规模上合成，用于癌症的化学预防和动物体内的化疗测试，重点是皮肤癌和乳腺癌(目标5)。总而言之，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洞察。