Efficient Use of the Iron Ortho‐Nitrophenylporphyrin Chloride to Mimic Biological Oxidations of Dimethylaminoantipyrine

Bazin, Marc; Shi, Huaizhong; Delaney, James C.; Kline, Billie J.; Zhu, Zhendong; Kuhn, Cyrille; Berlioz, Françoise; Farley, Kathleen A.; Fate, Gwen; Lam, W. W.; Walker, Gregory S.; Yu, Linning; Pollastri, Michael P.

doi:10.1111/j.1747-0285.2007.00568.x

Cited by 9 publications

(5 citation statements)

References 14 publications

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“…By testing the effect induced by samples of serum obtained from animals treated with the tetracycline derivatives, it was also possible to evaluate the antibacterial effect in vivo . This is particularly important when evaluating the activity of PMIN, as the potential cleavage of the pyrazoline ring, a process that is not highly unlikely, as it has been demonstrated for other drugs ( Bazin et al ., 2007 ), might lead to the formation of corresponding tetracyclines with antibacterial activity. If such a process occurred in vivo , the potential advantage of PMIN over usual tetracycline derivatives in the treatment of non‐infectious conditions would be lost.…”

Section: Discussionmentioning

confidence: 99%

A novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice

Bastos

Angusti

Vilaça

et al. 2008

British J Pharmacology

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Background and purpose: Many in vitro and fewer in vivo studies have shown that tetracyclines present anti-inflammatory activity. We investigated if a novel non-antibacterial, non-chelating hydroxypyrazoline derivative of minocycline, 12S-hydroxy-1,12-pyrazolinominocycline (PMIN), also induced antinociceptive and anti-inflammatory effects. Experimental approach: Antibacterial effects against a minocycline-sensitive Staphylococcus aureus strain were evaluated by applying a cylinder-plate agar diffusion technique. Antibacterial effects of diluted serum from mice pre-treated with minocycline or PMIN were also evaluated. Ca 2 þ binding activity was assessed by spectrophotometry. Formalin-induced nociceptive responses and carrageenan-induced paw oedema were evaluated in mice. The rota-rod apparatus was used to evaluate motor coordination. Key results: Minocycline, but not PMIN, inhibited bacterial growth. Serum from mice treated with minocycline, but not with PMIN, also induced such an effect. The UV absorption spectrum of solutions of minocycline, but not those of PMIN, was markedly changed in the presence of Ca 2 þ . Minocycline or PMIN inhibited both phases of formalin-induced nociception and carrageenan-induced paw oedema. It is unlikely that antinociception resulted from lack of motor coordination, as tetracycline did not impair the performance of mice on the rotating rod. Conclusions and implications:These results indicate that inhibition of nociception and oedema by tetracyclines is neither necessarily linked to antibacterial nor to Ca 2 þ chelating activities. This study supports the evaluation of the potential usefulness of PMIN in the treatment of painful and inflammatory diseases, as its lack of antibacterial and Ca 2 þ chelating activities might confer greater safety over conventional tetracyclines.

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Section: Discussionmentioning

confidence: 99%

A novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice

Bastos

Angusti

Vilaça

et al. 2008

British J Pharmacology

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“…Recent advances aimed at understanding the drug catabolism were applied by using various iron porphyrins as models of cytP 450 enzymes to mimic the oxidative conditions found in the target cells. 14,15 Oxidative N-dealkylation of drugs is known to contribute both to biological activity and toxic effects of drugs. 16,17 Hence, drug bioactivation should be considered as a pro-drug strategy.…”

Section: Introductionmentioning

confidence: 99%

“…In the presence of reactive oxygen species, the released heme is thought to catalyze numerous oxidation reactions, in particular with tertiary amine drugs (Scheme , pathway A). Recent advances aimed at understanding the drug catabolism were applied by using various iron porphyrins as models of cytP 450 enzymes to mimic the oxidative conditions found in the target cells. , Oxidative N -dealkylation of drugs is known to contribute both to biological activity and toxic effects of drugs. , Hence, drug bioactivation should be considered as a pro-drug strategy. On the basis of this hypothesis and on the knowledge of cytP 450 catalyzed oxidative N -dealkylation reactions, we aimed at the design of new 4-aminoquinolines with an amino side-chain substituted by the aliphatic Mannich base according to a reductive amination.…”

Section: Introductionmentioning

confidence: 99%

Antimalarial versus Cytotoxic Properties of Dual Drugs Derived From 4-Aminoquinolines and Mannich Bases: Interaction with DNA

et al. 2010

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The synthesis and biological evaluation of new organic and organometallic dual drugs designed as potential antimalarial agents are reported. A series of 4-aminoquinoline-based Mannich bases with variations in the aliphatic amino side chain were prepared via a three-steps synthesis. These compounds were also tested against chloroquine-susceptible and chloroquine-resistant strains of Plasmodium falciparum and assayed for their ability to inhibit the formation of beta-hematin in vitro using a colorimetric beta-hematin inhibition assay. Several compounds showed a marked antimalarial activity, with IC(50) and IC(90) values in the low nM range but also a high cytotoxicity against mammalian cells, in particular a highly drug-resistant glioblastoma cell line. The newly designed compounds revealed high DNA binding properties, especially for the GC-rich domains. Altogether, these dual drugs seem to be more appropriate to be developed as antiproliferative agents against mammalian cancer cells than Plasmodium parasites.

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“…Dimethylaminoantipyrin ( 39 , entzündungshemmend) trägt drei verschiedene Methylgruppen, von denen zwei im In‐vivo‐Metabolismus angegriffen werden können. Mit der Screening‐Plattform wurden Katalysatoren und Reaktionsbedingungen identifiziert, um diese metabolischen Schwachstellen selektiv anzugreifen (allylische und N , N ‐Dimethyl‐C‐H‐Bindungen) (siehe Schema ) . Die Kombination von Eisen[tetrakis( ortho ‐nitrophenyl)porphyrin]chlorid ([Fe(TNO 2 PP)Cl]) und Imidazol erbrachte den Alkohol 40 in guter Ausbeute (50 %).…”

Section: Biotransformation Chemische C‐h‐oxidationsverfahren Und Veunclassified

Die Erschließung von Wirkstoffmetaboliten durch übergangsmetallkatalysierte C‐H‐Oxidation: die Leber als Inspiration für die Synthese

Genovino

Sameš

Hamann³

et al. 2016

Angewandte Chemie

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Können klassische und moderne C‐H‐Oxidationsreaktionen Biotransformationen bei der Synthese von Wirkstoffmetaboliten ergänzen? Wir haben versucht, bei einer Durchsicht der Literatur eine Antwort auf diese wichtige Frage für die Praxis der pharmazeutischen Industrie zu finden. Solche Metaboliten werden während aller Phasen der Wirkstoffsuche und ‐entwicklung benötigt; ihre Synthese ist jedoch noch immer ein ungelöstes Problem. Dieser Aufsatz stellt relevante Anwendungen von chemischen C‐H‐Oxidationen, Elektrochemie und Mikrofluidiktechniken auf Wirkstoff‐Grundgerüste vor, mit denen Metaboliten zugänglich gemacht werden sollen, und fasst vielversprechende Reaktionen für diesen Zweck zusammen. Wo es möglich oder passend ist, wird der Vergleich zur Biotransformation gezogen. So haben wir versucht, bestehende Lücken zu finden, um weitere Aktivitäten auf diesem wichtigen Forschungsfeld anzuspornen.

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Efficient Use of the Iron Ortho‐Nitrophenylporphyrin Chloride to Mimic Biological Oxidations of Dimethylaminoantipyrine

Cited by 9 publications

References 14 publications

A novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice

A novel non‐antibacterial, non‐chelating hydroxypyrazoline derivative of minocycline inhibits nociception and oedema in mice

Antimalarial versus Cytotoxic Properties of Dual Drugs Derived From 4-Aminoquinolines and Mannich Bases: Interaction with DNA

Die Erschließung von Wirkstoffmetaboliten durch übergangsmetallkatalysierte C‐H‐Oxidation: die Leber als Inspiration für die Synthese

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