Engineered flavoproteins as bioorthogonal photo-triggers for the activation of metal-based anticancer prodrugs

Mazzei, Laura F; Gurruchaga-Pereda, Juan; Martínez, Álvaro; Calvo, Javier; Salassa, Luca; Cortajarena, Aitziber L.

doi:10.1039/d2cc06363h

Cited by 5 publications

(4 citation statements)

References 41 publications

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“…Rf‐NH 2 was synthesized and characterized as previously described by Mazzei et al [17] . Reaction scheme and all the characterization are reported in the Supporting Information (Figures S1–S6).…”

Section: Methodsmentioning

confidence: 99%

“…Silica gel (0.035-0.070 mm, 60 Å) was used for flash chromatography and Merck 60 F254 foils were used for thin layer chromatography. Rf-NH 2 was synthesized and characterized as previously described by Mazzei et al [17] Reaction scheme and all the characterization are reported in the Supporting Information (Figures S1-S6).…”

Section: Experimental Section Materialsmentioning

confidence: 99%

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

et al. 2023

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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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Section: Methodsmentioning

confidence: 99%

Section: Experimental Section Materialsmentioning

confidence: 99%

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

et al. 2023

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“…), or photoactivation, which are equally valuable. We refer the readers to more comprehensive recent reviews for such approaches. − …”

Section: Conclusion and Outlookmentioning

confidence: 99%

Metals in Cancer Research: Beyond Platinum Metallodrugs

Casini,

Pöthig

2024

ACS Cent. Sci.

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The discovery of the medicinal properties of platinum complexes has fueled the design and synthesis of new anticancer metallodrugs endowed with unique modes of action (MoA). Among the various families of experimental antiproliferative agents, organometallics have emerged as ideal platforms to control the compounds' reactivity and stability in a physiological environment. This is advantageous to efficiently deliver novel prodrug activation strategies, as well as to design metallodrugs acting only via noncovalent interactions with their pharmacological targets. Noteworthy, another justification for the advance of organometallic compounds for therapy stems from their ability to catalyze bioorthogonal reactions in cancer cells.When not yet ideal as drug leads, such compounds can be used as selective chemical tools that benefit from the advantages of catalytic amplification to either label the target of interest (e.g., proteins) or boost the output of biochemical signals. Examples of metallodrugs for the so-called "catalysis in cells" are considered in this Outlook together with other organometallic drug candidates. The selected case studies are discussed in the frame of more general challenges in the field of medicinal inorganic chemistry.

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“…In our research, we have discovered that flavins and flavoproteins, both in their natural and synthetic forms, possess the ability to photocatalyze the conversion of Pt(IV) anticancer prodrugs into clinically approved Pt(II) drugs in the presence of electron donors. [15][16][17][18][19][20] Unlike conventional catalysis, where metal complexes typically act as catalysts, in these reactions, they serve as substrates. 21 Flavin reactivity towards Pt(IV) complexes demonstrates remarkable selectivity and efficiency, particularly in terms of turnover number and frequency.…”

Section: Introductionmentioning

confidence: 99%

Red-Light Photocatalytic Activation Of Pt(IV) Anticancer Prodrugs Using Methylene Blue

Carrasco,

Bajetto,

Scoditti

et al. 2024

Preprint

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Catalysis-based approaches offer versatile strategies for activating anticancer prodrugs, potentially allowing precise control over drug release and localization within tumor tissues, while reducing systemic toxicity. In this study, we explore the role of the phenothiazine dye methylene blue (MB+) as a photocatalyst in conjunction with biologically relevant electron donors to facilitate the red-light conversion of two Pt(IV) complexes, denoted as cis,cis,trans-[PtCl2(NH3)2(O2CCH2CH2COOH)2] (1) and trans-[Pt(O2CCH2CH2COOH)21R,2R-(DACH)(ox)] (2), into cisplatin and oxaliplatin, respectively. Combining spectroscopic techniques (NMR, UV-Vis, flash photolysis) with computational methods, we reveal that the doubly reduced MB+ (leucomethylene blue, LMB) triggers the reductive elimination of axial ligands in the two Pt(IV) precursors, generating the corresponding Pt(II) anticancer drugs. In vitro experiments conducted on the human cervical cancer cell line CaSki, which harbors multiple copies of the integrated HPV-16 genome, and on non-tumoral cells (HaCat) demonstrate that co-administration with Pt(IV) prodrugs improves MB+'s antiproliferative efficacy in cancer cells, particularly under red light exposure. This enhancement arises from the catalytic production of Pt(II) species within the cellular environment.

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Engineered flavoproteins as bioorthogonal photo-triggers for the activation of metal-based anticancer prodrugs

Abstract: A multifunctional hybrid constructed for controlling the delivery and activation of Pt anticancer agents in vitro is described herein. We employed consensus tetratricopeptide repeat protein (CTPR) for the covalent co-anchoring...

Cited by 5 publications

References 41 publications

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

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

Metals in Cancer Research: Beyond Platinum Metallodrugs

Red-Light Photocatalytic Activation Of Pt(IV) Anticancer Prodrugs Using Methylene Blue

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