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Trioxatriangulinium ion (TOTA) is a planer carbocation, well known for its DNA intercalating and cytotoxic properties. Biological testing shows that the similar n-propyl-azadioxatriangulenium ion (Pr-ADOTA) and bis-(n-propyl) diazaoxatriangulenium ion (Pr-DAOTA) were very active with IC₅₀ values of 38 nM and 21 nM, respectively. Based on this, further analogues have been designed, synthesized, and tested for their antiproliferative activity against breast cancer cell line MDA-MB-231 and colon cancer cell line HCT116, to develop a SAR. SAR studies suggest that the cyclic-planar molecules are more active compare to non-cyclic molecules (tris(2,6-dimethoxyphenyl)methylium ion, dimethoxyphenyl-dimethoxydihydroacridinylium ion (DMPDMA⁺) and dimethoxyquinacridinium ion (DMQA⁺)) and cyclic-nonplanar molecules (H-TOTA and n-butyl-TOTA). Introducing an electron donating group (-NH₂ and -OH) on a side chain of ADOTA derivatives showed greater antiproliferative effect compared to electron-withdrawing groups. Further studies showed that DAOTA has greater antiproliferative activity compare to ADOTA and TOTA. Taking this lead, we synthesized a range of DAOTA derivatives and also developed a new convergent one-pot synthesis of symmetric and asymmetric DAOTA. Tested for their cytotoxicity gave new lead compounds having IC₅₀ values in between 24-72 nM and 37-172 nM for MDA-MB-231 and HCT116 cell lines, respectively. Dimers of ADOTA, DMQA, ADOTA-DMQA, and ADOTA-DMPDMA, using different linkers, showed moderate to good biological activity.

Lisa Pilkington

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