SYNTHESIS OF NEW NITRONES TARGETING MITOCHONDRIA WITH LOW CYTOTOXICITY

Sophie Thétiot-Laurent (1) , Caroline Delehedde (1) , Mathieu Esgulian (1) , Mathieu Cassien (1) , Marcel Culcasi (1) , Sylvia Pietri (1)

1 ICR - Institut de Chimie Radicalaire

Introduction: The free radicals (FR) occurrence in biological signalling or as pathologies triggers is well-documented and the design of specific scavengers to limit oxidative stress is enthralling. Because FR become inactivated upon addition to nitrones, efforts have focused on developing alpha-phenyl-N-tert-butylnitrone derivatives (PBNs) with promising pre-clinical data. To improve efficacy, a new generation of nitrones derived from 2-(diethoxyphosphoryl)-N-(benzylidene)propan-2-amine-N-oxide (PPNs) incorporating an antioxidant framework, gave rise to multipotent drugs exhibiting EPR-spin-trapping properties. As mitochondrial dysfunction is involved in many disorders, efforts have been concentrated on developing tools (pH probes) or pharmacological agents targeting-mitochondria. Materiel-Methods: A series of mitochondria-targeted PPNs was synthesized based on the improved biocompatibility of P-containing nitrones and the expected benefits of introducing a cationic vector. Spin-adducts EPR-parameters toward biologically-relevant FR were established. Cytotoxicity was determined on cells and mitochondria-permeation assessed in isolated rat organs. Results: a) synthesis of a series of vectorized PPNs with different linkers and vectors, b) spin-adducts EPR-parameters determination with various FR, c) comparative cytotoxicity studies in various normal and cancer cells and mitochondria permeation according to vectors. Conclusion: New mitochondria-targeting nitrones appeared as lower cytotoxic alternative to the commonly used mito-PBN and were safely applied for investigating the anticancer-mechanism of new drugs impacting mitochondria.

Domaines: Chimie organique

Sophie Thétiot-Laurent, Caroline Delehedde, Mathieu Esgulian, Mathieu Cassien, Marcel Culcasi, et al.. SYNTHESIS OF NEW NITRONES TARGETING MITOCHONDRIA WITH LOW CYTOTOXICITY. 9th World Congress on Targeting Mitochondria, Oct 2018, Berlin, Germany. ⟨hal-03025242⟩