Zweifel an einem Dogma: Hydrolyse äquatorialer Liganden von Pt^IV‐Komplexen unter physiologischen Bedingungen

Abstract

Pt IV -Komplexe gelten aufgrund ihrer hohen kineti-schenI nertheit und der folglich reduzierten Nebenreaktionen mit Biomolekülen als die Zukunft der Platintherapeutika. In dieser Arbeit wurde unter physiologischr elevanten Bedingungen die Stabilitäte iner Reihe von Pt IV -Biscarboxylatokomplexen in wässriger Lçsung untersucht. Entgegen des derzeitigen chemischen Kenntnisstandes zeigten (sogar in Zellkulturmedium und Serum) vor allem Oxaliplatin-und Satraplatinkomplexeeine schnelle äquatoriale Hydrolyse.Die gebildeten Hydrolyseprodukte unterscheiden sich besonders stark in ihrer Reduktionskinetik, einem entscheidenden Parameter fürd ie Aktivierung von Pt IV -Medikamenten, welcher auchmit der zytotoxischen Effizienz der Verbindungen in der Zellkultur korreliert. Die Entdeckung, dass intakte Pt IV -Komplexe an äquatorialer Position hydrolysiert werden kçnnen, widerspricht dem Dogma hinsichtlichd er allgemeinen kineti-schenI nertheit von Pt IV -Verbindungen und muss beim Screening und der Entwicklung neuer platin-basierter Krebsmedikamente berücksichtigtw erden.

Pt(IV) Anticancer Prodrugs – A Tale of Mice and Men

“…We developed new procedures for oxidation of Pt(II) compounds [29][30][31] and new protocols for conjugation of hydroxyl and amino containing molecules to the axial positions via carbonate and carbamate links. [27,28] We learned that Pt(IV) complexes are less stable than originally assumed [32,33] and that rates of reduction do not necessarily correlate with reduction potentials [34] and that reduction of Pt(IV) complexes can yield several products. [35] While curing cancer with Pt(IV) compounds is our ultimate goal, finding the right path to get there has proven to be a very elusive undertaking.…”

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum‐Resistant Metastatic CRC and CRPC Cell Models

“…It can be attributed to phosphorescence 3 IL emission due to the observation of al arge Stokes' shift and the quenching of the emission in the presence of oxygen ( Figure S11, Supporting Information). [21] First, we assessed the effect of the Pt II and Pt IV compounds on the proliferation of ac ancerp anel including SW620 (lymph node metastasis of colorectal cancer), PC-3 (bone metastasis of prostatec ancer), A549 (lung adenocarcinoma), and MCF-7 (breasta denocarcinoma). The obtained spectra ( Figure S12, Supporting Information) suggests the formationo famixture of solvato complexes,w hich is in line with recent observations of aquation of equatorial ligandsofP t IV compounds.…”

“…The obtained spectra ( Figure S12, Supporting Information) suggests the formationo famixture of solvato complexes,w hich is in line with recent observations of aquation of equatorial ligandsofP t IV compounds. [21] First, we assessed the effect of the Pt II and Pt IV compounds on the proliferation of ac ancerp anel including SW620 (lymph node metastasis of colorectal cancer), PC-3 (bone metastasis of prostatec ancer), A549 (lung adenocarcinoma), and MCF-7 (breasta denocarcinoma). Our results, summarized in Table 2, indicatet hat the IC 50 of all the compounds except 2a' and 2b' were significantly lower than both cisplatin ando xaliplatin for the breast cancer cell line MCF-7.…”