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.

Structure activity relationship (SAR) of DNA binding trioxatriangulines

ACS Spring Meeting 2021

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