Design and synthesis of improved analogs of trimethylangelicin (TMA) for personalized treatment of cystic fibrosis

Design, synthesis and biological evaluation of a library of TMA analogs were undertaken to identify a lead compound with optimized properties in respect to the parental TMA. Key tasks were to study the different properties of TMA analogs; to test photoreactivity and mutagenic properties; finally to derive structure-activity relationships aimed at rationalizing the structural determinants required to obtain the specific activities. Reserchers carried out comparative analyses of more than 40 newly synthesized TMA analogs and concluded that anti-inflammatory, CFTR potentiator and CFTR corrector activities can be separately obtained in TMA analogues. TMA analogues were identified displaying low or absent antinflammatory effects, but maintaining, and even increasing, the function of CFTR correctors. CFTR correctors were found with no mutagenic effects and without DNA photodamaging activities. Novel TMA analogues are proposed for preclinical studies aimed at the development of protocols for personalized therapy of cystic fibrosis.