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Cited by 65Cholesterol and Lipid MetabolismSteroid Chemistry and BiochemistryCancer, Lipids, and Metabolism

The Effect of Small Molecules on Sterol Homeostasis: Measuring 7-Dehydrocholesterol in Dhcr7-Deficient Neuro2a Cells and Human Fibroblasts

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Korade, Zeljka, Kim, Hye-Young H., Tallman, Keri A., Liu, Wei, Koczok, Katalin, Balogh, Istvan, Xu, Libin, Mirnics, Karoly +1 more·2016·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.5b01696PMC PMC4838819
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Abstract

Well-established cell culture models were combined with new analytical methods to assess the effects of small molecules on the cholesterol biosynthesis pathway. The analytical protocol, which is based on sterol derivation with the dienolphile PTAD, was found to be reliable for the analysis of 7-DHC and desmosterol. The PTAD method was applied to the screening of a small library of pharmacologically active substances, and the effect of compounds on the cholesterol pathway was determined. Of some 727 compounds, over 30 compounds decreased 7-DHC in Dhcr7-deficient Neuro2a cells. The examination of chemical structures of active molecules in the screen grouped the compounds into distinct categories. In addition to statins, our screen found that SERMs, antifungals, and several antipsychotic medications reduced levels of 7-DHC. The activities of selected compounds were verified in human fibroblasts derived from Smith-Lemli-Opitz syndrome (SLOS) patients and linked to specific transformations in the cholesterol biosynthesis pathway.

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  • Twenty-seven small molecules have been characterized as both enhancing myelination and elevating 8,9-unsaturated sterol intermediate levels.

    “In all we have characterized twenty-seven small molecules as both enhancing myelination and elevating 8,9-unsaturated sterol intermediate levels11,21,23”

    From Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination (2018) · cites this paper as [11]

    The Results (Validation of HTS Hit Compounds; page unavailable) report that several small molecules increased zymostenol or zymosterol levels, supporting the sterol-intermediate part of the claim. The paper does not characterize twenty-seven such molecules or report that they enhance myelination; its experiments examine sterol profiles in Neuro2a cells and human fibroblasts. (LLM, conf=0.86)

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  • Among the top 10 novel enhancers of oligodendrocyte formation, four molecules had previously been shown to inhibit TM7SF2 or EBP in CNS-derived cells.

    “Among the top 10 novel enhancers of oligodendrocyte formation, we noted four molecules had previously been shown to inhibit TM7SF2 or EBP in CNS-derived cells11,21”

    From Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination (2018) · cites this paper as [11]

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Authors
Korade, Z., Kim, H.-Y. H., Tallman, K. A., Liu, W., Koczok, K., Balogh, I., Xu, L., Mirnics, K., & Porter, N. A.
Affiliations
  • Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37235, United States
  • Vanderbilt University (US)
  • University of Debrecen (HU)
  • Department of Laboratory Medicine, Division of Clinical Genetics, University of Debrecen, Nagyerdei krt. 98, 4032 Debrecen, Hungary
Corresponding author
Porter, Ned A.
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2016-01-29
Volume
59
Issue
3
Pages
1102-1115
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.5b01696
PMC
PMC4838819
OpenAlex
W2270578321
Cited by
65
References
2
Citations by year
2026: 6 · 2025: 6 · 2024: 5 · 2023: 3 · 2022: 7 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 7 · 2017: 4 · 2016: 5
FWCI
8.49
Type
journal article
Language
en
Open access
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
Funders
  • National Institute of Environmental Health Sciences (R01 ES024133, R21 ES024666)
  • Orsz?gos Tudom?nyos Kutat?si Alapprogramok (K109076)
  • National Institute of Child Health and Human Development (R01 HD064727)
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
7-dehydrocholesterol, sterol homeostasis, cholesterol biosynthesis, N2a cells, human fibroblasts, Smith-Lemli-Opitz syndrome, sterol analysis, small molecule screening, statins, selective estrogen receptor modulators, antifungal agents, antipsychotic drugs, desmosterol
MeSH terms
Animals, Cell Line, Dehydrocholesterols, Dose-Response Relationship, Drug, Fibroblasts, Homeostasis, Humans, Molecular Conformation, Neurons, Sterols, Structure-Activity Relationship, Oxidoreductases Acting on CH-CH Group Donors, Mice, Small Molecule Libraries

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