Nadkarni Sharmin, Chodyński Michał, Krajewski Krzysztof, Cmoch Piotr, Marcinkowska Ewa, Brown Geoffrey, Kutner Andrzej
Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
J Steroid Biochem Mol Biol. 2016 Nov;164:45-49. doi: 10.1016/j.jsbmb.2015.08.022. Epub 2015 Aug 24.
There is a long lasting controversy over the biological activity of vitamin D as compared to vitamin D in terms of maintaining of calcium homeostasis and raising the level of circulating 25-OH-D. To shed more light on this relationship we synthesized 1α,25-dihydroxyvitamin D, by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D. The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D as well as a series of double point modified analogs of its (24R)-epimer, including C-22 hydroxy derivatives. The structure of the new analogs was determined by H and C NMR as well as by mass spectrometry. The influence of (5E,7E) modification, alone or in combination with additional modifications in the side chain, on the activity profile and metabolic deactivation of analogs of 1α,25-dihydroxyvitamin D still remains unknown. (5E,7E) modification in the structure of new analogs of 1α,25-dihydroxyvitamin D is expected to give analogs with no influence on calcium level, as was previously obtained for the analogs of 1α,25-dihydroxyvitamin D. Investigation of the affinities for the vitamin D receptor and cell differentiation, transcriptional and calcium activities of the most active form of vitamin D and of (5E,7E) analogs, compared to 1α,25-dihydroxyvitamin D, is underway in the collaborating laboratories.
在维持钙稳态和提高循环25-羟基维生素D水平方面，维生素D与维生素D的生物活性存在长期争议。为了更清楚地了解这种关系，我们通过一种新的汇聚策略合成了1α,25-二羟基维生素D，以便将该化合物与1α,25-二羟基维生素D的活性直接进行比较。相同的合成策略还提供了天然1α,25-二羟基维生素D的一系列(5E,7E)几何异构体以及其(24R)-差向异构体的一系列双点修饰类似物，包括C-22羟基衍生物。新类似物的结构通过氢核磁共振和碳核磁共振以及质谱测定。(5E,7E)修饰单独或与侧链中的其他修饰组合对1α,25-二羟基维生素D类似物的活性谱和代谢失活的影响仍然未知。1α,25-二羟基维生素D新类似物结构中的(5E,7E)修饰预计会产生对钙水平无影响的类似物，就像之前1α,25-二羟基维生素D类似物的情况一样。与1α,25-二羟基维生素D相比，正在合作实验室中研究维生素D最活跃形式和(5E,7E)类似物对维生素D受体的亲和力以及细胞分化、转录和钙活性。
