Novel Cyclic Phosphate Prodrug Approach for Cytochrome P450-activated Drugs Containing an Alcohol Functionality

Huttunen, Kristiina M.; Mähönen, Niina; Leppänen, Jukka; Vepsäläinen, Jouko; Juvonen, Risto O.; Raunio, Hannu; Kumpulainen, Hanna; Järvinen, Tomi; Rautio, Jarkko

doi:10.1007/s11095-006-9187-y

Cited by 21 publications

(12 citation statements)

References 24 publications

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“…15 2-Chloro-1,3,2-dioxaphosphorinane 2-oxide was synthesized by reacting phosphorus oxychloride with 1,3-propanediol as described in the literatures. 17,18 Methylphosphonic dichloride, methyl methylphosphonochloridate, and phenyl methyl phosphinyl chloride were prepared by adapting the synthesis methods mentioned in our previous work. 19 Synthesis of Organo-Phosphorus Flame Retardants (FRs).…”

Section: Methodsmentioning

confidence: 99%

Flame retardancies of novel organo-phosphorus flame retardants based on DOPO derivatives when applied to ABS

Hoang

Kim

et al. 2015

Macromol. Res.

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A series of novel organo-phosphorus flame retardants (FR) derived from 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) have been synthesized in order to investigate their flame retarding performances for acrylonitrile-butadiene-styrene copolymer (ABS). The success of synthesis was confirmed by 1 H and 31 P NMR. The flame retardancy performances evaluated by UL-94V test revealed that V-0 ratings are achieved when 27.5-30.0 wt% of FRs are added to the ABS/FR mixtures. The most dominating factors affecting the flame retardancy of phosphorus containing FR are the phosphorus (P) content in the mixture and the chemical structure of FR incorporated. It was found that 4.86-5.05 wt% P in the formulation is required to exhibit self-extinguishing ability when phosphinate or phophonate FRs are employed. On the other hand, no rating is obtained for phosphate type FR containing mixture even though higher amount of P, that is, 5.07 wt% is present in the mixture, indicating that oxidation state of the phosphorus element in FR is very important in governing the flame retardancy. The modes of actions of FRs in terms of gas versus condensed phase are also discussed. Thermogravimetric analysis (TGA) results showed that the FR containing compounds possess inferior thermal stability compared to neat ABS at the beginning of decomposition, suggesting that the thermal degradation of ABS is accelerated by the presence of FR at earlier stage of degradation and then hindered by the char formed at later stage of degradation.

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Section: Methodsmentioning

confidence: 99%

Flame retardancies of novel organo-phosphorus flame retardants based on DOPO derivatives when applied to ABS

Hoang

Kim

et al. 2015

Macromol. Res.

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“…1 We have recently reported that cyclic phosphates could serve as potential cytochrome P450 (CYP) 3A4-selective prodrugs of drug molecules having a free hydroxyl group. 10 To date, this prodrug approach has been successfully applied to 18βglycyrrhetinic acid to gain antiulcer and anti-inflammatory sustained-release effects. 11 Bioconversion of cyclic phosphate prodrugs have been designed to undergo an initial CYPcatalyzed oxidation at the C4 methine primarily by CYP3A forms (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

Design, Synthesis, and Evaluation of Novel Cyclic Phosphates of 5-Aminosalicylic Acid as Cytochrome P450-Activated Prodrugs

et al. 2012

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Four novel cyclic phosphates of the anti-inflammatory agent 5-aminosalicylic acid (5-ASA) were designed and synthesized as cytochrome P450 (CYP)-activated prodrugs. These prodrugs can be used for targeting into gut wall, since these types of cyclic phosphates are known to be activated mainly by CYP3A forms, which are expressed not only in the liver but also in the small intestine and to a lesser extent in the colon. The present study shows that aromatic ring activating substituents, like chlorine, are definitely needed to obtain the desired enzymatic cleavage of the cyclic phosphate prodrugs of 5-ASA. However, the position of the activating substituent has also a strong impact on the chemical stability, and therefore, an appropriate balance between the rates of prodrug bioactivation and chemical stability needs to be taken into consideration in future studies on cyclic phosphate prodrugs of 5-ASA.

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“…Among the enzymes that are traditionally used for activation are unspecific esterases, 3 alkaline phosphateses, 4 peptidases 5 and specific cytochrome P450s. 6,7 Nitroreductases (NTRs) are a relatively new class of enzyme in the area of prodrug activation. 8,9 Unlike traditional enzymes, which activate mostly carrier-linked prodrugs (drug with promoiety), NTRs are involved in the activation of bioprecursor prodrugs, which are transformed by direct reduction or reduction followed by elimination to the active agent.…”

mentioning

confidence: 99%

Modification of existing antibiotics in the form of precursor prodrugs that can be subsequently activated by nitroreductases of the target pathogen

Çelik

Yetiş

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Novel Cyclic Phosphate Prodrug Approach for Cytochrome P450-activated Drugs Containing an Alcohol Functionality

Cited by 21 publications

References 24 publications

Flame retardancies of novel organo-phosphorus flame retardants based on DOPO derivatives when applied to ABS

Flame retardancies of novel organo-phosphorus flame retardants based on DOPO derivatives when applied to ABS

Design, Synthesis, and Evaluation of Novel Cyclic Phosphates of 5-Aminosalicylic Acid as Cytochrome P450-Activated Prodrugs

Modification of existing antibiotics in the form of precursor prodrugs that can be subsequently activated by nitroreductases of the target pathogen

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