Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening

Abstract

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure.

New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease

“…The TMA analogues were synthesized as previously reported [18,19]. The GY971 derivative (6-p-aminophenyl-4,4 -dimethyl-angelicin, also called pANDMA), is characterized by an aniline moiety at position 6 of the furocoumarin structure (Figure 2).…”

“…The GY971 derivative (6-p-aminophenyl-4,4 -dimethyl-angelicin, also called pANDMA), is characterized by an aniline moiety at position 6 of the furocoumarin structure (Figure 2). The amino group, salified as mesylate salt, allowed the formation of a water-soluble derivative: the hydrophilic mesylate, named GY971a, demonstrated to be four-times more bioavailable than the parent GY971 [19]. Instead, typically all the TMA analogues were lipophilic and solubilize only in DMSO.…”

“…The aim was to modify the original TMA scaffold (Figure 1) in order to identify new compounds with biological properties comparable to TMA but with reduced or absent side effects. Therefore, a small library of derivatives was recently synthesized and studied [18,19]. Different substituents were inserted at positions 4, 6, or 4′ of the tricyclic nucleus to evaluate the role of these positions in the overall activity of the compounds.…”

“…In the present work, we selected some of these new TMA analogues to investigate their anti-inflammatory activity (Figure 2). Therefore, a small library of derivatives was recently synthesized and studied [18,19]. Different substituents were inserted at positions 4, 6, or 4 of the tricyclic nucleus to evaluate the role of these positions in the overall activity of the compounds.…”

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II

“…However, TMA shows serious disadvantages, such as poor solubility, phototoxicity, and mutagenicity. To overcome these side effects, Vaccarin et al [ 17 ] designed and synthesized a library of TMA analogs. The authors showed that bulky aromatic substituents at C-4 of TMA impaired DNA intercalation and prevented the photoreaction of the lactone or furan double bond of the furocoumarin scaffold with the nucleic acid.…”