Luminescent Pt^II and Pt^IV Platinacycles with Anticancer Activity Against Multiplatinum‐Resistant Metastatic CRC and CRPC Cell Models

Abstract

Platinum-based chemotherapy persists to be the only effective therapeutic option against aw idev ariety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common,ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encounteringa lternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reductions tudies, and luminescent properties of as eries of cyclometallated (C,N,N')Pt IV compounds derivedfrom amine-imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistantc olorectal cancer (CRC) and castration-resistant prostate cancer( CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effectivea nd selective for ab roader cancer panel,i ncludingb reast and lung cancer.A dditionally,s elected compounds have been further evaluated, findingashift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancerc ells, being also able to oxidize cysteine residues andi nhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.Platinum-based chemotherapy is often the only effective treatment against ab road spectrumo ft umors,even if their success is limited by side-effects and resistance. OctahedralP t IV compounds have been shown to be av ery promising kindo fp rodrugss ince they are kinetically inert compared to Pt II analoguesa nd the two extra coordination positions allow the tuningo ft heir properties. [1][2][3][4] In particular,m ultiple action Pt IV prodrugs derived from cisplatin have attracted mucha ttention in recent years. [5][6][7] On the other hand,c yclometallated Pt II compounds containing bidentate (C,N) or tridentate (C,N,N')l igands display interestingp roperties. [8][9][10] Thep resence of a s(PtÀC) bond increases the stabilityo ft hese compounds, thus allowingt hem to reach the cell unaltered. In addition, covalent coordinationt o DNA is favoured since the strong PtÀCb ondi ncreasest he lability of the ligand in a trans position. Moreover,t he presence of aromatic planarg roups might favour intercalative binding to DNA through noncovalent p-p stacking interactions. Furthermore, several cyclometallatedP t II anticancer agentse xhibit luminescence properties which make them potential luminescent probesf or DNA in living cells and also allows easy tracing of their cellular uptake and distribution by fluorescencem icroscopy. [11,12] Surprisingly,l ittle attention has been devoted to [a] A.

A C^N Cycloplatinated(II) Fluoride Complex: Photophysical Studies and Csp3–F Bond Formation

“…While transition-metal complexes with Cl, Br, and I ligands are very common, the F-containing analogues are much less available, especially for late-transition-metal cations in low oxidation states, − thus preventing a complete study across the group. For example, halide ligands (Cl, Br, and I) have been shown to largely influence the emission properties of Pt­(II), − Pt­(IV), , and Cu­(I) − complexes. The scarcity of transition-metal fluoride complexes is largely due to their high reactivity and limited synthetic methods, as predicted by the hard/soft acid–base theory that the fluoride ion (hard base) is mismatched with soft acids such as Pt­(II), Pd­(II), and Au­(I) …”

Effect of Gold(I) on the Room‐Temperature Phosphorescence of Ethynylphenanthrene

“…This phenomenon is difficult to be successfully achieved through pure organic molecules under normal conditions (room temperature and normal pressure) because of the weak spin‐orbital coupling (SOC) between excited singlet and triplet states as well as the fast non‐radiative deactivation of triplet excitons. Heavy atom induced phosphorescence of organic chromophores originating from SOC is a studied mechanism for RTP emitting materials owing to the well‐known heavy atom effect [7–13] . For these reasons, the phenomenon of RTP has become popular for inorganic and organometallic complexes, easily containing heavy metal atoms, which exhibit strong RTP, mostly originating from the 3 MLCT (metal to ligand charge transfer) transition [14] .…”

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

“…They were reported to exhibit approximately equivalent cytotoxicity to cisplatin, but were not cross-resistant with cisplatin, and had much higher selectivity and cellular accumulation. The fluorescent properties of these complexes could be fine-tuned by altering the size of the NˆN chelating ring or the substitutes of the aryl ring [89]. They were reported to exhibit approximately equivalent cytotoxicity to cisplatin, but were not cross-resistant with cisplatin, and had much higher selectivity and cellular accumulation.…”

“…They were reported to exhibit approximately equivalent cytotoxicity to cisplatin, but were not cross-resistant with cisplatin, and had much higher selectivity and cellular accumulation. The fluorescent properties of these complexes could be fine-tuned by altering the size of the N^N chelating ring or the substitutes of the aryl ring [89].…”