Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery

Abstract

Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.

Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification

“…Moreover, the variations in pH also correlated with differential responses to some metabolic drugs [ 39 ]. In a second work, we observed different sensitivity responses of breast cancer models to a chimeric small molecule developed for delivering the pyruvate dehydrogenase kinase inhibitor dichloroacetate to mitochondria [ 40 ].…”

Beyond the TPP+“gold standard”: a new generation mitochondrial delivery vector based on extended PN frameworks

“…[1][2][3][4] Mitochondria-selective accumulation of compounds can be accomplished by some cationic moieties commonly known as delocalised lipophilic cations (DLCs), [5][6][7][8] and this ability is frequently attributed to their delocalised cationic charge, resulting in increased lipid membrane permeability and accumulation within the negatively-charged mitochondrial matrix in accordance with the Nernst equation. 7,9 While there are a broad range of mitochondrial targeting species, from rhodamines, cyanines, mitochondrial-targeting peptides to thiophene-based vectors, 8,[10][11][12][13] triphenylphosphonium-based vectors are arguably the most widely used and have been applied for the delivery of numerous molecular cargoes as highlighted in the literature. 14 Due to the success in applying triphenylphosphonium (TPP + ) systems for mitochondrial delivery, there is an increasing interest in modifying the TPP + systems for enhanced delivery.…”

Mitochondria-Targeted Drug Delivery

“…Ripoll et al, have showed promising new carrier to target mitochondria based on nonprotonable, noncharged thiophene ring. Authors used this construction to prepare chimeric drug deliver using the carrier and pyruvate dehydrogenase kinase inhibitor dichloroacetate demonstrating utility of thiophene moiety as a noncharged carrier for targeting mitochondria with metabolism-targeting drugs [11]. Alternatively, the drugs maybe designed specifically.…”

“…In conclusion, this Special Issue underlines importance of mitochondria in pathophysiological situation such as: genetic disorders [1,2], cardiovascular diseases [3,4], inflammation [5] and cancer [6][7][8][9][10]. Indicates new tools to selective target mitochondria in order to: rescue aberrant cell phenotype, change cell metabolism or induces mitochondria dependent cell death [1][2][3][4][5][6][7][8][9][10][11][12].…”