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 )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.