作者: Cenas, Narimantas ; Bukelskiene, Virginija ; Jarasiene-Burinskaja, Rasa ; Alksne, Milda ; Voisniene, Violeta ; Burinskij, Jaroslav ; Bartuskiene, Violeta

A number of quinones have been shown to be efficient anticancer agents. However, some mechanisms of their action, in particular cell signaling are not well understood. The aim of this study was to partly fill this gap by characterizing the mode of cytotoxicity of 2,5-diaziridinyl-3,6-dimethyl-1,4-benzoquinone (MeDZQ) in malignant mouse hepatoma cells (MH-22A) with regard to the expression and activation of main molecules in MAPK cell signaling pathway. The study revealed unequal roles of MAP kinases in MeDZQ-induced cell death: the compound did not induce significant changes in ERK expression or its phosphorylation; JNK appeared to be responsible for cell survival, however, p38 kinase was shown to be involved in cell death. In order to assess the enzymatic activation mechanisms responsible for the action of MeDZQ, we have also found that the antioxidant N,N'-diphenyl-p-phenylene diamine, the iron-chelating agent desferrioxamine, and DT-diaphorase inhibitor, dicoumarol, partly protected the cells from MeDZQ cytotoxicity. It points to parallel oxidative stress and bioreductive alkylation modes of the cytotoxicity of MeDZQ.

2002-11-01·British Journal of Pharmacology2区 · 医学

Pharmacological approach towards the development of indolequinone bioreductive drugs based on the clinically inactive agent EO9

2区 · 医学

Article

作者: Paul M. Loadman ; Roger M. Phillips ; Michael C. Bibby

The bioreductive drug EO9 (3‐hydroxy‐5‐aziridinyl‐1‐methyl‐2[indole‐4,7‐dione]–prop‐β‐en‐α‐ol) has good pharmacodynamic properties in vitro, modest anti‐tumour activity in experimental tumour models, but failed to show activity in clinical trials. Understanding the reasons for its poor efficacy in vivo is important in terms of progressing second generation analogues into the clinic.

In two human tumour xenografts, direct intra‐tumoural injection resulted in improved anti‐tumour activity compared with intravenous administration suggesting that drug delivery to tumours is suboptimal. Compared with Mitomycin C (MMC) and the experimental agent MeDZQ, EO9 was rapidly cleared from the systemic circulation (t1/2=1.8 min) whereas MMC and MeDZQ had significantly increased plasma t1/2 values (14 and 22 min respectively). These three compounds demonstrated similar pharmacodynamic properties in terms of potency towards the NQO1 (NAD(P)H:Quinone oxidoreductase) rich H460 cell line in vitro but differed significantly in their in vivo activity with growth delays of 17.7, 4.5 and 1.0 days for MMC, MeDZQ and EO9 respectively. EO9 was rapidly metabolized by red blood cells in vitro (t1/2=14.5 min) which must contribute to its rapid pharmacokinetic elimination in vivo whereas MMC and MeDZQ were metabolized at comparatively slower rates (t1/2>120 min and 77.0 min respectively).

In conclusion, the development of second generation EO9 analogues should address the issue of drug delivery and analysis of drug metabolism by murine whole blood in vitro could be utilized as a preliminary screen to identify lead compounds that are likely to have improved pharmacokinetic profiles in vivo.

British Journal of Pharmacology (2002) 137, 701–709. doi:10.1038/sj.bjp.0704916

2001-03-01·Journal of Pharmaceutical and Biomedical Analysis3区 · 医学

Stability-indicating HPLC assay and solution stability of a new diaziridinyl benzoquinone

3区 · 医学

Article

作者: Paul Liu ; Namphuong Nguyen ; Andrew P. Cheung ; Elaine Struble

RH1, 3-methyl-6-hydroxymethyl-2,5-diaziridinyl-1,4-benzoquinone, is a NQO1 (NAD(P)H quinone oxidoreductase) directed anti-tumor agent. It is designed as a water soluble analog of MeDZQ (3,6-dimethyl-2,5-diaziridinyl-1,4-benzoquinone) and is a drug candidate for clinical evaluation. A HPLC assay has been developed for its analysis. The assay is sensitive (ldl<0.2 ng), precise (rsd<1%), linear (r(2)=0.9997), accurate (error<0.6%), and stability-indicating. Using the developed assay, aqueous stability of RH1 has been evaluated. Both aziridine rings in MeDZQ are known to be easily hydrolyzable in aqueous solutions, however, hydrolysis of the second aziridine ring in RH1 appears inhibited.

100 项与 MeDZQ (University of Colorado System) 相关的药物交易

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