A Mitochondriotropic Derivative of Quercetin: A Strategy to Increase the Effectiveness of Polyphenols

Abstract

Mitochondria-targeted compounds are needed to act on a variety of processes that take place in these subcellular organelles and that have great pathophysiological relevance. In particular, redox-active molecules that are capable of homing in on mitochondria provide a tool to intervene on a major cellular source of reactive oxygen species and on the processes they induce, notably the mitochondrial permeability transition and cell death. We have linked the 3-OH of quercetin (3,3',4',5,7-pentahydroxy flavone), a model polyphenol, and the triphenylphosphonium moiety, a membrane-permeant cationic group, to produce proof-of-principle mitochondriotropic quercetin derivatives. The remaining hydroxyls were sometimes acetylated to hinder metabolism and improve solubility. The new compounds accumulate in mitochondria in a transmembrane potential-driven process and are only slowly metabolised by cultured human colon cells. They inhibit mitochondrial ATPase activity much as quercetin does, and are toxic for fast-growing cells.

Synthesis and Bioactivity of Quercetin Aspirinates

“…16 This method was probably the most effective for protection of the catechol group, while other ones of protection with 1,2-dibromomethane or acetone according to the reported literatures 17,18 were not successful in our repeated experiments. Esterification of compound 2 under the common condition with aspirin and the sequent deprotection of 3a-c with H 2 and Pd/C 19 gave three products 4a-c what were confirmed by NMR and mass spectroscopy to be acyl and diacyl compounds at the 3-O and 7-O positions of quercetin.…”

Anti-inflammatory Activities and Gastric Ulcer-inducing Properties of Tetraacetylquercetin and Tetrapivaloylquercetin

“…This yielded 1.55 g (65.9 %) of white crystal with a melting point of 69.0-69.5°C. Analysis with 1 3,3',4',7-tetrapivaloylquercetin (3) was analogously synthesized according to the procedure reported by Mattarei, et al [10]. Pivaloyl chloride (12.06 ml, 0.1 mol) was added dropwise and under continuous stirring to a mixture of quercetin (1.55 g, 5 mmol) and anhydrous pyridine (4.25 ml, 50 mmol) that was previously cooled in a dry ice bath.…”

Redox Properties and Cytotoxicity of Synthetic Isomeric Mitochondriotropic Derivatives of the Natural Polyphenol Quercetin

“…In envisioning future elaborations amenable to reversibility, the regeneration of the parent compound once inside mitochondria, and to avoid destruction by C ring opening, we initially chose to link the TPP group using a butyl chain linker to the 3-OH group (Q-3BTPI, Scheme 1). [32,44] As mentioned, modifications of this group can, however, affect oxidation potential, reactivity and possibly biological activity as well. It is therefore important to assess the extent to which such a variation might alter the activity relative to that of quercetin and another regioisomer, carrying the substituent at position 7, which preserves the 3-OH functionality (Q-7BTPI, Scheme 1).…”

“…[42,43] We have applied this principle to produce mitochondria-targeted derivatives of quercetin (Scheme 1). [32,44] The rationale of such an approach calls for the delivery of compounds with physico-chemical properties and bioactivities similar to those of the parent compound. On the other hand, any modification of the chemical structure implies a modification of the properties.…”

“…[32,33] In most cells, mitochondria are the main site of ROS production; ROS are partly responsible for aging, neurodegenerative disorders, and ischemia/reperfusion damage, and they are an important factor in apoptosis, necrosis, carcinogenesis and mitogenesis. [34,35] Mitochondrial ROS production increases the metastatic potential of cells.…”