Design, synthesis, and SAR of antiproliferative activity of trioxatriangulene derivatives†

Abstract

Trioxatriangulene (TOTA⁺) and its derivatives, which are primarily used as dyes in biological systems, have received considerable attention owing to their photophysical and electronic properties. Notably, their DNA-intercalating properties have been well established. Previous studies have identified TOTA⁺ derivatives, particularly ADOTA⁺ (R = –C₃H₇) and DAOTA⁺ (R = R′ = –C₃H₇), as potent antiproliferative agents in triple-negative breast cancer (MDA-MB-231) and colorectal cancer (HCT-116) cell lines. However, the potential to enhance antiproliferative activity through different side chains prompted further investigation. In addition, partially cyclized tetramethoxyphenyl acridinium ion (TMPA⁺8) and dimethoxy quinacridinium ion (DMQA⁺9) intermediates were assessed to elucidate the structure–activity relationship (SAR) of the triangulenium core for antiproliferative activity. In this study, 83 molecules with various side chains were synthesized, including planar, partially planar, and non-planar derivatives. Evaluation of their antiproliferative activity in MDA-MB-231 and HCT-116 cell lines revealed that compound 6l (R = –C₄H₉, R′ = –C₂H₄N(Me)₂) was the most potent inhibitor, with IC₅₀ values of 18 ± 3 nM and 32 ± 14 nM, respectively. A new one-pot method was developed to synthesize symmetrically and asymmetrically substituted DAOTA⁺ molecules, enabling the introduction of acid-labile functional groups, such as alcohols, ethers, and alkylamines, in moderate to good yields.