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.
复制标题
将解偶联剂化合物与疏水性烃链缀合以实现脂肪组织选择性药物积累。
DOI：
10.1038/s41598-024-54466-2
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发表时间：
2024
影响因子：
4.6
通讯作者：
Ng MY
中科院分区：
文献类型：
--
作者：
Ng MY
治疗肥胖症的一个潜在方法是增加棕色和白色脂肪组织的能量消耗。在这里，我们的目标是通过选择性地将线粒体解偶联化合物靶向脂肪组织来实现这一结果，从而避免在其他组织中解偶联的副作用。已观察到许多亲脂化合物和染料在脂肪组织中选择性积聚药物。因此，我们探索了通过醚键将解偶联剂化合物与亲脂性C8-碳氢链偶联的可行性。我们发现，用C8-碳氢链取代解偶联剂FCCP中的三氟甲氧基可以得到很强的解偶联活性。尽管如此，该化合物没有在小鼠身上产生治疗效果，这可能是由于快速乙醚键裂解导致代谢不稳定的结果。解偶联剂化合物2，6-二硝基苯酚的亲脂类似物，其中C8-碳氢链通过对位(2，6-二硝基-4-(辛氧基)苯酚)的醚键共轭，表现出比母体化合物更高的解偶联活性。然而，体内药代动力学研究表明，2，6-二硝基-4-(辛氧基)苯酚在代谢上也不稳定。总之，疏水性碳氢链与解偶联剂化合物的偶联可持续或提高解偶联活性。然而，醚键的连接导致了代谢的不稳定，这表明需要通过其他化学键来连接亲脂基团。
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.