Novel polyamide amidine anthraquinone platinum(II) complexes: cytotoxicity, cellular accumulation, and fluorescence distributions in 2D and 3D cell culture models

Abstract

1-and 1,5-Aminoalkylamine substituted anthraquinones (AAQs, 1C3 and 1,5C3) were peptide coupled to 1-, 2-, and 3-pyrrole lexitropsins to generate compounds that incorporated both DNA minor groove and intercalating moieties. The corresponding platinum(II) amidine complexes were synthesized through a synthetically facile amine-to-platinum mediated nitrile 'Click' reaction. The precursors as well as the corresponding platinum(II) complexes were biologically evaluated in 2D monolayer cells and 3D tumour cell models. Despite having cellular accumulation levels that were up to five-fold lower than that of cisplatin, the platinum complexes had cytotoxicities that were only three-fold lower. Accumulation was lowest for the complexes with two or three pyrrole groups, but the latter was the most active of the complexes exceeding the activity of cisplatin in the MDA-MB-231 cell line. All compounds showed moderate to good penetration into spheroids of DLD-1 cells with the distributions being consistent with active uptake of the pyrrole containing complexes in regions of the spheroids starved of nutrients.

Photoactive and Luminescent Transition Metal Complexes as Anticancer Agents: A Guiding Light in the Search for New and Improved Cancer Treatments

“…A small family of polyamide conjugated complexes (Figure 9: PT16) has been created that incorporates multiple DNA-binding moieties, including minor and major groove binders as well as intercalating moieties. These complexes demonstrated moderate-to-good penetration of spheroids, which is promising for treating tumors some distance from the vasculature (Table 3: PT16) [87]. Photosensitizer platinum complexes: Y-shaped platinum complex PT1 [71]; square planar Pt(II) with weak photosensitizer, where BODIPY = boron-dipyrromethene, PT2 [72] and PT3 [73]; platinum-galadium complex PT4 [74]; triangular tri-platinum complex PT5 [75]; dual-platinum center Pt(II) diethienylcyclopentene PT6 in "open" and "closed" positions [76], PT7 [77], and PT8 [78]; platinum complexes (used to decorate a nanoparticle) PT9 [79] and PT10, [80]; platinum polymers PT11 [81] and PT12 [82]; and platinum complex (used as part of a nanoparticle) PT13 [83].…”

“…A small family of polyamide conjugated complexes (Figure 9: PT16) has been created that incorporates multiple DNA-binding moieties, including minor and major groove binders as well as intercalating moieties. These complexes demonstrated moderate-to-good penetration of spheroids, which is promising for treating tumors some distance from the vasculature (Table 3: PT16) [87].…”

“…The organo-metallic bond in cyclometallated complexes results in a net deprotonation of the carbon, making it a strong σ-donor, whereas the polypyridyl group is a good Figure 10. Platinum complexes with fluorescent moieties: PT13 [84]; PT15 Pt(II) imidazole phenanthroline complex [86]; and PT16 polyamide conjugated complex, where n = 2 [87]. Table 3.…”

“…A summary of the IC 50 values, luminescent properties, and special features of platinumbased luminescent anticancer complexes. Cyclometallated complexes PT17a, where R' = H, and PT17b, where R' = F [88]; Pt(II) imidazole phenanthroline complex PT15 [86]; platinum-decorated nanoparticle PT9 [79]; dual-platinum-center platinum(II) diethienylcyclopentene PT6 [76]; square planar Pt(II) with weak photosensitizer PT2 [72]; and polyamide conjugated complex PT16 [87].…”

“…Figure10. Platinum complexes with fluorescent moieties: PT13[84]; PT15 Pt(II) imidazole phenanthroline complex[86]; and PT16 polyamide conjugated complex, where n = 2[87].…”