Synthesis, photophysical, computational, and cytotoxicity evaluation of carborane-appended phenylene and triazine trimers: elucidating the role of the central core
Abstract
The development of tumor-selective boron carriers is critical for advancing targeted cancer therapies. In this study, we report the design, synthesis, and characterization of four ortho-carborane-appended symmetrical trimers, Ph-6-CB, Ph-9-CB, Tz-6-CB, and Tz-9-CB, to systematically compare the influence of central-core electronics and peripheral carborane density on photophysical and biological properties. Photophysical studies revealed that all four conjugates exhibit strong π-π* absorption in the 328-335 nm region; the triazine-cored derivatives show a modest blue shift relative to their phenylene analogs. Phenylene derivatives retain higher fluorescence quantum yields than their triazine analogs. Qualitative DFT analysis displays smaller HOMO-LUMO separations and substantially higher computed electrophilicity indices for triazine analogs than the phenylene analogs. Preliminary in vitro cytotoxicity assays against MDA-MB-231 triple-negative breast cancer cells and NIH/3T3 mouse embryo fibroblasts revealed higher potency and greater cancer selectivity of triazine derivatives than their phenylene counterparts. Tz-9-CB emerged as the lead candidate, with an IC50 of 6 µM against MDA-MB-231 cells and a selectivity index of 13 relative to NIH/3T3 fibroblasts. Mechanistic studies, including Live/Dead fluorescence imaging and caspase-3 activation assays, confirmed that Tz-9-CB induces cell death primarily through apoptosis. These findings highlight the potential of…
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