Design, synthesis, and SAR of antiproliferative activity of trioxatriangulene derivatives
Issued Date
2025-01-01
Resource Type
eISSN
26328682
Scopus ID
2-s2.0-105002048657
Journal Title
RSC Medicinal Chemistry
Rights Holder(s)
SCOPUS
Bibliographic Citation
RSC Medicinal Chemistry (2025)
Suggested Citation
Naiya M.M., Guan I.A., Sullivan M., Eurtivong C., Leung E., Pilkington L.I., Barker D. Design, synthesis, and SAR of antiproliferative activity of trioxatriangulene derivatives. RSC Medicinal Chemistry (2025). doi:10.1039/d4md00867g Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/109518
Title
Design, synthesis, and SAR of antiproliferative activity of trioxatriangulene derivatives
Corresponding Author(s)
Other Contributor(s)
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.