Medicinal Chemistry Targeting Mitochondria: From New Vehicles and Pharmacophore Groups to Old Drugs with Mitochondrial Activity

Abstract

Interest in tumor cell mitochondria as a pharmacological target has been rekindled in recent years. This attention is due in part to new publications documenting heterogenous characteristics of solid tumors, including anoxic and hypoxic zones that foster cellular populations with differentiating metabolic characteristics. These populations include tumor-initiating or cancer stem cells, which have a strong capacity to adapt to reduced oxygen availability, switching rapidly between glycolysis and oxidative phosphorylation as sources of energy and metabolites. Additionally, this cell subpopulation shows high chemo- and radioresistance and a high capacity for tumor repopulation. Interestingly, it has been shown that inhibiting mitochondrial function in tumor cells affects glycolysis pathways, cell bioenergy, and cell viability. Therefore, mitochondrial inhibition may be a viable strategy for eradicating cancer stem cells. In this context, medicinal chemistry research over the last decade has synthesized and characterized “vehicles” capable of transporting novel or existing pharmacophores to mitochondrial tumor cells, based on mechanisms that exploit the physicochemical properties of the vehicles and the inherent properties of the mitochondria. The pharmacophores, some of which have been isolated from plants and others, which were synthesized in the lab, are diverse in chemical nature. Some of these molecules are active, while others are prodrugs that have been evaluated alone or linked to mitochondria-targeted agents. Finally, researchers have recently described drugs with well-proven safety and efficacy that may exert a mitochondria-specific inhibitory effect in tumor cells through noncanonical mechanisms. The effectiveness of these molecules may be improved by linking them to mitochondrial carrier molecules. These promising pharmacological agents should be evaluated alone and in combination with classic chemotherapeutic drugs in clinical studies.

S-15176 Difumarate Salt Can Impair Mitochondrial Function through Inhibition of the Respiratory Complex III and Permeabilization of the Inner Mitochondrial Membrane

“…The derivative of TMZ S-15176 difumarate salt has been found to act as a regulator of intracellular metabolism and can interact with several molecular targets in mitochondria [16][17][18]24] that are known to be key to the supply of most of the ATP molecules used by cells, cell signaling, ion homeostasis, and the events leading up to apoptosis and necrosis [30][31][32][33]. Some studies have shown that targeting mitochondria with S-15176 has a therapeutic effect in the oxidative stress-related pathologies of different organs and tissues [19][20][21].…”

Mesoporous Silica Nanoparticles for Targeting Subcellular Organelles

“…Given that each chemotherapeutic exerts its action on a particular organelle, delivering the drugs near such a particular organelle may help to avoid drug resistance. In this sense, researchers have paid much attention to mitochondrial targeting, as mitochondria are involved in cell apoptosis, cell metabolism, and ROS generation [ 63 , 76 ].…”

“…In this sense, current approximations for improving mitochondrial internalization include linking a lipophilic cation (alkyltriphenylphosphonium and others) to a bioactive compound. Among them, Triphenylphosphine derivatives (TPP) are one of the most promising and widely used mitochondria-targeting ligands, especially in combination with MSNs [ 63 , 76 ].…”

“…As previously mentioned, the problems that chemotherapeutics have to face are drug resistance and subsequent cell exocytosis. In this sense, drug-loaded nanocarriers can also be functionalized for targeting the nucleus, delivering their cargo nearby their target [ 76 , 91 ]. It is well-known that there are numerous pore complexes of 20-70 nm in diameter on the nuclear membrane, which are the specific passages through which substances of up to 40-60 kDa diffuse from and to the cytoplasm.…”

Tumour Microenvironment: Roles of the Aryl Hydrocarbon Receptor, O-GlcNAcylation, Acetyl-CoA and Melatonergic Pathway in Regulating Dynamic Metabolic Interactions across Cell Types—Tumour Microenvironment and Metabolism

“…Although cancer treatment has focussed primarily on killing cancer cells, including by inhibiting tumour mitochondrial function [ 215 ], it has long been realised that a more sophisticated treatment would be to change the nature of cellular interactions in the tumour microenvironment, thereby allowing NK cells, CD8+ T cells, CD4+ T cells and γδ T cells to eliminate tumours. The dynamic complexity of the intercellular interactions of the tumour microenvironment have thwarted such attempts.…”