A small library of about 50 new TMA analogs were synthesized with structural modification in the 4 and 6 positions of the furocoumarin nucleus. Among them, some compounds were identified exhibiting CFTR modulation and/or NF-kB inhibition In regard to CFTR modulation activity they maintained the potentiation activity of CFTR and significantly rescued CFTR-dependent chloride efflux in several cell models. The CFTR correction was obtained by modifying MSD1 and indirectly stabilizing the interface between NBD1 and CL4. Moreover this new generation TMA analogs were shown to overcome the side effects of the parent TMA, maintaining CFTR modulation and/or anti-inflammatory properties. They are proposed as novel candidates with useful features and negligible side effects for pre-clinical studies.

Pubblications

– Lampronti I, Manzione MG, Sacchetti G et al “Differential Effects of Angelicines Analogues on NF-kB activity and IL-8 expression in cystic fibrosis IB3-1cells” Mediators of Inflammation, Volume 2017 (2017), Article ID 2389487
– Laselva O, Marzaro G, Vaccarin C et al. “Molecular mechanism of action of Trimethylangelicin derivatives as CFTR modulators” Frontiers in Pharmacology 2018, July 4
– Marzaro G, Lampronti I, D’Aversa E et al “Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB)” European Journal of Medicinal Chemistry 2018 May 10;151:285-293

Congress abstracts

– Chilin A, Marzaro G, Lampronti I et al. “New trimethylangelicin analogues as modulators of defective CFTR” 14th ECFS Basic Science Conference, 29 March – 01 April 2017, Albufeira, Portugal
– Chilin A “New generation trimethylangelicin (TMA) analogues for selective modulation of defective CFTR or inflammation” 14th Convention of FFC investigators in Cystic Fibrosis, 24-26 novembre 2016, Garda, Verona
– Laselva O, Marzaro G, Lampronti I et al. “Structurally diverse Trimethylangelicin derivatives correct the primary defect in p.Phe508del-CFTR by stabilizing the first membrane-spanning domain” ECFC Basic Science Conference 2018, 21 -24 March 2018, Loutraki Korinthias, Greece