| Summary: | A new series of cytotoxic platinum(IV) complexes (<b>1</b>–<b>8</b>) incorporating halogenated phenylacetic acid derivatives (4-chlorophenylacetic acid, 4-fluorophenylacetic acid, 4-bromophenylacetic acid and 4-iodophenylacetic acid) were synthesised and characterised using spectroscopic and spectrometric techniques. Complexes <b>1</b>–<b>8</b> were assessed on a panel of cell lines including HT29 colon, U87 glioblastoma, MCF-7 breast, A2780 ovarian, H460 lung, A431 skin, Du145 prostate, BE2-C neuroblastoma, SJ-G2 glioblastoma, MIA pancreas, the ADDP-resistant ovarian variant, and the non-tumour-derived MCF10A breast line. The in vitro cytotoxicity results confirmed the superior biological activity of the studied complexes, especially those containing 4-fluorophenylacetic acid and 4-bromophenylacetic acid ligands, namely <b>4</b> and <b>6</b>, eliciting an average GI<sub>50</sub> value of 20 nM over the range of cell lines tested. In the Du145 prostate cell line, <b>4</b> exhibited the highest degree of potency amongst the derivatives, displaying a GI<sub>50</sub> value of 0.7 nM, which makes it 1700-fold more potent than cisplatin (1200 nM) and nearly 7-fold more potent than our lead complex, <b>56ME<i>SS</i></b> (4.6 nM) in this cell line. Notably, in the ADDP-resistant ovarian variant cell line, <b>4</b> (6 nM) was found to be almost 4700-fold more potent than cisplatin. Reduction reaction experiments were also undertaken, along with studies aimed at determining the complexes’ solubility, stability, lipophilicity, and reactive oxygen species production.
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