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 of riboflavin (photocatalyst) and a Pt(IV) prodrug complex. The Pt-loaded flavoprotein induced a 40% reduction in PANC-1 cell viability as a result of the photocatalytic formation of cisplatin.
Subject(s)
Antineoplastic Agents , Prodrugs , Prodrugs/pharmacology , Flavoproteins , Cisplatin , Antineoplastic Agents/pharmacology , Riboflavin/pharmacology , Cell Line, TumorABSTRACT
Photoactivatable Pt(IV) prodrugs represent nowadays an intriguing class of potential metal-based drugs, endowed with more chemical inertness in their oxidized form and better selectivity for the target with respect to the clinically established Pt(II) compounds. In fact, they have the possibility to be reduced by light irradiation directly at the site of interest. For this reason, we synthesized a new Pt(IV) complex, [Pt(OCOCH3)3(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (1), that is well soluble in aqueous medium and totally unreactive towards selected model biomolecules until its reduction. The highlight of this work is the rapid and efficient photoreduction of 1 with visible light (460 nm), which leads to its reactive Pt(II) analogue. This behavior was made possible by taking advantage of an efficient catalytic system based on flavin and NADH, which is naturally present in the cellular environment. As a comparison, the reduction of 1 was also studied with simple UV irradiation, but both UV-Vis spectrophotometry and 1H-NMR spectrometry showed that the flavin-catalyzed reduction with visible light was faster. Lastly, the reactivity against two representative biological targets, i.e., human serum albumin and one monofilament oligonucleotide fragment, was evaluated by high-resolution mass spectrometry. The results clearly pointed out that the prodrug 1 did not interact with these targets until its photoreduction to the Pt(II) analogue.
Subject(s)
Antineoplastic Agents , Prodrugs , Humans , Antineoplastic Agents/chemistry , Organoplatinum Compounds/chemistry , Light , Magnetic Resonance Spectroscopy , Prodrugs/chemistryABSTRACT
Our recent work demonstrates that certain flavoproteins can catalyze the redox activation of Pt(IV) prodrug complexes under light irradiation. Herein, we used site-directed mutagenesis on the mini singlet oxygen generator (mSOG) to modulate the photocatalytic activity of this flavoprotein toward two model Pt(IV) substrates. Among the prepared mutants, Q103V mSOG displayed enhanced catalytic efficiency as a result of its longer triplet excited-state lifetime. This study shows, for the first time, that protein engineering can improve the catalytic capacity of a protein toward metal-containing substrates.
Subject(s)
Coordination Complexes/chemistry , Flavoproteins/chemistry , Platinum/chemistry , Protein Engineering , Catalysis , Models, Molecular , Molecular Structure , Photochemical ProcessesABSTRACT
Catalysis has strongly emerged in the field of medicinal inorganic chemistry as a suitable tool to deliver new drug candidates and to overcome drawbacks associated to metallodrugs. In this Concept article, we discuss representative examples of how catalysis has been applied in combination with metal complexes to deliver new therapy approaches. In particular, we explain key achievements in the design of catalytic metallodrugs that damage biomolecular targets and in the development of metal catalysis schemes for the activation of exogenous organic prodrugs. Moreover, we discuss our recent discoveries on the flavin-mediated bioorthogonal catalytic activation of metal-based prodrugs; a new catalysis strategy in which metal complexes are unconventionally employed as substrates rather than catalysts.
