Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery

• Published in: Pharmaceutics 2021-02, Vol.13 (2), p.254
• Main Authors: Ripoll, Consuelo, Herrero-Foncubierta, Pilar, Puente-Muñoz, Virginia, Gonzalez-Garcia, M Carmen, Miguel, Delia, Resa, Sandra, Paredes, Jose M, Ruedas-Rama, Maria J, Garcia-Fernandez, Emilio, Roldan, Mar, Rocha, Susana, De Keersmaecker, Herlinde, Hofkens, Johan, Martin, Miguel, Cuerva, Juan M, Orte, Angel
• Format: Article
• Language: English
• Subjects: antitumor agents; fluorescence lifetime imaging; medicinal chemistry; metabolic drug; mitochondrial carrier
• ISSN: 1999-4923; 1999-4923
• DOI: 10.3390/pharmaceutics13020254

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.