Development of selective nuclear receptor modulators with a 2,25-modified seco-steroidal skeleton

开发具有 2,25-修饰的 sec-steroidal 骨架的选择性核受体调节剂

• 批准号: 17590012
• 负责人: KITTAKA Atsushi
• 金额: $ 2.24万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590012/
• 关键词: active vitamin D_3; vitamin D receptor; agonist; 19-norvitamin D_3; modulator; osteoporosis; structure-activity relationship; bone formation; 核内受容体; 転写共役因子; ハイスループット評価

1α,25-Dihydroxyvitamin D_3 (1α,25(OH)_2D_3) is known to inhibit the proliferation and invasiveness of prostate cancer cells. However, 1α,25(OH)_2D_3 can cause hypercalcemia and is not suitable as a therapeutic agent. 19-Norvitamin D derivatives are known to be less calcemic when administered systemically. In order to develop more potent anti-cancer agents with less calcemic side effect, we therefore utilized ^3H-thymidine incorporation as an index for cell proliferation and examined the antiproliferative activities of fifteen C-2-substituted 19-nor-1α,25(OH)_2D_3 analogs including 14-epi analogs in the immortalized PZ-HPV-7 normal prostate cell line. Among the fifteen analogs we observed that the substitution with the 2α- or 2β-hydroxypropyl group produced two analogs having antiproliferative potency that is approximately 500- to 1000-fold higher than the natural 1α,25(OH)_2D_3. The ^3H-thymidine incorporation data were supported by the cell counting data after cells were treated with … More 1α,25(OH)_2D_3, 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)_2D_3 or 19-nor-2β-(3-hydroxypropyp-1α,25(OH)_2D_3 for 7days. 19-Nor-2α-(3-hydroxypropyl)-1α,25(OH)_2D_3 and 19-nor-2β-(3-hydroxypropy1)-1α,25(OH)_2D_3 were also shown to be about 10-fold more active than 1α,25(OH)_2D_3 in cell invasion studies using prostate cancer cells.We also found that one of the 14-epi-19-nor-1α,25(OH)_2D_3 analogs with a 2-substituent showed bone formation effect on the OVX model rats, which was 18% increase in bone density after 0.1 μg/kg treatment a day in one week. This analog has no effect for hypercalcemia with that dose. We have more than eleven million patients of osteoporosis in Japan, today, therefore, it is very important to develop effective anti-osteoporosis drugs.In conclusion, a substitution at the C-2 position of 19-nor-1α,25(OH)_2D_3 molecule with a 3-hydroxypropyl group greatly increased the antiproliferative and anti-invasion potencies. Thus, these two analogs could be developed to be effective therapeutic agents for treating early and late stages of prostate cancer. We also found the 14-epi-19-nor-1α,25(OH)_2D_3 analog which has strong bone formation activity without calcemic effect. Less

已知1α，25-二羟基维生素D_3（1α，25（OH）_2D_3）抑制前列腺癌细胞的增殖和侵袭性。但是，1α，25（OH）_2D_3可能引起高钙血症，不适合作为治疗剂。众所周知，在系统施用时，众所周知，19-脱氧素D衍生物的钙化较小。为了开发更多的潜在抗癌药物具有较低的钙化副作用，我们因此将 ^3H-胸苷掺入为细胞增殖的指标，并检查了包括15（OH）_2d_3类似物在内的15（OH）_2d_3类似物的抗增殖活性，包括14- ePi-eperation-prasters in 14- epi cyrate in narkation in narkation in narkation-prasters in n ander ins in n ander ins in n anderage insex insex。在15个类似物中，我们观察到用2α-或2β-羟基丙基群的取代产生了两个具有抗增殖效力的类似物，比天然1α高约500至1000倍，25（OH）_2D_3。在细胞后，细胞计数数据支持 ^3H-胸腺苷掺入的数据。 19-nor-2α-（3-羟基丙基）-1α，25（OH）_2d_3和19-nor-2β-（3-羟基植物1）-1α，25（OH）_2D_3也显示出使用prostantate Cells的_2d_3的活性大约10倍。 14-EPI-19-NOR-1α，25（OH）_2D_3类似物具有2个取代的类似物对OVX模型大鼠的骨形成影响，在一周内每天0.1μg/kg治疗后，骨密度增加了18％。该类似物对高钙血症没有影响。因此，我们在日本有超过一千万名骨质疏松症患者，因此，开发有效的抗骨质疏松药物非常重要。这两个类似物可以发展为有效的治疗。治疗前列腺癌早期和晚期的药物。我们还发现14-EPI-19-NOR-1α，25（OH）_2D_3模拟具有强骨形成活性而没有钙化作用。较少的

项目成果

ビタミンD_3ラクタム誘導体

维生素D_3内酰胺衍生物

• 发表时间: 2008

特許権

专利权

• 发表时间: 2018

知っておきたい有機反応100

你需要知道的100个有机反应

• 发表时间: 2005
• 作者: Shin Aoki;Daisuke Kagata;Motoo Shiro;Kei Takeda;Eiichi Kimura;望月正隆 他10名;望月正隆 他10名(日本薬学会編)
• 通讯作者: 望月正隆 他10名(日本薬学会編)

High-throughput system for analyzing ligand-induced cofactor recruitment by vitamin D receptor

• DOI: 10.1021/bc0601121
• 发表时间: 2007-05-01
• 期刊: BIOCONJUGATE CHEMISTRY
• 影响因子: 4.7
• 作者: Arai, Midori A.;Takeyama, Ken-ichi;Kittaka, Atsushi
• 通讯作者: Kittaka, Atsushi

Creative Synthesis of Novel Vitamin D Analogs for Health and Disease

用于健康和疾病的新型维生素 D 类似物的创造性合成

• 发表时间: 2007
• 期刊: J. Steroid Biochem. Mol. Biol. 103
• 作者: Atsushi Kittaka;Nozomi Saito;Sinobu Honzawa;Kazuya Takenouchi;Seiichi Ishizuka;Tai C. Chen;Sara Peleg;Sigeaki Kato Midori A. Arai
• 通讯作者: Sigeaki Kato Midori A. Arai