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.