Membrane Permeable Lipophilic Cations as Mitochondrial Directing Groups

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.

Pharmacological Development of Target-Specific Delocalized Lipophilic Cation-Functionalized Carboranes for Cancer Therapy

“…Notably, following their pretreatment with DLC-carboranes, only normal cells were seen to recapitulate their full proliferation potential in media that were free from these compounds; this effect was verified through dilution assays. The selective effect of the functionized carboranes appears to be linked to their DLC moiety, which elicits a cytotoxic response with a therapeutic potential through mitochondrial targets [11,18], since: a) triphenylphosphonium ions (TPPs), have been exploited as small molecule directing groups to achieve mitochondrial delivery [17]; b) rhodamine functionalities have been utilized in mitochondria-specific dyes [11,15,20]; and, c) dequalinium (DQA) has been evaluated in a therapeutic approach for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), acute promyelocytic leukemia (APL) and hepatocellular carcinoma (HCC) [32,33]. [42,43].…”

“…It has been suggested that as long as technological advancements empower the translational medicine capacity in enabling the pharmacological exploitation of cancer cell molecular and genomic knowledge, the advances to therapeutically overcome heterogeneity and to target the tumor cell microenvironment will occur at increasing rates [2][3][4][5][6][7][8][9][10]. A major milestone towards organelle-specific drug delivery was reached by the discovery of delocalized lipophilic cations (DLCs) [11]. These molecular structures are guided selectively towards tumors by the higher mitochondrial transmembrane potential (~60 mV difference) that is consequent to the correspondingly higher metabolic activity of cancer cells relative to that of normal cells [12][13][14][15][16].…”

“…These molecular structures are guided selectively towards tumors by the higher mitochondrial transmembrane potential (~60 mV difference) that is consequent to the correspondingly higher metabolic activity of cancer cells relative to that of normal cells [12][13][14][15][16]. The resonance-stabilized delocalization of the positive charge of DLCs, coupled with their inherent lipophilicity, leads to a decrease in the cost associated with the free energy change that accompanies the diffusion of DLCs through cell membranes, and provides the 5 driving force for their observed highly selective accumulation (>100 fold) in the mitochondrial matrix of cancer cells [13,17,18] and the associated high (>5 fold) difference between their cytoplasmic and extracellular concentrations [11]. Towards the development of highly selective target-specific anticancer agents that are applicable to boron neutron capture therapy (BNCT) of cancer, this study builds on preliminary evaluations that indicated the selective accumulation of boronated DLC compounds in cancer cells [19,20].…”

Teaching the basics of cancer metabolism: Developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism

“…Not all cationic compounds are MDR-recognizable and, with highly lipophilic analogs, the positive charge becomes less important for recognition and the subsequent effluxing mechanism by MDR [73]. Studies also suggest that cancer cell phenotypes that do not express MDR and have greater mitochondrial membrane potential are more likely to be sensitive to delocalized lipophilic cations and mitochondria-targeted cationic agents [74], [75].…”

π-Delocalized Lipophilic Cations as New Candidates for Antimalarial, Antitrypanosomal and Antileishmanial Agents: Synthesis, Evaluation of Antiprotozoal Potency, and Insight into Their Action Mechanisms

“…20) He proposed that π-delocalized lipophilic cations (DLCs) could penetrate the hydrophobic barriers of the plasma and mitochondria membrane under a cross-membrane negative potential. [21][22][23] The mitochondrial membrane potentials of carcinoma cells are more negative than those of normal cells, and this negative membrane charge induces the selective transfer of DLCs into carcinoma mitochondria. If DLCs are toxic to mitochondria at high concentrations, their selective accumulation in carcinoma mitochondria should induce selective carcinoma cell killing.…”