Potent Platinum(IV) Prodrugs That Incorporate a Biotin Moiety to Selectively Target Cancer Cells

Abstract

Four platinum(IV) prodrugs incorporating a biotin moiety to selectively target cancer cells were synthesised, characterised, and their biological activity assessed. All complexes exhibited exceptional in vitro cytotoxicity against a panel of cancer cell lines, with [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (2) exhibiting the lowest GI50 of 4 nM in the prostate Du145 cancer cell line. Each complex displayed significantly enhanced activity compared to cisplatin, with 2 being 1000-fold more active in the HT29 colon cancer cell line. Against the MCF-7 breast cancer cell line, in which high levels of biotin receptors are expressed, 2, [Pt(4,7-dimethoxy-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (3), and [Pt(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)(biotin)(hydroxido)](NO3)2, (4) exhibited enhanced activity compared to their platinum(II) cores, with 4 being 6-fold more active than its platinum(II) precursor. Furthermore, 3 exhibited 3-fold greater selectivity towards MCF-7 breast cancer cells compared to MCF10A breast healthy cells, and this was further confirmed by platinum uptake studies, which showed 3 to have almost 3-fold greater uptake in MCF-7 cells, compared to MCF10A cells. The results show that lipophilicity and selectivity both contributed to the cellular uptake of 1–4; however, this was not always translated to the observed cytotoxicity.

Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents

“…The methylene (α) and methyl (β) protons near the carbonyl group of NPX were assigned to the quartet and doublet at 3.50 and 1.15 ppm, respectively. Finally, the chemical multiplicity in the aliphatic region (1-3 ppm) exhibited by the ancillary ligand, SS-DACH agrees with the literature data [22,25,52,53,[55][56][57][58][59]66].…”

“…In addition, CD experiments were undertaken to confirm if the chirality of the ancillary ligand, SS-DACH, was retained by the resulting complexes. The patterns observed in the CD spectra 1-6 (Figures S43-S48) were also consistent with the literature data [22,52,53,[55][56][57][58][59]66]. All notable peaks in the UV and CD spectra of the complexes are outlined in Table 4.…”

“…The electronic transitions demonstrated in the UV measurements were comparable with similar complexes in the literature [22,52,53,[55][56][57][58][59]66]. The UV spectra of 1-6 (Figures S37-S42) were acquired as previously reported [52,53,55].…”

“…To further confirm the successful coordination of NPX to the platinum core and only occupied one axial position, 1 H-195 Pt-HMQC experiments were undertaken at -2800 and 400 ppm. Normally, the platinum(II) scaffolds used in this study resonate at −2800 ppm while their corresponding platinum(IV) derivatives resonate at 400 ppm, as previously reported [22,25,52,53,[55][56][57][58][59]66]. According to the 1 H-195 Pt-HMQC spectrum of 1 (Figure 7), the correlation of the phen protons to the platinum was confirmed when two peaks resonated at 545 ppm.…”

“…Lipophilicity measurements were undertaken using HPLC, as previously described (see Supplementary Materials) [53,[55][56][57][58][59].…”