Synthesis and preliminary biological evaluation of 20-epi-eldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]
Synthesis and preliminary biological evaluation of 20-epi-eldecalcitol [20-epi-1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3: 20-epi-ED-71]
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DOI：
10.1016/j.jsbmb.2010.03.041
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
S. Hatakeyama;M. Yoshino;Kohei Eto;Keisuke Takahashi;Jun Ishihara;Y. Ono;H. Saito;N. Kubodera
中科院分区：
文献类型：
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作者：
S. Hatakeyama;M. Yoshino;Kohei Eto;Keisuke Takahashi;Jun Ishihara;Y. Ono;H. Saito;N. Kubodera
艾地骨化醇[1α，25-二羟基-2 β-（3-羟基丙氧基）维生素D3，开发代码：艾德-71]是活性维生素D3的类似物，即1α，25-二羟基维生素D3[1，25（OH）2D 3]，在1，25（OH）2D 3的2β-位具有羟基丙氧基取代基。艾地骨化醇对骨骼具有强大的生物学作用，目前正在日本准备批准作为治疗骨质疏松症的有前途的药物。为了探索艾地骨化醇与相关类似物之间的化学结构-生物活性关系，我们已经合成了1-表-艾地骨化醇，3-表-艾地骨化醇和1，3-二表-艾地骨化醇，并评估了它们的生物反应。20-epi-1，25（OH）2D 3是1，25（OH）2D 3的一种非对映异构体，在其侧链的20-位上有一个反向的甲基取代基，与母体化合物1，25（OH）2D 3相比，其生物活性显著增强。作为对艾地骨化醇修饰研究的继续，我们对20-表艾地骨化醇及其生物学效应产生了极大的兴趣。本文报道了20-表-艾地骨化醇的合成及其体外生物活性的初步评价。在诱导人髓性白血病细胞（HL-60）分化、抑制人组织细胞性淋巴瘤细胞（U937）增殖和增加人骨肉瘤细胞（MG-63）中的骨钙素浓度方面，20-表-艾地骨化醇显示出与艾地骨化醇相比显著增强的活性。
Eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3, developing code: ED-71] is an analog of active vitamin D3, 1α,25-dihydroxyvitamin D3[1,25(OH)2D3] that possesses a hydroxypropoxy substituent at the 2β-position of 1,25(OH)2D3. Eldecalcitol has potent biological effects on bone and is now in preparation for approval as a promising medicine for the treatment of osteoporosis in Japan. To explore chemical structure–biological activity relationships between eldecalcitol and related analogs, we have already synthesized 1-epi-eldecalcitol, 3-epi-eldecalcitol, and 1,3-diepi-eldecalcitol with inherent biological interests of each targeted analog and evaluated their biological responses. It has been reported that 20-epi-1,25(OH)2D3, a diastereomer of 1,25(OH)2D3that possesses an inverted methyl substituent at the 20-position of the side chain, shows remarkably enhanced biological activities compared to parental compound, 1,25(OH)2D3. As a continuation of our modification studies on eldecalcitol, we took great interest in 20-epi-eldecalcitol and its biological responses. In this paper, the synthesis of 20-epi-eldecalcitol by the Trost coupling reaction between the A-ring fragment and the C/D-ring fragment as well as in vitro preliminary biological evaluation of 20-epi-eldecalcitol are described. In the induction of human myeloid leukemia cell (HL-60) differentiation, inhibition of the human histiocytic lymphoma cell (U937) proliferation, and increase in osteocalcin concentration in the human osteosarcoma cell (MG-63), 20-epi-eldecalcitol showed significantly enhanced activity compared to eldecalcitol.