Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery

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


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.