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.