新型维生素D类似物作为潜在治疗药物：代谢、毒性分析及抗增殖活性
Novel vitamin D analogs as potential therapeutics: metabolism, toxicity profiling, and antiproliferative activity.
作者信息
Chen Jianjun, Wang Jin, Kim Tae-Kang, Tieu Elaine W, Tang Edith K Y, Lin Zongtao, Kovacic Dianne, Miller Duane D, Postlethwaite Arnold, Tuckey Robert C, Slominski Andrzej T, Li Wei
机构信息
Department of Pharmaceutical Science, University of Tennessee Health Science Center, 847 Monroe Avenue, Memphis, TN 38163, U.S.A.
出版信息
Anticancer Res. 2014 May;34(5):2153-63.
Abstract
AIM
To discover novel [20(OH)D3] analogs as antiproliferative therapeutics.
MATERIALS AND METHODS
We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism.
RESULTS
20S- and 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 μg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes.
CONCLUSION
Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.
摘要
目的
发现新型[20(OH)D3]类似物作为抗增殖治疗药物。
材料与方法
我们研究了体外肝微粒体稳定性、使用小鼠的体内毒性、维生素D受体（VDR）转位、体外抗增殖作用、CYP酶代谢。
结果
20S-(OH)D3和20R-(OH)D3在肝微粒体中的半衰期分别为50分钟和30分钟（平均），较为合理。在60μg/kg的高剂量下它们不会引起高钙血症。设计、合成并测试了三种新型20(OH)D3类似物。与1,25(OH)2D3相比，它们在抑制正常角质形成细胞增殖以及诱导VDR从细胞质转位至细胞核方面表现出更高或相当的效力。这些新类似物通过一系列维生素D代谢CYP酶表现出不同程度的代谢。
结论
它们在高剂量下缺乏高钙血症毒性且具有高生物活性，这表明这种新型20(OH)D3支架可能代表了一个有前景的平台，可用于进一步开发治疗用药物。
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