Metal substrate catalysis in the confined space for platinum drug delivery

Velasco‐Lozano, Susana; Castro, Silvia Alonso‐de; Sanchez‐Cano, Carlos; Benítez‐Mateos, Ana I.; López‐Gallego, Fernando; Salassa, Luca

doi:10.1039/d1sc05151b

Cited by 11 publications

(20 citation statements)

References 58 publications

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“…In the first instance, we immobilized FMN onto AG beads functionalized with diethyl aminoethyl groups (AG-DEAE) through electrostatic interactions, as previously reported. [8] So, we obtained catalysts, dubbed as FMN@AG-DEAE, that were loaded with 0.69-5.79 µmol g -1 of flavin (entries 1-3). In parallel, we synthesized an aminated flavin (Rf-NH2) through N3 functionalization of riboflavin with a Br-alkyl amine (see Supporting Information, Figure S1-S6) and explored its covalent attachment on porous AG beads, bearing epoxide (AG-E, Table 1, entries 4-6) or aldehyde groups (AG-G, Table 1, entries 7-10).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, we detected NOX activity upon incubation of FMN@AG-DEAE with NADH in the dark, confirming our previous results. [8] This was possible due to the electrostatic absorption of NAD + onto the AG-DEAE surface, where colocalization with the immobilized FMN facilitated the electron transfer from the enzymatically produced NADH to the flavin. To confirm that the co-immobilization of the flavin and the dehydrogenase is the driver of the in situ regeneration of NAD + in the absence of light, we performed the reaction in the dark using free FMN and BsADH.…”

Section: Resultsmentioning

confidence: 99%

“…AG-DEAE: FMN@AG-DEAE were prepared as described in our previous work. [8] Approximately 50 mg of AG-DEAE were prewashed three times by soaking and shaking the microbeads for 10 min (0.5 mL x 3) in Tris buffer (10 mM, pH 7.6). Then, FMN (0.15-1 mM, 0.5 mL) was dissolved in the same buffer and sequentially loaded on the AG beads.…”

Section: Synthesis Of Ag-gmentioning

confidence: 99%

“…Recently, our groups demonstrated that NADH could be effectively oxidized in the dark when a platinum coordination compound is used as the ultimate electron acceptor by co-immobilization of FMN and NADH on porous materials, such as agarose (AG) microbeads, through electrostatic interactions. [8], [9] This system mimics the cofactor organization of most NADH oxidases (NOX) as both FMN and NADH intimately co-localize across the structure of the porous chassis in which they are confined. [10] Thus, the chances for electron transfer between the two cofactors increase, although the flavin is not photoexcited.…”

Section: Introductionmentioning

confidence: 99%

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Chemoenzymatic oxidation of diols catalyzed by co-immobilized flavins and dehydrogenases

Pacheco

Plata

Santos³

et al. 2023

Preprint

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Enzyme driven oxidations catalyzed by alcohol dehydrogenases rely on the in situ NAD(P)+ regeneration. A wide variety of chemoenzymatic and fully enzymatic methods have been reported over the last 30 years to integrate the cofactor regeneration in biocatalytic oxidations. However, the most examples are limited to homogeneous systems where the reuse of both enzymes and chemical catalysts are challenging. In this work, we co-immobilized an alcohol dehydrogenase from Bacillus stearothermophilus with a flavin derivative (FMN), which performs as an organocatalyst that oxidizes NADH back to NAD+. This latter oxidized cofactor is sequentially utilized by the dehydrogenase to oxidize 1,-diols. Remarkably, the immobilization chemistry of the FMN determines its efficiency to recycle the nicotinamide cofactor and, unlike in its free state, the immobilized FMN can oxidizes NADH in dark. This was possible because the support where both enzyme and FMN are immobilized also captures NADH, and makes the electron transfer from the substrates to the cofactors more efficient. This work illustrates how the co-immobilization and confinement of bio and chemical catalysts on solid materials (heterogeneous system) enable chemoenzymatic cascades that are precluded in solution (homogeneous system).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Ag-gmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Chemoenzymatic oxidation of diols catalyzed by co-immobilized flavins and dehydrogenases

Pacheco

Plata

Santos³

et al. 2023

Preprint

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“…7,8 Furthermore, the incorporation of flavins onto hydrogels could be exploited for engineering catalytic delivery devices for cisplatin. 9 In these catalytic reactions (Figure 1), the light-irradiated flavin catalyst is first reduced in the presence of an electron donor (e.g. NADH or ascorbate) to form the doubly reduced flavin hydroquinone FlH2 (or FlHat pH > 7).…”

Section: Introductionmentioning

confidence: 99%

Flavin-conjugated Pt(IV) anticancer agents

Sánchez-Camacho

Tadeo-Infante

Carrasco

et al. 2023

Preprint

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In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control anticancer activity and overcome off-target toxicity linked to classic platinum chemotherapeutic agents. Herein, we present the design and synthesis of two new asymmetric Pt(IV) derivatives of cisplatin and oxaliplatin (1·TARF and 2·TARF, respectively) bearing a 2',3',4',5'-tetraacetylriboflavin moiety (TARF) covalently bonded. 1H and 195Pt NMR spectroscopy shows that 1·TARF and 2·TARF can be effectively activated into toxic Pt(II) species, when incubated with NADH, sodium ascorbate, and glutathione (GSH) in the dark and under light irradiation. Density functional theory studies of the dark Pt(IV)-to-Pt(II) conversion of 2·TARF indicate that the process involves first a hydride transfer from the donor to the flavin moiety of the complex, followed by electron transfer to the Pt(IV) center. When administered to MDA-MB-231 breast cancer cells pre-incubated with non-toxic amounts of ascorbate, 2·TARF displays enhanced toxicity (between one and two orders of magnitude), suggesting that generation of oxaliplatin can selectively be triggered by redox activation. Such an effect is not observed when 2 and TARF are co-administered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.

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Chemoenzymatic Oxidation of Diols Catalyzed by Co‐Immobilized Flavins and Dehydrogenases**

et al. 2023

Self Cite

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Enzyme driven oxidations catalyzed by alcohol dehydrogenases rely on the in situ NAD(P) + regeneration. A wide variety of chemoenzymatic and fully enzymatic methods have been reported over the last 30 years to integrate the cofactor regeneration in biocatalytic oxidations. However, the majority of examples are limited to homogeneous systems where the reuse of both enzymes and chemical catalysts are challenging. In this work, we co-immobilize an alcohol dehydrogenase from Bacillus stearothermophilus with a flavin derivative (FMN), which performs as an organocatalyst that oxidizes NADH back to NAD + . This latter oxidized cofactor is sequentially utilized by the dehydrogenase to oxidize 1,ω-diols. Remarkably, the immobilization chemistry of FMN determines its efficiency to oxidize NADH and, unlike in its free state, the immobilized FMN can recycle NAD + in dark. This is possible because the support where both enzyme and FMN are immobilized also captures NADH, making the electron transfer from the substrates to the cofactors more efficient. This work illustrates how the coimmobilization and confinement of bio and chemical catalysts on solid materials (heterogeneous phase) enable chemoenzymatic cascades that are precluded in solution (homogeneous phase).

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Metal substrate catalysis in the confined space for platinum drug delivery

Abstract: Loading of a flavin catalyst and Pt prodrug onto a hydrogel affords biomaterials for the catalytic generation and delivery of cisplatin upon light irradiation or addition of electron donors. Confinement boosts the turnover frequency of the flavin.

Cited by 11 publications

References 58 publications

Chemoenzymatic oxidation of diols catalyzed by co-immobilized flavins and dehydrogenases

Chemoenzymatic oxidation of diols catalyzed by co-immobilized flavins and dehydrogenases

Flavin-conjugated Pt(IV) anticancer agents

Chemoenzymatic Oxidation of Diols Catalyzed by Co‐Immobilized Flavins and Dehydrogenases**

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