title: Convergent synthesis of double point modified analogs of 1α,25-dihydroxyvitamin D2for biological evaluation.
abstract: There is a long lasting controversy over the biological activity of vitamin D2as compared to vitamin D3in 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 D2, by a novel convergent strategy, to compare this compound directly with the activity of 1α,25-dihydroxyvitamin D3. The same synthetic strategy also provided a series of (5E,7E) geometric isomers of the natural 1α,25-dihydroxyvitamin D2as 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 by1H and13C 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 D2still remains unknown. (5E,7E) modification in the structure of new analogs of 1α,25-dihydroxyvitamin D2is expected to give analogs with no influence on calcium level, as was previously obtained for the analogs of 1α,25-dihydroxyvitamin D3. Investigation of the affinities for the vitamin D receptor and cell differentiation, transcriptional and calcium activities of the most active form of vitamin D2and of (5E,7E) analogs, compared to 1α,25-dihydroxyvitamin D3, is underway in the collaborating laboratories.
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland. Electronic address: s.nadkarni@ifarm.eu.
authors: Sharmin
authors: S
authors: Nadkarni
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Michał
authors: M
authors: Chodyński
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Krzysztof
authors: K
authors: Krajewski
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Piotr
authors: P
authors: Cmoch
authors: Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, 50-383 Wrocław, Poland.
authors: Ewa
authors: E
authors: Marcinkowska
authors: School of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT West Midlands, UK.
authors: Geoffrey
authors: G
authors: Brown
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Andrzej
authors: A
authors: Kutner
mesh_terms: D002117:Calcitriol / Q000031:analogs & derivatives; D018360:Crystallography, X-Ray; D015195:Drug Design; D004872:Ergocalciferols / Q000138:chemical synthesis* / Q000737:chemistry*; D006801:Humans; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010100:Oxygen / Q000737:chemistry; D020033:Protein Isoforms; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D004872:Ergocalciferols; D020033:Protein Isoforms; D018167:Receptors, Calcitriol; C003564:1,25-dihydroxyergocalciferol; D002117:Calcitriol; D010100:Oxygen
keywords: (5E,7E) geometric isomers; 1α,25-dihydroxyvitamin D(2); Dess–Martin oxidation; Double point modified analogs; Modified Julia olefination; convergent synthesis