Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation
One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/174947 |
| _version_ | 1826124959806652416 |
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| author | Ng, Mei Ying Song, Zhi Jian Venkatesan, Gopalakrishnan Rodriguez-Cuenca, Sergio West, James A. Yang, Shili Tan, Choon Hong Ho, Paul Chi-Lui Griffin, Julian L. Vidal-Puig, Antonio Bassetto, Marcella Hagen, Thilo |
| author2 | School of Physical and Mathematical Sciences |
| author_facet | School of Physical and Mathematical Sciences Ng, Mei Ying Song, Zhi Jian Venkatesan, Gopalakrishnan Rodriguez-Cuenca, Sergio West, James A. Yang, Shili Tan, Choon Hong Ho, Paul Chi-Lui Griffin, Julian L. Vidal-Puig, Antonio Bassetto, Marcella Hagen, Thilo |
| author_sort | Ng, Mei Ying |
| collection | NTU |
| description | One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds. |
| first_indexed | 2024-10-01T06:29:17Z |
| format | Journal Article |
| id | ntu-10356/174947 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:29:17Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1749472024-04-22T15:36:39Z Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation Ng, Mei Ying Song, Zhi Jian Venkatesan, Gopalakrishnan Rodriguez-Cuenca, Sergio West, James A. Yang, Shili Tan, Choon Hong Ho, Paul Chi-Lui Griffin, Julian L. Vidal-Puig, Antonio Bassetto, Marcella Hagen, Thilo School of Physical and Mathematical Sciences Chemistry Adipose tissue Energy metabolism One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds. Ministry of Education (MOE) Published version The work was funded in part by an NUH seed fund grant from the Singapore Ministry of Education Academic Research Fund Tier 1 (Grant number R-183-000-448-114). 2024-04-17T02:07:20Z 2024-04-17T02:07:20Z 2024 Journal Article Ng, M. Y., Song, Z. J., Venkatesan, G., Rodriguez-Cuenca, S., West, J. A., Yang, S., Tan, C. H., Ho, P. C., Griffin, J. L., Vidal-Puig, A., Bassetto, M. & Hagen, T. (2024). Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation. Scientific Reports, 14(1), 4932-. https://dx.doi.org/10.1038/s41598-024-54466-2 2045-2322 https://hdl.handle.net/10356/174947 10.1038/s41598-024-54466-2 38418847 2-s2.0-85186248685 1 14 4932 en R-183-000-448-114 Scientific Reports © The Author(s) 2024. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. application/pdf |
| spellingShingle | Chemistry Adipose tissue Energy metabolism Ng, Mei Ying Song, Zhi Jian Venkatesan, Gopalakrishnan Rodriguez-Cuenca, Sergio West, James A. Yang, Shili Tan, Choon Hong Ho, Paul Chi-Lui Griffin, Julian L. Vidal-Puig, Antonio Bassetto, Marcella Hagen, Thilo Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| title | Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| title_full | Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| title_fullStr | Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| title_full_unstemmed | Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| title_short | Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| title_sort | conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation |
| topic | Chemistry Adipose tissue Energy metabolism |
| url | https://hdl.handle.net/10356/174947 |
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