Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery.

Consuelo Ripoll,Jose M Paredes,M Carmen Gonzalez-Garcia,Herlinde De Keersmaecker,Miguel Martin,Delia Miguel,Mar Roldan,Sandra Resa,Susana Rocha,Juan M Cuerva,Angel Orte,Virginia Puente-Muñoz,Emilio Garcia-Fernandez,Maria J Ruedas-Rama,Johan Hofkens,Pilar Herrero-Foncubierta

doi:10.3390/pharmaceutics13020254

Consuelo Ripoll, Jose M Paredes + Show 14 more

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https://doi.org/10.3390/pharmaceutics13020254

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Journal: Pharmaceutics	Publication Date: Feb 12, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: University of Granada, KU Leuven

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.

Highlights

We showed that simple acridone-based fluorescent probe 1, containing a thiophene side group (Chart 1), exhibited enhanced mitochondrial accumulation compared to its thiophene-lacking counterpart [40]
Apart from acridone 1, we synthesized a xanthene derivative with the thiophene group included on a flexible chain (2), a xanthene derivative with the thiophene incorporated in the central ring (3) and a BODIPY derivative (4)
In seeking new, noncharged organelle-targeting carriers, we found that neutral acridone dyes underwent mitochondrial accumulation when modified with a thiophene ring [40]

Summary

Introduction

Mitochondria are essential organelles for cellular metabolism; understanding their function is critical for biologists and biochemists [1]. Cellular metabolism, through mitochondrial activity, plays a central role in many physiological alterations and diseases. Alterations in mitochondrial metabolism play a crucial role in cancer [2,3]. The anabolic pathways derived from the mitochondrial oxidative metabolism, such as tricarboxylic acid cycle (TCA)-derived biosynthetic reactions, are significantly essential to sustain high proliferative rates in many cancer types [4]. Other cancer cells display an apparent independence on mitochondrial oxidative metabolism, Pharmaceutics 2021, 13, 254.

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