New synthesis of 6[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid and evaluation of the influence of adamantyl group on the DNA binding of a naphthoic retinoid

6[3-(1-Adamantyl)-4-methoxyphenyl]-2-naphthoic acid (Adapalene®), a synthetic aromatic retinoid specific for RARβ and RARγ receptors, has been prepared utilizing a Pd/C-mediated Suzuki coupling between 6-bromo-2-naphthoic acid and 4-methoxyphenyl boronic acid, followed by introduction of an adamantyl group in the position 3 of the formed 6-(4-methoxyphenyl)-2-naphthoic acid. The interaction of 6-(4-methoxyphenyl)-2-naphthoic acid/ethyl ester and the 3-adamantyl analogs with DNA was studied in aqueous solution at physiological conditions by UV–vis spectroscopy. The calculated binding constants Kligand–DNA ranged between 1.1 × 104 M−1 and 1.1 × 105 M−1, the higher values corresponding to those of the adamantylated compounds. Molecular modeling studies have emphasized that the intercalative binding of adapalene and its derivatives to DNA is mainly stabilized by hydrophobic interactions related to the presence of the adamantyl group.

6-(4-Methoxyphenyl)-2-naphthoic acid/ethyl ester and their 3-adamantyl analogs, synthesized by a new protocol, interact with DNA in aqueous solution at physiological conditions.. The binding constants Kligand–DNA evaluated by UV-vis spectroscopic analysis ranged between 1.1 × 104 M−1 and 1.1 × 105 M−1. The higher values correspond to those of the adamantylated compounds and molecular modeling studies suggest that the intercalative binding to DNA is mainly stabilized by hydrophobic interactions related to the presence of the adamantyl group.Figure optionsDownload as PowerPoint slideHighlights
► A new synthetic route to the preparation of Adapalene® and related esters.
► Preparation of adamantylated and non-adamantylated phenyl-naphthoic acids.
► In vitro DNA binding of adamantylated and non-adamantylated phenyl-naphthoic acids.
► Adamantyl group stabilizes DNA binding through hydrophobic interactions.
► Molecular modelling of adamantylated and non-adamantylated acids/esters.