Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2 as potential therapeutics

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Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2 as potential therapeutics. / Bolla, Narasimha Rao; Corcoran, Aoife; Yasuda, Kaori; Chodyński, Michał; Krajewski, Krzysztof; Cmoch, Piotr; Marcinkowska, Ewa; Brown, Geoffrey; Sakaki, Toshiyuki; Kutner, Andrzej.

In: The Journal of Steroid Biochemistry and Molecular Biology, 28.08.2015.

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Bolla, Narasimha Rao ; Corcoran, Aoife ; Yasuda, Kaori ; Chodyński, Michał ; Krajewski, Krzysztof ; Cmoch, Piotr ; Marcinkowska, Ewa ; Brown, Geoffrey ; Sakaki, Toshiyuki ; Kutner, Andrzej. / Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2 as potential therapeutics. In: The Journal of Steroid Biochemistry and Molecular Biology. 2015.

Bibtex

@article{5848f45983c04b79bef801c342fcca70,
title = "Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2 as potential therapeutics",
abstract = "An improved convergent strategy was developed for the synthesis of the previously obtained side-chain extended and rigidified analogs of 1α,25-dihydroxyvitamin D2, PRI-1906 and PRI-1907. New (24Z) geometric isomers of the analogs, PRI-1916 and PRI-1917, were also obtained and identified. These side-chain isomers were separable by flash chromatography, as C-25 alcohols, from the synthetic precursors of PRI-1906 and PRI-1907, respectively. The structures of new analogs were determined by advanced techniques of (1)H and (13)C NMR, including COSY, HSQC and HMBC sequences. Binding affinities of the geometric analogs PRI-1906 and PRI-1916 and their respective C-26, C-27 homologs PRI-1907 and PRI-1917 for the full-length human vitamin D receptor were determined by a fluorescence polarization competition assay. The binding affinity of (24Z) methyl analog PRI-1906 was much higher than that of (24E) analog PRI-1906, while the affinity of (24Z) ethyl analog PRI-1917 was lower than that of the respective PRI-1907. Investigation of the metabolism of these compounds by human CYP24A1 revealed they are much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2, indicating they could have longer-term biological effects on target tissues.",
author = "Bolla, {Narasimha Rao} and Aoife Corcoran and Kaori Yasuda and Micha{\l} Chody{\'n}ski and Krzysztof Krajewski and Piotr Cmoch and Ewa Marcinkowska and Geoffrey Brown and Toshiyuki Sakaki and Andrzej Kutner",
note = "Copyright {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",
year = "2015",
month = aug
day = "28",
doi = "10.1016/j.jsbmb.2015.08.025",
language = "English",
journal = "The Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2 as potential therapeutics

AU - Bolla, Narasimha Rao

AU - Corcoran, Aoife

AU - Yasuda, Kaori

AU - Chodyński, Michał

AU - Krajewski, Krzysztof

AU - Cmoch, Piotr

AU - Marcinkowska, Ewa

AU - Brown, Geoffrey

AU - Sakaki, Toshiyuki

AU - Kutner, Andrzej

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/8/28

Y1 - 2015/8/28

N2 - An improved convergent strategy was developed for the synthesis of the previously obtained side-chain extended and rigidified analogs of 1α,25-dihydroxyvitamin D2, PRI-1906 and PRI-1907. New (24Z) geometric isomers of the analogs, PRI-1916 and PRI-1917, were also obtained and identified. These side-chain isomers were separable by flash chromatography, as C-25 alcohols, from the synthetic precursors of PRI-1906 and PRI-1907, respectively. The structures of new analogs were determined by advanced techniques of (1)H and (13)C NMR, including COSY, HSQC and HMBC sequences. Binding affinities of the geometric analogs PRI-1906 and PRI-1916 and their respective C-26, C-27 homologs PRI-1907 and PRI-1917 for the full-length human vitamin D receptor were determined by a fluorescence polarization competition assay. The binding affinity of (24Z) methyl analog PRI-1906 was much higher than that of (24E) analog PRI-1906, while the affinity of (24Z) ethyl analog PRI-1917 was lower than that of the respective PRI-1907. Investigation of the metabolism of these compounds by human CYP24A1 revealed they are much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2, indicating they could have longer-term biological effects on target tissues.

AB - An improved convergent strategy was developed for the synthesis of the previously obtained side-chain extended and rigidified analogs of 1α,25-dihydroxyvitamin D2, PRI-1906 and PRI-1907. New (24Z) geometric isomers of the analogs, PRI-1916 and PRI-1917, were also obtained and identified. These side-chain isomers were separable by flash chromatography, as C-25 alcohols, from the synthetic precursors of PRI-1906 and PRI-1907, respectively. The structures of new analogs were determined by advanced techniques of (1)H and (13)C NMR, including COSY, HSQC and HMBC sequences. Binding affinities of the geometric analogs PRI-1906 and PRI-1916 and their respective C-26, C-27 homologs PRI-1907 and PRI-1917 for the full-length human vitamin D receptor were determined by a fluorescence polarization competition assay. The binding affinity of (24Z) methyl analog PRI-1906 was much higher than that of (24E) analog PRI-1906, while the affinity of (24Z) ethyl analog PRI-1917 was lower than that of the respective PRI-1907. Investigation of the metabolism of these compounds by human CYP24A1 revealed they are much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2, indicating they could have longer-term biological effects on target tissues.

U2 - 10.1016/j.jsbmb.2015.08.025

DO - 10.1016/j.jsbmb.2015.08.025

M3 - Article

C2 - 26321387

JO - The Journal of Steroid Biochemistry and Molecular Biology

JF - The Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

ER -