Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

M Marinozzi; FF Castro Navas; Daniela Maggioni; E Carosati; G Bocci; M Carloncelli; G. Giorgi; Gabriele Cruciani; R Fontana; V Russo

doi:10.1021/acs.jmedchem.7b00091

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

M Marinozzi, FF Castro Navas, Daniela Maggioni, E Carosati, G Bocci, M Carloncelli, G. Giorgi, Gabriele Cruciani, R Fontana, V Russo

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

Abstract

A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC 50 = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively. © 2017 American Chemical Society.

Original language	English
Pages (from-to)	6548-6562
Number of pages	15
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	15
DOIs	https://doi.org/10.1021/acs.jmedchem.7b00091
Publication status	Published - 2017

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@article{1210549e85dd4eb78e6796063e17e5ac,

title = "Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists",

abstract = "A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC 50 = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively. {\textcopyright} 2017 American Chemical Society.",

author = "M Marinozzi and {Castro Navas}, FF and Daniela Maggioni and E Carosati and G Bocci and M Carloncelli and G. Giorgi and Gabriele Cruciani and R Fontana and V Russo",

year = "2017",

doi = "10.1021/acs.jmedchem.7b00091",

language = "English",

volume = "60",

pages = "6548--6562",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "15",

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TY - JOUR

T1 - Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

AU - Marinozzi, M

AU - Castro Navas, FF

AU - Maggioni, Daniela

AU - Carosati, E

AU - Bocci, G

AU - Carloncelli, M

AU - Giorgi, G.

AU - Cruciani, Gabriele

AU - Fontana, R

AU - Russo, V

PY - 2017

Y1 - 2017

N2 - A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC 50 = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively. © 2017 American Chemical Society.

AB - A series of stigmasterol and ergosterol derivatives, characterized by the presence of oxygenated functions at C-22 and/or C-23 positions, were designed as potential liver X receptor (LXR) agonists. The absolute configuration of the newly created chiral centers was definitively assigned for all the corresponding compounds. Among the 16 synthesized compounds, 21, 27, and 28 were found to be selective LXRα agonists, whereas 20, 22, and 25 showed good selectivity for the LXRβ isoform. In particular, 25 showed the same degree of potency as 22R-HC (3) at LXRβ, while it was virtually inactive at LXRα (EC 50 = 14.51 μM). Interestingly, 13, 19, 20, and 25 showed to be LXR target gene-selective modulators, by strongly inducing the expression of ABCA1, while poorly or not activating the lipogenic genes SREBP1 and SCD1 or FASN, respectively. © 2017 American Chemical Society.

U2 - 10.1021/acs.jmedchem.7b00091

DO - 10.1021/acs.jmedchem.7b00091

M3 - Article

SN - 0022-2623

VL - 60

SP - 6548

EP - 6562

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 15

ER -

Side-Chain Modified Ergosterol and Stigmasterol Derivatives as Liver X Receptor Agonists

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