Recent advances in the chemistry of iron-based chemotherapeutic agents

Basu, Uttara; Roy, Mithun; Chakravarty, Akhil R.

doi:10.1016/j.ccr.2020.213339

Cited by 83 publications

(59 citation statements)

References 178 publications

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“…[4] In principle, iron is a convenient choice, since it is a bioavailable element and nontoxic in many forms; [5] moreover, its earth abundancy has made several cost-effective compounds available to the researchers for the exploration of the reactivity and the consequent development of new structural motifs. A variety of mono-iron compounds has been investigated for the anticancer potential, [6,7] and substituted ferrocenes (ferrocifens) have been regarded as promising drug candidates. [8] The feasible Fe + II to Fe + III oxidation in the physiological environment and the conjugation of suitable organic moieties to the robust sandwich scaffold are responsible for a considerable activity, which is basically related to the production of damaging metabolites within cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

Biancalana

Franco

Ciancaleoni

et al. 2021

Chemistry A European J

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A straightforward two‐step procedure via single CO removal allows the conversion of commercial [Fe2Cp2(CO)4] into a range of amphiphilic and robust ionic complexes based on a hybrid aminocarbyne/iminium ligand, [Fe2Cp2(CO)3{CN(R)(R’)}]X (R, R’=alkyl or aryl; X=CF3SO3 or BF4), on up to multigram scales. Their physicochemical properties can be modulated by an appropriate choice of N‐substituents and counteranion. Tested against a panel of human cancer cell lines, the complexes were shown to possess promising antiproliferative activity and to circumvent multidrug resistance. Interestingly, most derivatives also retained a significant cytotoxic activity against human cancer 3D cell cultures. Among them, the complex with R=4‐C6H4OMe and R’=Me emerged as the best performer of the series, being on average about six times more active against cancer cells than a noncancerous cell line, and displayed IC50 values comparable to those of cisplatin in 3D cell cultures. Mechanistic studies revealed the ability of the complexes to release carbon monoxide and to act as oxidative stress inducers in cancer cells.

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Section: Introductionmentioning

confidence: 99%

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

Biancalana

Franco

Ciancaleoni

et al. 2021

Chemistry A European J

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“…Iron is an attractive element in this respect due to its bioavailability, which substantially limits the toxic effects of its compounds, and the feasible redox chemistry in physiological media, usually involving the +II and +III oxidation states [ 17 , 18 ]. A variety of monoiron complexes have been assessed for the anticancer potential both in vitro and in vivo [ 19 , 20 , 21 , 22 ]. Following the successful experience with ferroquine, a conjugate between ferrocene and the drug chloroquine, which entered phase II clinical trials as an antimalarial agent ( Figure 1 , structure I ) [ 4 , 23 , 24 ], the anticancer properties of related ferrocene derivatives have been intensively investigated (an example in Figure 1 , structure II ) [ 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

et al. 2021

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A series of 16 novel diiron complexes of general formula [Fe2Cp2(CO)(μ-CO){μ-η1:η3-C(R′)C(R″)CN(R)(Y)}]CF3SO3 (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron μ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH2Ph, R′ = R″ = Me) and 3a (R = CH2CH=CH2, Y = R′ = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV–Vis methods were used to assess the D2O solubility, the stability in aqueous solution at 37 °C and the octanol–water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2–7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R′ = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR).

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“…Subsequent deprotonation, a second oxidation to generate a ferrocenyl-stabilized carbocation, and a final deprotonation, allows the iron to regain its initial +2 state; the resulting quinone methide is a new bioorganometallic entity that behaves as a selective electrophile. The redox potential of the iron is particularly suitable for biology [89,90], such that on cancer cells the ferrocifens initially produce Reactive Oxygen Species (ROS) that unlock the above-mentioned sequence of reactions. Moreover, the ability of the OM-QM to undergo nucleophilic addition of cellular thiols or selenols, that normally control oxidative stress, plays a crucial role in its bioactivity.…”

Section: Discussionmentioning

confidence: 99%

Multifaceted chemical behaviour of metallocene (M = Fe, Os) quinone methides. Their contribution to biology

Vessières

Wang

McGlinchey

et al. 2021

Coordination Chemistry Reviews

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Recent advances in the chemistry of iron-based chemotherapeutic agents

Cited by 83 publications

References 178 publications

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

Easily Available, Amphiphilic Diiron Cyclopentadienyl Complexes Exhibit in Vitro Anticancer Activity in 2D and 3D Human Cancer Cells through Redox Modulation Triggered by CO Release

Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

Multifaceted chemical behaviour of metallocene (M = Fe, Os) quinone methides. Their contribution to biology

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