2. Academic Validation
  3. Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

  • Sci Rep. 2024 Feb 28;14(1):4932. doi: 10.1038/s41598-024-54466-2.
Mei Ying Ng 1 2,  Zhi Jian Song 3,  Gopalakrishnan Venkatesan 4,  Sergio Rodriguez-Cuenca 5,  James A West 6,  Shili Yang 4,  Choon Hong Tan 3,  Paul Chi-Lui Ho 4 7,  Julian L Griffin 8,  Antonio Vidal-Puig 5,  Marcella Bassetto 9,  Thilo Hagen 10
Affiliations

Affiliations

  • 1 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 School of Physical and Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University, Singapore, Singapore.
  • 4 Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore.
  • 5 Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, The University of Cambridge, Cambridge, UK.
  • 6 Department of Biochemistry, The University of Cambridge, Cambridge, UK.
  • 7 School of Pharmacy, Monash University Malaysia, 47500, Subang Jaya, Malaysia.
  • 8 The Rowett Institute of Nutrition and Health, The University of Aberdeen, Aberdeen, UK.
  • 9 School of Pharmacy and Pharmaceutical Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK. BassettoM1@cardiff.ac.uk.
  • 10 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. bchth@nus.edu.sg.
PMID: 38418847 DOI: 10.1038/s41598-024-54466-2
Abstract

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.

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