Oxali(IV)Fluors: Fluorescence Responsive Oxaliplatin(IV) Complexes Identify a Hypoxia-Dependent Reduction in Cancer Cells

Abstract

Platinum(IV) anticancer agents have demonstrated the potential to overcome the limitations associated with the widely used Pt(II) chemotherapeutics, cisplatin, carboplatin, and oxaliplatin. In order to identify therapeutic scenarios where this type of chemotherapy can be applied, an improved understanding on the intracellular reduction of Pt(IV) complexes is needed. Here, we report the synthesis of two fluorescence responsive oxaliplatin(IV)(OxPt) complexes, OxaliRes and OxaliNap. Sodium ascorbate (NaAsc) was shown to reduce each OxPt(IV) complex resulting in increases in their respective fluorescence emission intensities at 585 and 545 nm. The incubation of each OxPt(IV) complex with a colorectal cancer cell line resulted in minimal changes to the respective fluorescence emission intensities. In contrast, the treatment of these cells with NaAsc showed a dosedependent increase in fluorescence emission intensity. With this knowledge in hand, we tested the reducing potential of tumor hypoxia, where an oxygen-dependent bioreduction was observed for each OxPt(IV) complex with <0.1% O 2 providing the greatest fluorescence signal. Clonogenic cell survival assays correlated with these observations demonstrating significant differences in toxicity between hypoxia (<0.1% O 2 ) and normoxia (21% O 2 ). To the best of our knowledge, this is the first report showing carbamatefunctionalized OxPt(IV) complexes as potential hypoxia-activated prodrugs.

Exploring the Impact of Head Group Modifications on the Anticancer Activities of Fatty-Acid-like Platinum(IV) Prodrugs: A Structure–Activity Relationship Study

“…The synthesis of the Pt(IV) prodrug (2-8) is depicted in Figure S1A in the Supplementary Materials. Briefly, amino moieties with different hydrophobicities (10)(11)(12)(13)(14)(15)(16) were conjugated to compound 1 via the HATU-catalyzed amide bond formation reaction. The final compounds were purified via flash column chromatography and/or recrystallization.…”

Advances in technical strategies for monitoring the reduction of platinum(iv) complexes

“…Sedgwick's group utilized a similar method to incorporate the fluorophore resorufin into a Pt( iv ) complex, and a fluorescence probe 46 was obtained (Scheme 10B). 156 This carbamate-functionalized probe displayed sodium ascorbate-dependent increases in fluorescence emission intensities. Complex 46 showed potential as a hypoxia-activated prodrug.…”

Pt(iv) anticancer prodrugs bearing an oxaliplatin scaffold: what do we know about their bioactivity?

“…12A). 42 The fluorescence of their axial ligands (resofurin and naphthalimide, respectively) drastically increases when released upon Pt( iv ) reduction. Authors also described an increased Pt( iv ) reduction under hypoxic conditions, a feature typical of tumor microenvironments, in HCT116 cells treated with OxaliRes and OxaliNap for 6 h (Fig.…”