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Flavin-Conjugated Pt(IV) Anticancer Agents
journal contribution
posted on 2023-03-30, 01:03 authored by Juan Sánchez-Camacho, Sonia Infante-Tadeo, Ana C. Carrasco, Stefano Scoditti, Álvaro Martínez, Fabienne Barroso-Bujans, Emilia Sicilia, Ana M. Pizarro, Luca SalassaIn
situ activation of Pt(IV) to Pt(II) species is a promising strategy
to control the anticancer activity and overcome the 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 covalently bonded 2′,3′,4′,5′-tetraacetylriboflavin
moiety (TARF). 1H and 195Pt NMR
spectroscopy shows that 1·TARF and 2·TARF can be effectively activated into toxic Pt(II) species, when incubated
with nicotinamide adenine dinucleotide, sodium ascorbate, and glutathione
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 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 preincubated with nontoxic amounts of ascorbate, 2·TARF displays enhanced toxicity (between 1 and 2 orders of magnitude),
suggesting that the generation of oxaliplatin can selectively be triggered
by redox activation. Such an effect is not observed when 2 and TARF are coadministered under the same conditions,
demonstrating that covalent binding of the flavin to the Pt complex
is pivotal.
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target toxicity linkednicotinamide adenine dinucleotidemagnitude ), suggestingdisplays enhanced toxicitytarf b195 sup2 boxaliplatin (< b1 sup2 orderssitu activationredox activationpromising strategynontoxic amountslight irradiationelectron transfereffectively activatedcovalent bindinganticancer agentsanticancer activity
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