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Membrane Permeable Lipophilic Cations as Mitochondrial Directing Groups

[ Vol. 15 , Issue. 8 ]

Author(s):

Joseph T. Madak and Nouri Neamati   Pages 745 - 766 ( 22 )

Abstract:


The mitochondrion’s negatively charged membrane potential has been well documented to drive the accumulation of membrane permeable delocalized lipophilic cations (DLC). DLC attachments to known bioactive compounds can direct organelle localization and improve drug exposure to targets within the mitochondria. Due to the mitochondria’s essential function and its regulation of cell death, DLC targeted therapies are the focus of drug discovery projects altering cellular fate via mitochondrial targets. This review provides an update on recent developments for the two main applications of DLCs: cytoprotective therapies aimed at reducing oxidative stress and cytotoxic therapies aimed at initiating cell death for the treatment of various cancers. Both approaches have produced significant improvements using DLC conjugated compounds that include improved potency, pharmacokinetic properties, and the potential to overcome resistance mechanisms.

Keywords:

Anticancer, Cytotoxicity, Delocalized lipophilic cations, Mitochondria-targeted delivery, Oxidative stress, Smallmolecule drug design, Triphenylphosphonium.

Affiliation:

Department of Medicinal Chemistry, College of Pharmacy, Translational Oncology Program, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Bldg 520, Ann Arbor, MI 48109, USA.

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