TPP-based mitocans: a potent strategy for anticancer drug design

Abstract

Triphenylphosphonium can selectively target various “cargos” to mitochondria based on the high mitochondrial membrane potential of tumor cells.

An Angiopep2-PAPTP Construct Overcomes the Blood-Brain Barrier. New Perspectives against Brain Tumors

“…The residue was purified by flash chromatography (DCM/acetone 99:1 as eluent) to afford 10 (751 mg, 1.45 mmol, 99% yield) as a white solid [6]. 1 Synthesis of (4- (3-(4-(((1-(tert-butoxy)-3-methyl-1-oxopentan-2-yl)carbamoyl)oxy)phenyl) propoxy)phenyl)(3-(4-(4-((7-oxo-7H-furo[3,2-g]chromen-4-yl)oxy)butoxy)phenyl)propyl) diphenylphosphonium 2,2,2-trifluoroacetate (12) We dissolved 11 (1.07 g, 1.34 mmol, 1.0 eq), 4 (659 mg, 1.39 mmol, 1.0 eq) and Et 3 N (374 µL, 2.68 mmol, 2.0 eq) in anhydrous DMF (6.0 mL). The reaction mixture was stirred for 5 h at 80 • C in a sealed vial, then it was diluted with EtOAc (200 mL) and washed with HCl 0.5 M (200 mL).…”

“…These compounds, (3-(4-(4-((7-oxo-7 H -furo[3,2-g]benzopyran-4-yl)oxy)butoxy)phenyl)propyl) triphenyl phosphonium iodide (PAPTP) and (3-(((4-(4-((7-oxo-7 H -furo[3,2-g]chromen-4-yl)oxy) butoxy)phenoxy)carbonyl) amino)propyl)triphenylphosphonium iodide (PCARBTP) ( Figure 1 and Figure S1 ), concentrate in the organelles, bind to and inhibit the K + channel Kv1.3 present in the inner mitochondrial membrane (IMM) [ 9 ], interact with Complex I of the respiratory chain [ 10 ], and thereby cause oxidative stress which selectively kills cancer cells sparing normal ones [ 6 ]. Accumulation in mitochondria is determined by the presence in the molecule of a lipophilic permanent cation (in this case, as most often, triphenylphosphonium (TPP) [ 11 , 12 ]), and is essential. The parent compounds not containing this mitochondrial “address” are vastly less powerful, since inhibition of only the Kv1.3 population residing in the plasma membrane inhibits proliferation [ 13 , 14 ] but does not result in cell death.…”

pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

“…The effects of PTX mainly involve mitochondria [ 13 ] and microtubules [ 14 ] of cancer cells. Selective delivery of a drug to the mitochondria can be achieved by mitochondria-targeting signal peptides [ 15 ], oligoguanidinium [ 16 ], and triphenylphosphonium (TPP) [ 17 ] to modify drug carriers in the drug delivery systems. TPP is often used in delocalized lipophilic cations, which are usually modified on the surface of nanomicelles or covalently linked with nanocarriers to achieve mitochondrial targeting [ 3 ].…”

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

“…However, other authors have reported that these molecules have limited activity when used as a monotherapy. The most current data suggest that mitocans may be best used in combination with other chemotherapies, such as compounds that act on proliferating cells [ 25 , 26 ].…”

“…Initially, this DLC was used as a molecular probe to study the relationship between ∆Ψm and OXPHOS and to measure ∆Ψm [ 86 ]. This DLC can selectivity accumulate in cancer cell mitochondria at levels >100 fold over non-tumor cells, principally because of the natural difference in ∆Ψm between cancer (ΔΨm~180–220 mV) [ 26 , 87 ] and normal cells (ΔΨ~140 mV) [ 88 ]. This characteristic offers an attractive target for mitochondrial-disrupting anticancer agents.…”