New approach to the activation of anti-cancer pro-drugs by metalloporphyrin-based cytochrome P450 mimics in all-aqueous biologically relevant system

Spasojević, Ivan; Colvin, O. Michael; Warshany, Keith R.; Batinić‐Haberle, Ines

doi:10.1016/j.jinorgbio.2006.07.013

Cited by 35 publications

(54 citation statements)

References 59 publications

(86 reference statements)

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“…Also, like cyt P450 enzymes, metalloporphyrins in their own right, when metal site is reduced, can bind oxygen and reduce it to superoxide and hydrogen peroxide, leading eventually to the oxidation of other biomolecules. Fe porphyrins are more successful than Mn analogues in doing so, as we reported with hydroxylation of cyclophosphamide (304). Further, a suggestion was made by Ohse et al (239) that, like ''free'' iron, the Fe(II) site of FeTM-4-PyP 5þ reacts with H 2 O 2 (formed through O 2 ·À dismutation), giving rise to · OH radicals.…”

Section: Fe Porphyrinssupporting

confidence: 52%

“…Thus, we observed that in the presence of ascorbate in phosphate buffer at pH 7.8, Mn(III) N-alkylpyridylporphyrins undergo oxidative degradation; UV=VIS evidence suggests that degradation involves H 2 O 2 formation (36-38). We also showed that both Fe and (less so) Mn porphyrins can mimic the cyt P450-catalyzed cyclophosphamide hydroxylation under biologically relevant conditions, using O 2 as a final electron acceptor and ascorbate as a sacrificial reductant (304). In another study, the cytotoxic effects of MnTE-2-PyP 5þ , MnTnHex-2-PyP 5þ , and MnTnHex-3-PyP 5þ in four cancer cell lines were studied in the presence and absence of ascorbate (346).…”

Section: Reactivity Towardmentioning

confidence: 80%

“…The Tauskela group (314,315,342) suggested the action of MnP on Ca 2þ metabolism (which may again be ROS modulated), whereas the Kalyanaraman group (176) reported on the induction of heme oxygenase by MnP. Because of the biologically accessible metal-centered reduction potential and the ability to reach four oxidation states in vivo (þ2, þ 3, þ 4, and þ 5), cationic Mn porphyrins can redox cycle with a number of biologic molecules, such as cellular reductants, flavoenzymes and cytochrome P450 reductase, and can mimic the cyt P450 family of enzymes (79,108,304); as a consequence of their rich chemistry and redoxcycling capabilities, these compounds may be easily involved in beneficial and in adverse pathways. The possibility that 882 BATINIĆ -HABERLE ET AL.…”

Section: A Metalloporphyrinsmentioning

confidence: 99%

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Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

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467

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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Section: Fe Porphyrinssupporting

confidence: 52%

Section: Reactivity Towardmentioning

confidence: 80%

Section: A Metalloporphyrinsmentioning

confidence: 99%

See 1 more Smart Citation

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

Self Cite

467

689

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“…The TD 50 was found to be 91.5 mg when MnTE-2-PyP 5+ was administered subcutaneously. a We have reported that Mn porphyrins can mimic cyt P450, yet to a lower extent than Fe analogous porphyrins [65]. It was also shown that Mn porphyrin can redox cycle with cyt P450 reductase which action was claimed to have possible beneficial and/or adverse effects [66].…”

Section: Resultsmentioning

confidence: 99%

Pharmacokinetics of the potent redox-modulating manganese porphyrin, MnTE-2-PyP5+, in plasma and major organs of B6C3F1 mice

Spasojević

Chen

Noel

et al. 2008

Free Radical Biology and Medicine

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Mn(III)tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP 5+ , a potent catalytic superoxide and peroxynitrite scavenger, has been beneficial in several oxidative stress-related disease thus far examined. Pharmacokinetic studies are essential for the better assessment of the therapeutic potential of MnTE-2-PyP 5+ and similar compounds, as well as for the modulation of their bioavailability and toxicity. Despite high hydrophilicity, this drug entered mitochondria after single 10 mg/kg intraperitoneal injection at levels high enough (5.1 µM; 2.95 ng/mg protein) to protect it against superoxide/peroxynitrite damage. Utilizing the same analytical approach, which involves the reduction of MnTE-2-PyP 5+ , followed by the exchange of Mn 2+ with Zn 2+ , and HPLC/fluorescence detection of ZnTE-2-PyP 4+ , we measured levels of MnTE-2-PyP 5+ in mouse plasma, liver, kidney, lung, heart, spleen, and brain over a period of 7 days after a single intraperitoneal injection of 10 mg/ kg. Two B6C3F1 female mice per time point were used. The pharmacokinetic profile in plasma and organs was complex; thus a non-compartmental approach was utilized to calculate the area under the curve (AUC), c max , t max , and drug elimination half-time (t 1/2 ). In terms of levels of MnTE-2-PyP 5+ found, the organs can be classified into 3 distinct groups: (1) high levels: kidney, liver, and spleen; (2) moderate levels: lung and heart; and (3) low levels: brain. The maximal levels in plasma, kidney, spleen, lung, and heart are reached within first 45 minutes whereas in case of liver a prolonged absorption phase was observed with the maximal concentration reached at 8 hours. Moreover, accumulation of the drug in brain continues beyond time of the experiment (7 days) and is likely driven by the presence of negatively charged phospholipids. For tissues other than brain, a slow elimination phase (single exponential decay, t 1/2 = 60 to 135 hours) is observed. The calculated pharmacokinetic parameters will be used to design optimal dosing regimens in future preclinical studies utilizing this and similar compounds.

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“…Much effort has been focused on the search for both more stable and catalytically efficient Fe and Mn porphyrins [1][2][3][6][7][8] that are able to promote selective oxidation/oxygenation reactions of a variety of organic compounds under mild conditions. These P450-type C-H activation reactions carried out under biomimetic conditions make use of a number of oxygen-atom donors, such as the mechanistically friendly PhIO [3,4,[8][9][10] and ClO À [8,9,11] or the environmentally relevant H 2 O 2 [8,[12][13][14] and O 2 [4,6,7,[15][16][17].…”

Section: Introductionmentioning

confidence: 99%