Studies on the Physiological Activities of Novel Vitamin D_3 Derivatives

新型维生素D_3衍生物的生理活性研究

• 批准号: 02671024
• 负责人: KOBAYASHI T
• 金额: $ 1.6万
• 依托单位: Kobe Women's College of Pharmacy
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02671024/
• 关键词: Active Vitamin D_3; Calcium; Osteporosis; Vitamin D Binding Protein; Differentiation; Immune Regulating Activity; Parathyroid; Receptor; 活性型ビタミンD_3; ビタミンD_3; 活性型ビタミンD_3誘導体; レセプタ-; ビタミンD結果蛋白質

We have synthesized the two novel vitamin D_3 derivatives, 22-oxa-1,25-dihydroxyvitamin D_3 (oxacalcitriol : OCT) and 2beta-hydroxypropoxy-1,25-dihydroxy-vitamin D_3 (Hydroxypropoxycalcitriol : HCT), and studied their physiological activities. The results are summarized in the following ;.Although OCT behaved similar to 1,25-dihydroxyvitamin D_3 (1,25-D_3) in the in vitro bone resorption, it did not give response in the in vivo calcemic activities which were different from 1,25-D_3. Since OCT shows similar activity to 1,25-D_3 in inducing differentiation of leukemia cells to normal macrophage cells, it is a promising candidate for treatment of leukemia and other calcinogenic diseases without causing hypercalcemia.2.We have established a method for the determination of HCT in plasma and found that the half-life of HCT in blood is longer than that of 1,25-D_3 because of stronger vinding to plasma vitamin D binding protein than 1,25-D_3. We have also studied the preventive and therapeutic effects on bone mineral loss in ovariectomized rats and showed that HCT improved bone mineral density and mechanical bone strength in the pre-osteoporosis and osteoprosis model rats made by ovariectomy more effectively than 1,25-D_3. The results suggest that HCT is a promising candidate for treatment of osteoporosis.

合成了两种新的维生素D_3衍生物22-oxa-1,25-二羟基维生素D_3 （oxacalcitriol: OCT）和2- β -羟基丙氧基-1,25-二羟基维生素D_3 (Hydroxypropoxycalcitriol: HCT)，并对其生理活性进行了研究。研究结果总结如下：虽然OCT在体外骨吸收中的表现与1,25-二羟基维生素D_3 （1,25-D_3）相似，但在体内的钙化活性却与1,25-D_3不同。由于OCT在诱导白血病细胞向正常巨噬细胞分化方面显示出与1,25- d_3相似的活性，因此它是治疗白血病和其他不引起高钙血症的致钙化疾病的有希望的候选药物。我们建立了血浆中HCT的测定方法，发现HCT在血液中的半衰期比1,25- d_3长，因为它对血浆维生素D结合蛋白的亲和力比1,25- d_3强。我们还研究了对去卵巢大鼠骨矿物质流失的预防和治疗作用，发现HCT比1,25- d_3更有效地改善了去卵巢前骨质疏松和骨质疏松模型大鼠的骨矿物质密度和机械骨强度。结果表明，HCT是治疗骨质疏松症的一个有希望的候选人。

项目成果

Tadashi Kobayashi: "Metabolism and transporting system of 22-oxacalcitriol" Contribution to Nephrology. Vol.91. 129-133 (1991)

Tadashi Kobayashi：“22-奥沙骨化三醇的代谢和运输系统”对肾脏病学的贡献。

岡野 登志夫: "Regulatory Activities of 2βー(3ーHydroxypropoxy)ー1α,25ーdihydroxyvitamin D_3,a Novel Synthetic Vitamin D Derivative,on Calcium Metabolism" Biochem.Biophys.Res.Commun.163. 1444-1449 (1989)

Toshio Okano：“新型合成维生素 D 衍生物 2β-(3-羟基丙氧基)-1α,25-二羟基维生素 D_3 对钙代谢的调节活性”Biochem.Biophys.Res.Commun.163 (1989)。

小林 正: "2β-(3-Hydroxypropoxy)-1α,25-dihydroxyvitamin D3 (ED-71), preventive and therapeutic effects on bone mineral loss in ovariectomized rats" Bioorganic and Medical Chemistry Letters.

Tadashi Kobayashi：“2β-(3-羟基丙氧基)-1α,25-二羟基维生素 D3 (ED-71)，对卵巢切除大鼠骨矿物质流失的预防和治疗作用”《生物有机和医学化学快报》。

小林 正: "Transporting systems and tissue distribution of 22-oxa-1α,25-dihydroxyvitamin D_3,a noncalcemic analogue of 1α,25-dihydroxyvitamin D_3,in rats" European J. Biochemistry.

Tadashi Kobayashi：“大鼠体内 22-oxa-1α,25-二羟基维生素 D_3（1α,25-二羟基维生素 D_3 的非钙血症类似物）的转运系统和组织分布”《欧洲生物化学杂志》。

小林 正: "Transporting System and Tissue Distribution of 22ーOxaー1,25ーdihydroxyvitamin D_3,a Noncalcemic Analogue of 1,25ーDihydroxyvitamin D_3,in Rats" Eur.J.Biochem.

Tadashi Kobayashi：“22－Oxa－1,25－二羟基维生素 D_3（1,25－二羟基维生素 D_3 的非钙血症类似物）在大鼠体内的运输系统和组织分布”Eur.J.Biochem。